key: cord-0904069-tshbspge
authors: Izquierdo, J. L.; Almonacid, C.; Gonzalez, Y.; Del Rio-Bermudez, C.; Ancochea, J.; Cardenas, R.; Soriano, J. B.
title: The impact of COVID-19 on patients with asthma: A Big Data analysis
date: 2020-07-24
journal: nan
DOI: 10.1101/2020.07.24.20161596
sha: 28eafa359cb751e563f8cc99f0f0d02d882a69d6
doc_id: 904069
cord_uid: tshbspge

Background: From the onset of the COVID-19 pandemic, an association between the severity of COVID-19 and the presence of certain medical chronic conditions has been suggested. However, unlike influenza and other viruses, the burden of the disease in patients with asthma has been less evident. Objective: This study aims at a better understanding of the burden of COVID-19 in patients with asthma and the impact of asthma, its related comorbidities, and treatment on the prognosis of COVID-19. Methods: We analyzed clinical data from patients with asthma from January 1st to May 10th, 2020 using big data analytics and artificial intelligence through the SAVANA Manager clinical platform. Results: Out of 71,192 patients with asthma, 1,006 (1.41%) suffered from COVID-19. Compared to asthmatic individuals without COVID-19, patients with asthma and COVID-19 were significantly older (55 vs. 42 years), predominantly female (66% vs. 59%), had higher prevalence of hypertension, dyslipidemias, diabetes, and obesity, and smoked more frequently. Contrarily, allergy-related factors such as rhinitis and eczema were less frequent in asthmatic patients with COVID-19 (P < .001). Higher prevalence of hypertension, dyslipidemia, diabetes, and obesity was also confirmed in those patients with asthma and COVID-19 who required hospital admission. The percentage of individuals using inhaled corticosteroids (ICS) was lower in patients who required hospitalization due to COVID-19, as compared to non-hospitalized patients (48.3% vs. 61.5%; OR: 0.58: 95% CI 0.44-0.77). During the study period, 865 (1.21%) patients with asthma were being treated with biologics. Although these patients showed increased severity and more comorbidities at the ear, nose, and throat (ENT) level, their hospital admission rates due to COVID-19 were relatively low (0.23%). COVID-19 increased inpatient mortality in asthmatic patients (2.29% vs 0.54%; OR 2.29: 95% CI 4.35-6.66). Conclusion: Our results indicate that the number of COVID-19 cases in patients with asthma has been low, although higher than the observed in the general population. Patients with asthma and COVID-19 were older and were at increased risk due to comorbidity-related factors. ICS and biologics are generally safe and may be associated with a protective effect against severe COVID-19 infection.

was conducted in accordance with legal and regulatory requirements and followed 115 research practices described in the ICH Guidelines for Good Clinical Practice, the 116 Declaration of Helsinki in its latest edition, the Guidelines for Good 117

Pharmacoepidemiology Practice (GPP), and local regulations. Given the retrospective 118 and observational nature of the study, physicians' prescribing habits and patient 119 assignment to a specific therapeutic strategy were solely determined by the physician, 120 team, or hospital concerned. Likewise, a standard informed consent does not apply to 121 this study. All actions towards data protection were taken in accordance with the The terminology used by SAVANA is based on multiple sources such as 150 SNOMED CT (19), which includes medical codes, concepts, synonyms, and definitions 151 regarding symptoms, diagnoses, body structures, and substances commonly used in 152 clinical documentation. Due to the novel methodological approach of this study, we 153 complemented our clinical findings with the assessment of EHRead's performance. This 154 evaluation was aimed at verifying the system's accuracy in identifying records that 155 contain mentions of asthma and COVID-19 and its related variables. For a 156 comprehensive description of the evaluation procedure, see (19) . Briefly, the annotations 157 made by the medical experts were used to generate the gold standard to assess the 158 performance of EHRead's output; performance is calculated in terms of the standard 159 metrics of accuracy (P), recall (R), and their harmonic mean F-score (20). 160

All statistical analyses were conducted using SPSS software (V25.0). Unless 161 otherwise indicated, qualitative variables are expressed as absolute frequencies and 162 percentages, while quantitative variables are expressed as means and standard 163 deviations. For the assessment of statistical significance of numerical variables, we used 164 independent samples Student's T-tests or ANOVA. To measure the relative distribution 165 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 24, 2020. . https://doi.org/10.1101/2020.07.24.20161596 doi: medRxiv preprint

We identified 71,192 patients with asthma during the study period (January 1, 2019 -170

May 10, 2020). The search terms used to identify patients with bronchial asthma are 171 listed in eTable 1. For the linguistic evaluation of the variable 'asthma', we obtained 172

Precision, Recall, and F-Scores of 0.88, 0.75, and 0.81, respectively; these metrics 173 indicate that patients with asthma were properly identified within the target population. 174

The patient flowchart for asthmatics with and without COVID-19 is depicted in Figure 1 . 175

Patients' age (mean ± SD) was 42 + 20 years; 59% of patients were women. 176

Overall, 1,006 (1.41%) asthma patients were also diagnosed with COVID-19. EHRead 177 identified COVID-19 with a Precision of 0,99, a Recall of 0,75, and a F-Score of 0,93; 178 again, these results indicate that within our population with asthma, COVID-19 cases 179 were accurately identified. COVID-19 diagnosis was confirmed by PCR in 61% of 180 patients (n = 611); in the remaining cases, and considering the epidemiological context 181 of the pandemic in the study area between March and May 2020, diagnosis was based 182 on rapid serological tests or clinical, radiological, and/or analytical evaluation, Notably, 183 the percentage (95% CI) of patients diagnosed with COVID-19 in the population of 184 patients with asthma (1.41%; 1.33 -1.50) was significantly higher than in the general 185 population of Castilla La-Mancha (Spain) (0.86%; 0.85 -0.87), P <.001. 186

Patients with asthma who also had a diagnosis of COVID-19 were older, 187 predominantly women, and had higher prevalence rates of hypertension, dyslipidemia, 188 diabetes, obesity, and smoking habits than asthmatic individuals without COVID-19 (all 189 P <.05). By contrast, atopy-related factors such as rhinitis or eczema were significantly 190 more frequent in patients without COVID-19 ( Table 1) . The higher prevalence of 191 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 24, 2020. . https://doi.org/10.1101/2020.07.24.20161596 doi: medRxiv preprint requiring hospital admission, as compared with those who only required outpatient 193 management ( Table 2) . 194

The proportion of patients with asthma using inhaled corticosteroids (ICS) was 52-year-old male with high blood pressure, diabetes mellitus, and dyslipidemia. 212

Compared with information from patients with asthma available since January 213 2019, the data collected during the study period (January 1 st to May 10 th , 2020) show 214 that COVID-19 significantly increased in-hospital mortality in this population (0.54% vs 215 hospital mortality mainly affected elderly patients, with an average age (±SD) of 76 (±12) 217 years in patients with both asthma and COVID-19, and 78 (±17) in COVID-19-free 218 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 24, 2020. . https://doi.org/10.1101/2020.07.24.20161596 doi: medRxiv preprint patients with asthma, P <.001); most of these patients were women in both study periods 219 (61% and 71%, respectively, and had previously diagnosed comorbidities (Table 4) . On 220 the other hand, the age distribution (mean ± SD) of patients without asthma who died 221 from COVID-19 was 79 ± 11 years, and 63% (n = 296) of them were male. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 24, 2020. . https://doi.org/10.1101/2020.07.24.20161596 doi: medRxiv preprint by the pandemic in Spain, which in turn has been one of the most hard-hit countries in 246

Europe. Second, it has a good EHR system, which has been standardized and is shared 247 across all five provinces. Finally, the SAVANA Manager ® tool is widely available in the 248 region, allowing access to large amounts of clinical information (25). 249

In the present study, we analyzed clinical data from the largest population of 250 asthma patients published to date (n = 71,192); 1,006 of these patients were diagnosed 251

with COVID-19. The study period was January 1, 2019-May 10, 2020. Although the 252 system allows us to analyze data from 2011 onwards, we selected this temporal cut-off 253 to include asthmatic patients with updated follow-up information and with the active form 254 of the disease. 255

The proportion of patients with both asthma and COVID-19 during the study 256 period was 1.41%, which is markedly higher than the 0.86% observed in the general 257 population. Although these data show a higher frequency of COVID-19 in patients with 258 asthma, the manifestation of the disease in this clinical population was not particularly 259 severe, with low rate of hospital admissions. In addition, this proportion is lower than the 260 reported for patients with other chronic diseases. Some of the reasons that may explain 261 this phenomenon include remission of seasonal influenza, lack of exposure to 262 environmental factors, greater monitoring of hygiene measures during lockdown in these 263 patients, the significant reduction in air pollution during this period, and/or better control 264 of the disease by improving adherence to treatment due to fear of worsening 265 symptomatology. This trend was already observed since the initial phases of the 266 pandemic in patient populations with other respiratory diseases such as COPD (26) . 267

Comorbidities play a major role in the manifestation of COVID-19-related 268 complications. In our study, the manifestation of COVID-19 in patients with asthma was 269 favored by older age, male sex, and the presence of several comorbidities. High blood 270 pressure, dyslipidemia, diabetes, and obesity were the main risk factors for hospital 271 admission due to poor prognosis. The lower risk associated with rhinitis and eczema is 272 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 24, 2020. . https://doi.org/10.1101/2020.07.24.20161596 doi: medRxiv preprint consistent with previous observations that allergic sensitization in asthma is linked to 273 lower expression of ACE2 receptors in both upper and lower respiratory airways, 274 suggesting a potential protective effect (27). As previously observed in the general 275 population, mortality due to COVID-19 in patients with asthma mainly occurred in the 276

The possibility that different therapeutic options in patients with chronic 278 respiratory diseases affects the incidence and prognosis of COVID-19 has been a matter 279 of intense debate. As for asthma, it has been suggested that the use of ICS might yield 280 a protective effect against COVID-19 (28,29). Although an antiviral effect has been 281 described in rhinovirus-induced exacerbations, these results are highly controversial. Whether treatment with biologics in patients with asthma impacts SARS-CoV-2 295 infection or the incidence and prognosis of COVID-19 also remains unknown. In this 296 context, there is no evidence supporting that either omalizumab or other drugs that 297 suppress eosinophils directly modulate viral processes in patients with asthma (32,33). 298

In our study, we identified a total of 865 patients treated with biologics. Among these, 299 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 24, 2020. . https://doi.org/10.1101/2020.07.24.20161596 doi: medRxiv preprint two patients required admission and only one died from COVID-19; this patient, however, 300 had other comorbidities in addition to severe asthma, which may have contributed to his 301 poor clinical outcome. Overall, our results support the safety of these drugs for the 302 treatment of asthma in patients diagnosed with COVID-19. As with ICS use, our data 303 suggest that biologics might be associated with a protective effect on the clinical course 304 of these patients. However, we cannot rule out that the aforementioned favorable factors 305 also contributed to a better disease prognosis. 

The strengths of the present study include immediacy, large sample size, and real-world 318 evidence. In addition, our results must be interpreted in light of the following limitations. 319

Frist, the main limitation of this type of studies is perhaps the lack of documented 320 information. In Castilla-La Mancha, the digitalization of clinical records has been optimal 321 since 2011. Not only the EHRs system is homogenous throughout the region, but its use 322 has been universal for the past five years. Second, unlike classical research methods, 323

reproducibility is not generally considered in big data studies, since the latter involve 324 large amounts of information collected from the whole target population. Because we 325 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 24, 2020. . https://doi.org/10.1101/2020.07.24.20161596 doi: medRxiv preprint exclusively analyzed the data captured in EHRs, the quality of the results reported for 326 some variables is directly tied to the quality of the clinical records; in many cases, EHRs 327 may be partially incomplete and not capture all the relevant clinical information from a 328 given patient. Third, because this study was not designed to collect variables in a strict, 329 a priori fashion, there were some variables that were not properly documented and were 330 therefore not analyzed. Finally, our study sample comprised COVID-19 cases confirmed 331 by both PCR/serological tests and clinical criteria (i.e. symptomatology, imaging, and 332 laboratory results). Of note, PCR and other rapid laboratory tests for the detection of We conclude that a) the frequency of SARS-CoV-2 infection has been low in patients 341 with asthma, although higher than in the general population, b) the increased risk for 342 hospitalization due to COVID-19 in patients with asthma is largely associated with age 343 and related comorbidities; mortality mainly affected elderly patients, c) ICS showed a 344 safe profile; compared to asthmatic patients who required hospitalization due to COVID-345 19, a significantly higher percentage of non-hospitalized patients used ICS, and d) 346

although biologics-treated patients with asthma typically present with the most severe 347 manifestations of the disease, the number of COVID-19-related admissions and mortality 348 in these patients was strikingly low, thus suggesting a protective effect associated with 349 the use of these therapeutic agents. 350 351 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 24, 2020. available EHRs, the number of patients with asthma, the number of patients diagnosed 479

with COVID-19, and of those, the number of hospitalizations after diagnosis during the 480 study period (January 1 st , 2020-May 10 th , 2020). All percent values are computed in 481 relation to the immediately above level. 482 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 24, 2020. 

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 24, 2020. . https://doi.org/10.1101/2020.07.24.20161596 doi: medRxiv preprint 

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 24, 2020. . https://doi.org/10.1101/2020.07.24.20161596 doi: medRxiv preprint 

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 24, 2020. . https://doi.org/10.1101/2020.07.24.20161596 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 24, 2020. .

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SAVANA: Re-using Electronic Health Records with Artificial 401

SAVANA: A Global Information Extraction and Terminology Expansion 405 Framework in the Medical Domain Procesamiento del Lenguaje Natural

The Strengthening the Reporting of Observational Studies in

STROBE) statement: guidelines for reporting observational 410 studies

Summary of a 426 study protocol to estimate the prevalence of severe asthma in Spain using big-427 data methods

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Prevalence and characterization of asthma 463 in hospitalized and non-hospitalized patients with COVID-19

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Detection of SARS-CoV-2 in

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Report of 1014 Cases

Unstable asthma • Adult-onset asthma • Intrinsic asthma • Asthma attack / Asthma exacerbation • Acute asthma • Exercise-induced asthma • Childhood asthma • Asthmatic bronchitis • Cough-variant asthma • Allergic asthma • Mild asthma • Moderate asthma • Occasional asthma • Severe asthma • Chemical-induced asthma • Substance-induced asthma • Intermittent asthma • Seasonal Asthma • Occupational Asthma • Chronic obstructive airway disease with asthma • Asthma with irreversible airway obstruction • Untreated Asthma • Persistent asthma • Induced asthma • Neutrophilic asthma • Cortico-dependent asthma