key: cord-0759777-hn239gs2 authors: Villamañán, Elena; Sobrino, Carmen; Carpio, Carlos; Moreno, Marta; Arancón, Ana; Lara, Catalina; Pérez, Ester; Jiménez, Carlos; Zamarrón, Ester; Jiménez-Nácher, Inmaculada; Herrero, Alicia; Álvarez-Sala, Rodolfo title: Inhaled bronchodilators use and clinical course of adult inpatients with Covid-19 pneumonia in Spain: A retrospective cohort study() date: 2021-06-12 journal: Pulm Pharmacol Ther DOI: 10.1016/j.pupt.2021.102007 sha: 02bdc6e3e2ffb167ad1ff1fd3c33645b522d428d doc_id: 759777 cord_uid: hn239gs2 BACKGROUND: In the current coronavirus health crisis, inhaled bronchodilators(IB) have been suggested as a possible treatment for patients hospitalized. Patients with evidence of Covid-19 pneumonia worldwide have been prescribed these medications as part of therapy for the disease, an indication for which this medications could be ineffective taken on account the pathophysiology and mechanisms of disease progression. OBJECTIVE: The main objective was to evaluate whether there is an association between IB use and length of stay. Primary end points were the number of days that a patient stayed in the hospital and death as a final event in a time to event analysis. Pneumonia severity, oxygen requirement, involved drugs, comorbidity, historical or current respiratory diagnoses and other drugs prescribed to treat coronavirus pneumonia were also evaluated. METHODS: A descriptive, observational, cross-sectional study was performed in this tertiary hospital in Madrid (Spain). Data were obtained regarding patients hospitalized with Covid-19, excluding those who were intubated. The primary and secondary outcomes such as duration of hospitalization and death were compared in patients who received IB with those in patients who did not. RESULTS: 327 patients were evaluated, mean age was 64.4±15.8 years. Median length of hospitalization stay was 10 days. Of them 292 (89.3%) overcame the disease, the remaining 35 died. Patients who had received IB did not have less mortality rate (odds ratio 0.839; 95% CI: 0.401 to 1.752) and less hospitalization period when compared with patients who did not received IB (odds ratio 1.280; 95% CI: 0.813 to 2.027). There was no significant association between IB use and recovery or death. Hypertension and diabetes were the most common comorbidities. The prevalence of chronic respiratory disease in our cohort was low (21.1%). Anticholinergics were the IB more frequently prescribed for Covid-19 pneumonia. Better response in patients treated with inhaled corticosteroids was not observed. CONCLUSION: Off-label indication of inhaled-bronchodilators for Covid-19 patients are common in admitted patients. Taken on account our results, the use of IB for coronavirus pneumonia apparently is not associated with a significantly patient´s improvement. Our study confirms the hypothesis that inhaled bronchodilators do not improve clinical outcomes or reduce the risk of Covid-19 mortality. This could be due to the fact that the virus mainly affects the lung parenchyma and the pulmonary vasculature and probably not the airway. More researches are necessary in order to fill the gap in evidence for this new indication. In the current coronavirus health crisis, inhaled bronchodilators(IB) have been suggested as a possible treatment for patients hospitalized. Patients with evidence of Covid-19 pneumonia worldwide have been prescribed these medications as part of therapy for the disease, an indication for which this medications could be ineffective taken on account the pathophysiology and mechanisms of disease progression. The main objective was to evaluate whether there is an association between IB use and length of stay. Primary end points were the number of days that a patient stayed in the hospital and death as a final event in a time to event analysis. Pneumonia severity, oxygen requirement, involved drugs, comorbidity, historical or current respiratory diagnoses and other drugs prescribed to treat coronavirus pneumonia were also evaluated. A descriptive, observational, cross-sectional study was performed in this tertiary hospital in Madrid (Spain). Data were obtained regarding patients hospitalized with Covid-19, excluding those who were intubated. The primary and secondary outcomes such as duration of hospitalization and death were compared in patients who received IB with those in patients who did not. 327 patients were evaluated, mean age was 64.4±15.8 years. Median length of hospitalization stay was 10 days. Of them 292 (89.3%) overcame the disease, the J o u r n a l P r e -p r o o f remaining 35 died. Patients who had received IB did not have less mortality rate (odds ratio 0.839; 95% CI: 0.401 to 1.752) and less hospitalization period when compared with patients who did not received IB (odds ratio 1.280; 95% CI: 0.813 to 2.027). There was no significant association between IB use and recovery or death. Hypertension and diabetes were the most common comorbidities. The prevalence of chronic respiratory disease in our cohort was low (21.1%). Anticholinergics were the IB more frequently prescribed for Covid-19 pneumonia. Better response in patients treated with inhaled corticosteroids was not observed. Off-label indication of inhaled-bronchodilators for Covid-19 patients are common in admitted patients. Taken on account our results, the use of IB for coronavirus pneumonia apparently is not associated with a significantly patient´s improvement. Our study confirms the hypothesis that inhaled bronchodilators do not improve clinical outcomes or reduce the risk of Covid-19 mortality. This could be due to the fact that the virus mainly affects the lung parenchyma and the pulmonary vasculature and probably not the airway. More researches are necessary in order to fill the gap in evidence for this new indication. Therapeutic approach for Covid-19 worldwide has been primarily supportive therapy and, to date, there is no specific treatment. The fact that it is a new disease leads to the lack of approved medications for this indication. To date, only remdesivir has been authorized by the FDA via emergency use authorization. 1 As a consequence, a large number of patients around the world have received off-label treatments since there is currently no clinical evidence supporting the efficacy and safety of medications used against Covid-19 2 . Increasing the understanding of the coronavirus disease is essential in order to initiate timely and targeted therapy. It is known that it has three consecutive stages 3 : the early stage characterized by flu-like symptoms and subsequently viral pneumonia, followed by pulmonary inflammation, coagulopathy and increased levels of inflammatory biomarkers associated with the development of acute respiratory distress syndrome. Finally, the third stage of the disease with an increased risk of lung fibrosis. In this scenario, inhaled bronchodilators (IB) have been suggested as a possible treatment. According to the WHO´s Anatomical Therapeutic Chemical (ATC) Classification, IB include inhaled adrenergics, anticholinergics and corticosteroids. 4 Thousands of hospitalized patients with evidence of Covid-19 pneumonia worldwide have been prescribed these medications as part of treatment for the disease. 5 However, taking into account the pathophysiological mechanism of the disease previously exposed, with development of hyperinflammation hypercoagulability and potential fibrosis, the use of these drugs may be ineffective given the absence of airway pathology. Although scarcely, some researchers are already carrying out studies of this type. 13, 14 Given this situation, the following study was undertaken. We hypothesised that the use of IB for Covid-19 patients could be useless taken on account the pathophysiology and mechanisms of disease progression. We conducted this study in Madrid, the epicentre of the pandemic in Spain, in one of the hospitals with the largest number of patients admitted with Covid-19. A descriptive, observational, cross-sectional study was performed in this tertiary hospital Although a treatment protocol was established at the centre for these patients, the decision to prescribe, including IB, was left to the discretion of the treatment team for each individual patient. Adult patients diagnosed of Covid-19 at admission were included in the study. As exclusion criteria we considered Covid-19 patients admitted to critical care units. The institutional review board of our center approved this analysis under an expedited review. The main objective was to evaluate whether there is an association between IB use and length of stay. Pneumonia severity, oxygen requirement, involved drugs, comorbidity, historical and current respiratory diagnoses, other drugs prescribed to treat coronavirus and whether IB had been initiated at admission or before admission were also evaluated. From the clinical data warehouse, we obtained data from all prescription events of hospitalised patients with Covid-19 under IB treatment (according to the WHO´s ATC classification 4 ) who presented respiratory illness, which was defined as a resting oxygen saturation of less than 94% being treated with IB. The data obtained included patients' demographic details, medication administration data, historical and current medication lists, historical diagnoses, oxygen requirements. A database was designed to reflect the case report content form, in which a data entry The mean, SD, median, maximum, minimum, and 25% and 75% quartiles were included. For the categorical data, the frequency distributions (absolute and relative) were presented. In addition, 95% CIs were calculated when appropriate. The statistical analysis was performed using SAS9.3 (SAS Institute, Cary, North Carolina, USA). The median length of hospitalization was 10 days, that´s the reason why we chose this value when dichotomizing the variable. J o u r n a l P r e -p r o o f We also analysed the coronavirus pneumonia severity of patients using inhalers compared with those who did not. When using the CURB-65 pneumonia severity score 15 we found that 78/327 (23.8%) suffered severe pneumonia symptoms. Moreover, better results for patients with low and high risk of mortality according to the CURB-65 were observed ( figure 3) . Stratifying by severity and inhaled therapy, we did not find in our observational cohort that patients treated with IB showed a better prognosis for the same stratum of severity. The assessment of IB off-label prescription in a setting not previously described renders clinical relevance and strength to this study. However, it is limited by weaknesses inherent in a cross-sectional and single-centre study. Other limitations may be that there could have been patients who met inclusion criteria but were not assessed because of missing data for some variables and potential for inaccuracies in the electronic health records such as lack of documentation of coexisting illness for some patients. Finally, the response to systemic corticosteroids could interfere with the results, although very few patients were treated and existed in both groups, whether or not they received IB. Off-label indication of inhaled-bronchodilators for Covid-19 patients are common in admitted patients. Taken on account our results, the use of IB for coronavirus pneumonia apparently is not associated with a significantly patient´s improvement. Our study confirms the hypothesis that inhaled bronchodilators do not improve clinical outcomes or reduce the risk of Covid-19 mortality. This could be due to the fact that the virus mainly affects the lung parenchyma and the pulmonary vasculature and probably not the airway. Even though our study do not support this use for IB, it proves that more researches are necessary in order to fill the gap in evidence for this new indication. The authors declare no conflict of interest in this article. 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