key: cord-0998919-u9petk5t
authors: Abelenda-Alonso, Gabriela; Rombauts, Alexander; Gudiol, Carlota; Oriol, Isabel; Simonetti, Antonella; Coloma, Ana; Rodríguez-Molinero, Alejandro; Izquierdo, Elisenda; Díaz-Brito, Vicens; Sanmartí, Montserrat; Padullés, Ariadna; Grau, Inmaculada; Ras, M. Mar; Bergas, Alba; Guillem, Lluïsa; Blanco-Arévalo, Alejandro; Alvarez-Pouso, Claudia; Pallarés, Natalia; Videla, Sebastián; Tebé, Cristian; Carratalà, Jordi
title: Immunomodulatory therapy, risk factors and outcomes of hospital-acquired bloodstream infection in patients with severe COVID-19 pneumonia: a Spanish case-control matched multicenter study (BACTCOVID)
date: 2021-07-07
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.06.041
sha: be23ad41b48419545be2d0a4ca824524c0a399b7
doc_id: 998919
cord_uid: u9petk5t

OBJECTIVES: The effect of the use of immunomodulatory drugs on the risk of developing hospital-acquired bloodstream infection (BSI) in patients with COVID-19 has not been specifically assessed. We aim to identify risk factors for, and outcomes of, BSI among hospitalized patients with severe COVID-19 pneumonia. METHODS: We performed a severity matched case-control study (1:1 ratio) nested in a large multicenter prospective cohort of hospitalized adults with COVID-19. Cases with BSI were identified from the cohort database. Controls were matched for age, sex, and acute respiratory distress syndrome. A Cox proportional hazard ratio model was performed. RESULTS: Of 2005 patients, 100 (4.98%) presented 142 episodes of BSI, mainly caused by coagulase-negative staphylococci, Enterococcus faecalis, and Pseudomonas aeruginosa. Polymicrobial infection accounted for 23 episodes. The median time from admission to the first episode of BSI was 15 days (IQR 9 - 20), and the most frequent source was catheter-related infection. The characteristics of patients with and without BSI were similar, including the use of tocilizumab, corticosteroids, and combinations. In the multivariate analysis, the use of these immunomodulatory drugs was not associated with an increased risk of BSI. A Cox proportional hazard ratio (HR) model showed that after adjusting for the time factor, BSI was associated with a higher in-hospital mortality risk (HR 2.59 [1.65 – 4.07]; <0.001). CONCLUSIONS: Hospital-acquired BSI in patients with severe COVID-19 pneumonia was uncommon and the use of immunomodulatory drugs was not associated with its development. When adjusting for the time factor, BSI was associated with a higher mortality risk.

3 bloodstream infection (BSI) in patients with COVID-19 has not been specifically assessed. We 4 aim to identify risk factors for, and outcomes of, BSI among hospitalized patients with severe 5 COVID-19 pneumonia. 6 Methods 7

We performed a severity matched case-control study (1:1 ratio) nested in a large multicenter 8 prospective cohort of hospitalized adults with COVID-19. Cases with BSI were identified from 9 the cohort database. Controls were matched for age, sex, and acute respiratory distress 10 syndrome. A Cox proportional hazard ratio model was performed.

Of 2005 patients, 100 (4.98%) presented 142 episodes of BSI, mainly caused by coagulase-13 negative staphylococci, Enterococcus faecalis, and Pseudomonas aeruginosa. Polymicrobial 14 infection accounted for 23 episodes. The median time from admission to the first episode of 15 BSI was 15 days , and the most frequent source was catheter-related infection. The 16 characteristics of patients with and without BSI were similar, including the use of tocilizumab, 17 corticosteroids, and combinations. In the multivariate analysis, the use of these 18 immunomodulatory drugs was not associated with an increased risk of BSI. A Cox proportional

To date, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused 28 more than 116 million cases and more than 2,5 million deaths worldwide 1 . After a decade of 29 austerity in the public health system, and with as many as 3 164 983 cases and 71 727 30 confirmed deaths up to 9 th March 2021, Spain has been particularly badly hit by the COVID-19 31 pandemic 2,3 .

In this setting, various therapeutic strategies have been implemented. These approaches 33 include immunomodulatory drugs such as corticosteroids and monoclonal antibodies, which 34 may potentially increase the risk of infectious complications. Indeed, corticosteroid treatment 35 has previously been associated with viral clearance delay, and anti-IL-6 drugs with a 36 suppressed innate immune response 4, 5 . Significantly, during the COVID-19 pandemic it has 37 been difficult to maintain infection control standards due to the overburdening of the 38 healthcare systems. In particular, the shortage of staff and critical care resources 6 

The cause-specific multivariate analysis did not reveal the use of immunomodulatory 145 drugs as significant risk factors for the development of BSI (Table 4) . Instead, the d-dimer > 146 700ug /L appears as the only independent predictor of BSI (HR 2.68; p<0.001). Among episodes 147 of BSI, advanced age (69 years vs. 60 years; HR 1.09) and lymphopenia (830/mm 3 vs. 148 1000/mm 3 ; HR 1.00] were independent risk factors for in-hospital mortality (Appendix D. 

In our large multicenter cohort of hospitalized severity-matched patients with 158 pneumonia due to SARS-CoV-2, we found that hospital-acquired BSI was uncommon, mainly 159 limited to patients admitted to the ICU, and not associated with immunomodulatory therapy.

Most studies conducted so far have analyzed community-acquired and hospital-161 acquired coinfection together 10-13 . However, these two scenarios should be analyzed 162 separately since they represent different clinical presentations requiring different approaches.

On the one hand, empirical antibiotic treatment is usually given in cases of suspected 164 coinfection; however, this does not seem to be justified in view of the low rates of bacterial 165 coinfection observed on hospital admission 16 , which are lower than those reported during the 166 H1N1 influenza pandemic 17 . On the other, nosocomial infection may be more closely related to 167 host characteristics and to the management during hospitalization. In this regard, the 168 prevalence of BSI in the setting of our cohort of patients with severe SARS-CoV-2 pneumonia 169 was similar to that reported in other critically ill patients 14,18 . However, one recent multicenter 170 case-cohort study, based on a large ICU cohort in France, found that the ICU-BSI risk was 171 higher for COVID-19 than non-COVID-19 critically ill patients after seven days of ICU stay 19 .

One interesting finding in our study was the longer median time to the first BSI episode 173 in our cohort compared with reports of H1N1 influenza infection and other COVID-19 studies 174 mentioned above. In addition, in our study Staphylococcus aureus was less frequently 175 recorded than in influenza pneumonia 20 . Interestingly, we identified a higher rate of 

This study has several limitations that should be acknowledged. Firstly, the prospective 218 cohort in which this study was conducted was not designed for study of this kind. Secondly, 219 the study was conducted in a limited geographical area; although the prospective database of 220 the COVID-Metrosud cohort includes five hospitals, only two were selected for this analysis. J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

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