Association between tocilizumab treatment of hyperinflammatory patients with COVID-19 in a critical care setting and elevated incidence of hospital-acquired bacterial and invasive fungal infections

Minihan, B; McAuliffe, E; Powell, James; Wong, Sam; Wilkie, K; Murphy, Carl; Maher, A; Power, Lorraine; O’Connell, Nuala H.; Dunne, Colum P.

doi:10.1016/j.jhin.2022.04.007

Cited by 10 publications

(5 citation statements)

References 30 publications

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“…Moreover, the prolonged use of steroids and immunomodulatory therapies plays a role in the immune depression of these patients, increasing the risk of HAIs. Among the drugs used for COVID-19, tocilizumab has showed a correlation with P. aeruginosa BSIs [ 75 , 76 ]. Peng et al reported a decreased mortality among COVID-19 patients treated with tocilizumab, but a higher number of fungal infections [ 77 ]; Minihan et al also noticed that among COVID-19 patients who received tocilizumab, the number of infections was double that of patients who did not receive it [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa Bloodstream Infections in SARS-CoV-2 Infected Patients: A Systematic Review

Bongiovanni

Barda

2023

JCM

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Bacterial co-infections increase the severity of respiratory viral infections and are frequent causes of mortality in COVID-19 infected subjects. During the COVID-19 period, especially at the beginning of the pandemic, an inappropriate use of broad-spectrum antibiotic treatments has been frequently described, mainly due to prolonged hospitalization, especially in intensive care unit departments, and the use of immune-suppressive treatments as steroids. This misuse has finally led to the occurrence of infections by multi-drug resistant (MDR) bacteria in hospitalized COVID-19 patients. Although different reports assessed the prevalence of Gram-negative infections in COVID-19 infected patients, scarce data are currently available on bloodstream infections caused by Pseudomonas aeruginosa in hospitalized COVID-19 patients. The aim of our systematic review is to describe data on this specific population and to discuss the possible implications that these co-infections could have in the management of COVID-19 pandemics in the future. We systematically analysed the current literature to find all the relevant articles that describe the occurrence of P. aeruginosa bloodstream infections in COVID-19 patients. We found 40 papers that described in detail P. aeruginosa HAIs-BSI in COVID-19 patients, including 756,067 patients overall. The occurrence of severe infections due to MDR bacteria had a significant impact in the management of hospitalized patients with COVID-19 infections, leading to a prolonged time of hospitalization and to a consequent increase in mortality. In the near future, the increased burden of MDR bacteria due to the COVID-19 pandemic might partially be reduced by maintaining the preventive measures of infection control implemented during the acute phase of the COVID-19 pandemic. Finally, we discuss how the COVID-19 pandemic changed the role of antimicrobial stewardship in healthcare settings, according to the isolation of MDR bacteria and how to restore on a large scale the optimization of antibiotic strategies in COVID-19 patients.

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Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa Bloodstream Infections in SARS-CoV-2 Infected Patients: A Systematic Review

Bongiovanni

Barda

2023

JCM

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“…Prolonged hospitalizations due to persistent respiratory failure are unfortunately common in severe COVID-19 pneumonia, and there appears to be an increased risk for acute kidney injury (AKI), with at least one study reporting 20–40% of patients hospitalized with COVID-19 will develop AKI. Furthermore, in patients hospitalized with COVID-19, kidney injury itself appears to be associated with an increased risk of serious bacterial and fungal infections [ 31 , 32 ]. In other studies assessing tocilizumab, Gupta and colleagues reported numerically more infections, and Viega et al reported no difference in secondary infection between groups, but no trial has looked specifically at the effects of renal replacement therapy and tocilizumab [ 29 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…This study has limitations owing to its observational nature and single-institution design, although other institutions have reported similar findings [ 31 , 34 ]. The exclusion of all potential confounders is virtually impossible, and biases regarding the individual use of tocilizumab and the timing and number of doses utilized cannot be completely excluded.…”

Section: Limitationsmentioning

confidence: 94%

Tocilizumab Is Associated with Increased Risk of Fungal Infections among Critically Ill Patients with COVID-19 and Acute Renal Failure: An Observational Cohort Study

Burger

Epps

Cárdenas

et al. 2023

Life

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Research Question: Does treatment with tocilizumab increase the risk of a fungal infection in critically ill patients with coronavirus-19? Background: Numerous therapies have been evaluated as possible treatments for coronavirus-2019 caused by severe acute respiratory syndrome coronavirus-2. Tocilizumab is a humanized monoclonal antibody directed against the interleukin-6 receptor that has found a role as a therapy for patients with severe coronavirus-19 pneumonia. The immunomodulatory effects of tocilizumab may have the unintended consequence of predisposing recipients to secondary infections. We sought to assess the risk of invasive fungal disease and the therapeutic impact of tocilizumab on the hospital length of stay, duration of mechanical ventilation, and intensive-care-unit length of stay in critically ill patients with severe coronavirus-19 pneumonia. Methods: Records of critically ill patients with coronavirus-2019 admitted from March to September 2020 at our institution were reviewed. The risk for fungal infections, intensive-care-unit length of stay, hospital length of stay, and duration of mechanical ventilation in those that received tocilizumab in addition to standard coronavirus-2019 treatments was assessed. Results: Fifty-six critically ill patients treated with dexamethasone and remdesivir for coronavirus-2019 were included, of which 16 patients also received tocilizumab. The majority of the cohort was African American, Asian, or of other ethnic minorities (53.6%). Invasive fungal infections occurred in 10.7% of all patients, and infection rates were significantly higher in the tocilizumab group than in the control group (31.2% vs. 2.5%, risk difference [RD] = 28.8%, p < 0.01). The increased risk in the tocilizumab group was strongly associated with renal replacement therapy. There was a dose–response relationship between the risk of fungal infection and number of tocilizumab doses received, with 2.5% of infections occurring with zero doses, 20% with a single dose (RD = 17.5%), and 50% with two doses (RD = 47.5%) (trend test p < 0.001). In addition, ICU LOS (23.4 days vs. 9.0 days, p < 0.01), the duration of mechanical ventilation (18.9 vs. 3.5 days, p = 0.01), and hospital length of stay (LOS) (29.1 vs. 15.5, p < 0.01) were increased in patients that received tocilizumab. Conclusions: Repurposed immunomodulator therapies, such as tocilizumab, are now recommended treatments for severe coronavirus-2019 pneumonia, but safety concerns remain. In this early pandemic cohort, the addition of tocilizumab to dexamethasone was associated with an increased risk of fungal infection in those that were critically ill and received renal replacement therapy. Tocilizumab use was also associated with increased ICU and hospital LOSs and duration of mechanical ventilation.

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“…Our data from the tertile analysis of nonlinear variables suggest that the window of opportunity lies between 9 and 12 days from symptom onset—in the early phase of severe disease. This is probably due to the inhibition of immunothrombosis before significant damage occurs, leading to ARDS, as studies in critical COVID-19 requiring mechanical ventilation and ICU transfer report unsatisfactory efficacy in this subset of patients [ 75 , 76 , 77 , 78 ]. Moreover, we found that a time period less than or equal to 5 days from the onset of the dyspnea doubled the chance of a good clinical response.…”

Section: Discussionmentioning

confidence: 99%

Identification of Clinical Response Predictors of Tocilizumab Treatment in Patients with Severe COVID-19 Based on Single-Center Experience

Schmidt

Pawlak-Buś

Jóźwiak³

et al. 2023

JCM

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Hyperinflammation in COVID-19 plays a crucial role in pathogenesis and severity; thus, many immunomodulatory agents are applied in its treatment. We aimed to identify good clinical response predictors of tocilizumab (TCZ) treatment in severe COVID-19, among clinical, laboratory, and radiological variables. We conducted a prospective, observational study with 120 patients with severe COVID-19 not improving despite dexamethasone (DEX) treatment. We used parametric and non-parametric statistics, univariate logistic regression, receiver operating characteristic (ROC) curves, and nonlinear factors tertile analysis. In total, 86 (71.7%) patients achieved the primary outcome of a good clinical response to TCZ. We identified forty-nine predictive factors with potential utility in patient selection and treatment monitoring. The strongest included time from symptom onset between 9 and 12 days, less than 70% of estimated radiological lung involvement, and lower activity of lactate dehydrogenase. Additional predictors were associated with respiratory function, vitamin D concentration, comorbidities, and inflammatory/organ damage biomarkers. Adverse events analysis proved the safety of such a regimen. Our study confirmed that using TCZ early in the hyperinflammatory phase, before severe respiratory failure development, is most beneficial. Considering the described predictive factors, employing simple and widely available laboratory, radiological, and clinical tools can optimize patient selection for immunomodulatory treatment with TCZ.

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Association between tocilizumab treatment of hyperinflammatory patients with COVID-19 in a critical care setting and elevated incidence of hospital-acquired bacterial and invasive fungal infections

Cited by 10 publications

References 30 publications

Pseudomonas aeruginosa Bloodstream Infections in SARS-CoV-2 Infected Patients: A Systematic Review

Pseudomonas aeruginosa Bloodstream Infections in SARS-CoV-2 Infected Patients: A Systematic Review

Tocilizumab Is Associated with Increased Risk of Fungal Infections among Critically Ill Patients with COVID-19 and Acute Renal Failure: An Observational Cohort Study

Identification of Clinical Response Predictors of Tocilizumab Treatment in Patients with Severe COVID-19 Based on Single-Center Experience

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