IL6 inhibition in critically ill COVID-19 patients is associated with increased secondary infections

Anti-inflammatory therapies such as IL-6 inhibition have been proposed for COVID-19 in a vacuum of evidence-based treatment. However, abrogating the inflammatory response in infectious diseases may impair a desired host response and predispose to secondary infection. To determine whether IL-6 inhibition is associated with an increased occurrence of secondary infections in patients admitted to the intensive care unit (ICU). We retrospectively reviewed the medical record of patients during an 8-week span and compared the incidence of secondary infection in patients who did and did not receive tocilizumab. The study was approved by the IRB. Additionally, we included representative histopathologic post-mortem findings from several COVID-19 cases that underwent autopsy at our institution. The study was conducted in a cohorted COVID-19 ICU at a tertiary care university medical center. Patients 18 years of age or older admitted to the adult COVID-19 intensive care unit with COVID-19 were randomly selected. We reviewed the occurrence and nature of secondary infections and clinical outcomes in patients who did and did not receive tocilizumab. Measures were formulated prior to the study. For autopsy findings, we were interested in the lung pathology. 60 patients were selected of which 28 had received tocilizumab while 32 had not. Receiving tocilizumab was associated with a higher risk of secondary bacterial (64.3% vs. 31.3%, p=0.010) and fungal (7.1% vs. 0%, p=0.096) infections. 7 cases underwent autopsy. In 3 cases, tocilizumab had previously been given. All 3 patients demonstrated evidence of pneumonia on pathology. Of the 4 cases that had not been given tocilizumab, 2 showed evidence of aspiration pneumonia and 2 exhibited diffuse alveolar damage. Experimental therapies are currently being applied to COVID-19 outside of clinical trials. Anti-inflammatory therapies such as anti-IL-6 therapy have the potential to impair viral clearance, predispose to secondary infection, and cause harm. We seek to raise physician awareness of these issues and highlight the need to better understand the immune response in COVID-19.

While there has been an increase in the number of clinical trials, currently there are no effective therapies for COVID-19 infection. As a result, the management of COVID-19 patients including those who are critically ill remains supportive. Reports from China suggested that an exaggerated immune response may play a role in the development of respiratory failure, shock, and multiorgan dysfunction in critically ill patients with COVID-19 1 . Similarities between the exaggerated immune response associated with COVID-19 or sepsis in general and the cytokine release syndrome (CRS) reported in patients with CAR T-cell therapy led to the use of tocilizumab, an anti-IL-6 therapy to attenuate hyperimmune responses associated with COVID 2 .
At this time, we do not have any evidence that patients with COVID-19 benefit from tocilizumab or which criteria to apply in selecting patients to receive tocilizumab. Inhibition of IL-6 may also have adverse consequences. Mice lacking a normal IL-6 response have impaired immunity against viral, bacterial and fungal pathogens 3 . Humans treated with tocilizumab had higher risk of serious bacterial, skin and soft tissue infections 4-6 .
We observed increased bacterial infections in critically ill COVID-19 patients and thus sought to determine whether there was an association between tocilizumab administration and secondary infections. The study was approved by the University of Chicago Institutional Review Board.
Adult patients (>18 years of age) admitted to the adult COVID-19 intensive care unit with COVID-19 between the dates of March 1, 2020 and April 27, 202 were randomly selected for analysis. Out of 60 critically ill COVID-19 patients, 28 received tocilizumab 400 mg once except for three patients who received two doses (800 mg total) and one patient who received a single 800 mg dose. Our protocol recommended 400 mg flat dosing of tocilizumab with the potential for redosing based on clinical response (e.g. oxygenation status, hemodynamic stability, inflammatory marker response). We compared bacterial and fungal infections in those that received the drug to those that did not. There were no differences in patient baseline characteristics (including age, sex, Charlson co-morbidity index (CCI), as well as variables that All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) 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 May 20, 2020. . https://doi.org/10.1101/2020.05.15.20103531 doi: medRxiv preprint may not be captured by the latter index such as immunosuppression, hypertension, etc.) between the two groups (Table 1). Secondary infections were defined by positive culture data or high clinical suspicion of infection requiring the initiation of antimicrobials and documentation in the progress note.
Receiving tocilizumab was associated with a higher incidence of secondary bacterial infections including hospital acquired pneumonia and ventilator associated pneumonia (64.3% vs. 31.3% p=0.010). In a logistic regression model for bacterial infections as the outcome that also contained age, sex, and the CCI as independent variables, tocilizumab administration was independently associated with presence of secondary bacterial infections (Odds ratio: 3.960 (95% CI 1.351-11.607), p=0.033). While there were two patients with fungal infections, including one patient with Mucor pneumonia and another patient with sinusitis in the tocilizumab group compared with none in the non-tocilizumab group, this did not reach statistical significance.
Lastly, we performed post-mortem evaluation of 7 cases; 3 received tocilizumab and 4 did not.
All three cases who received tocilizumab had evidence of pneumonia on pathology ( Figure 1).
Two of four patients who did not receive tocilizumab were nursing home residents with history of stroke and dementia and they died on the same day of admission. Their post-mortem evaluation showed evidence of aspiration pneumonia. The other two patients who did not receive tocilizumab were hospitalized for 4 and 12 days. Their lungs demonstrated only pathological changes consistent with diffuse alveolar damage without any evidence of pneumonia ( Figure 1).
These findings raise concerns about the use of tocilizumab in the presence of an infection to attenuate CRS. In particular, the occurrence of secondary bacterial infections may prolong ICU stays, and the occurrence of secondary fungal infections stands out as unusual in critical care patients without traditional risk factors (e.g. neutropenia). Since microbiologic identification of the causative organism is frequently not achieved in infections, it is possible that our definition is too broad and may capture some patients who were treated for clinical deterioration. However, All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) 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 May 20, 2020. All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) 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 May 20, 2020. . *T-tests, Mann-Whitney U, Chi-Square, or Fisher Exact tests were used as appropriate. # One patient had fungal infection in different sites. One additional patient who received tocilizumab developed oral thrush.
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(which was not certified by peer review) 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 May 20, 2020. . Figure 1. Postmortem histopathology of lungs from COVID-19 patients. Low (100x) and high power (200x) images of lungs from patients who died due to COVID-19. A. Organizing hyaline membranes are seen in the lung which has pre-existing emphysema (100x). Higher power shows fibrin, fibroblasts and mononuclear cells incorporated into the alveolar walls (200x). B. There is diffuse alveolar damage with hyaline membranes lining alveoli (100x). Higher power shows minimal inflammation with only a few mononuclear cells (200x). C. There is extensive intra-alveolar inflammation (neutrophils) in an otherwise normal lung (100x). On higher power, there is minimal alveolar wall thickening by inflammatory cells (also mainly neutrophils on myeloperoxidase staining and only rare lymphocytes) (200x). D. Majority of the sections from this case show organizing intra-alveolar fibrin (100x). Several foci of acute inflammation with alveolar filling are present, as seen here on higher power (200x).

FIGURE LEGEND
All rights reserved. No reuse allowed without permission.
(which was not certified by peer review) 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 May 20, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.