key: cord-0880929-qx16i7s1
authors: Pettit, Natasha N.; Nguyen, Cynthia T.; Mutlu, Gökhan M; Wu, David; Kimmig, Lucas; Pitrak, David; Pursell, Kenneth
title: Late Onset Infectious Complications and Safety of Tocilizumab in the Management of COVID‐19
date: 2020-08-13
journal: J Med Virol
DOI: 10.1002/jmv.26429
sha: 65e89bd5417506c597e5238e307c826ec98a7b06
doc_id: 880929
cord_uid: qx16i7s1

BACKGROUND: Tocilizumab (TCZ) has been used in the management of COVID‐19‐related cytokine release syndrome (CRS). Concerns exist regarding the risk of infections and drug‐related toxicities. We sought to evaluate the incidence of these TCZ complications among COVID‐19 patients. METHODS: All adult inpatients with COVID‐19 between March 1(st) and April 25(th), 2020 that received TCZ were included. We compared the rate of late‐onset infections (>48 hours following admission) to a control group matched according to intensive care unit admission and mechanical ventilation requirement. Post‐TCZ toxicities evaluated included: elevated liver function tests (LFTs), GI perforation, diverticulitis, neutropenia, hypertension, allergic reactions, and infusion‐related reactions. RESULTS: Seventy‐four patients were included in each group. Seven‐teen infections in the TCZ group (23%) and 6 (8%) infections in the control group occurred >48 hours after admission (p=0.013). Most infections were bacterial with pneumonia being the most common manifestation. Among patients receiving TCZ, LFT elevations were observed in 51%, neutropenia in 1.4%, and hypertension in 8%. The mortality rate among those that received TCZ was greater than the control (39% versus 23%, p=0.03). CONCLUSION: Late onset infections were significantly more common among those receiving TCZ. Combining infections and TCZ‐related toxicities, 61% of patients had a possible post‐TCZ complication. While awaiting clinical trial results to establish the efficacy of TCZ for COVID‐19 related CRS, the potential for infections and TCZ related toxicities should be carefully weighed when considering use. This article is protected by copyright. All rights reserved.

Immune-modulators targeting interleukin-6 (IL-6) have been implemented in the management of patients with severe coronavirus disease 2019 (COVID-19) presenting with a hyperinflammatory response resembling cytokine release syndrome (CRS).

COVID-19 related CRS is associated with elevated levels of several inflammatory markers, including IL-6. 1-2 Tocilizumab (TCZ), an IL-6 receptor monoclonal antibody, has gained attention as a potential option to treat the hyperinflammatory state that develops in patients with severe COVID-19 based predominantly on case reports and non-randomized studies. [3] [4] [5] [6] [7] [8] However, concerns exist regarding the potential for an increased risk of infection, as TCZ can blunt the immune response, in addition to concerns for other toxicities known to be associated with its use (e.g. liver dysfunction, This article is protected by copyright. All rights reserved.

gastrointestinal perforation, diverticulitis, hypertension, neutropenia, and infusion related reactions). [9] [10] The occurrence of these complications following the administration of offlabel TCZ among patients with COVID-19 related hyperinflammatory response is not well established. We sought to evaluate the incidence of these potential complications following the use of TCZ among COVID-19 patients.

This was a single-center, retrospective, observational study comparing patients who received TCZ to those who did not receive TCZ. All adult inpatients with COVID-19 admitted between March 1, 2020 to May 25, 2020 who received at least one 400 mg dose of TCZ for CRS were included. During the study period, the institutional guideline recommended administration of TCZ 400 mg intravenous once (with the option of redosing based on clinical response within 12-24 hours) if patients presented with severe and rapidly progressing hypoxia in addition to elevated inflammatory markers (e.g. D-Dimer >2 mg/L, C-reactive protein (CRP) >100mg/L, and/or ferritin >600 mcg/L (or >300mcg/L if ferritin doubled in the previous 24hrs)). TCZ use was avoided in patients with confirmed or suspected bacterial infections, neutropenia, thrombocytopenia, or if liver function tests (LFTs) were > 10x upper limit of normal. TCZ for this indication required approval by the inpatient infectious diseases consultation service. Patients receiving TCZ as part of a clinical trial were excluded. Our protocol for the management of COVID-19 patients did not recommend corticosteroids or other immune-modulating therapies during the included analysis period. This project received a formal Determination of Quality Improvement status according to University of Chicago This article is protected by copyright. All rights reserved.

Medicine institutional policy. As such, this initiative was deemed not human subjects research and was therefore not reviewed by the Institutional Review Board.

Infection, other than SARS-CoV-2, was defined as a positive culture or nucleic acid amplification test (NAAT) for which directed therapy was initiated. Late-onset infections were those that occurred >48 hours after admission. We evaluated respiratory cultures, blood cultures, tissue cultures, fluid cultures, cytomegalovirus infection, and We also assessed if patients developed GI perforation, diverticulitis, hypertension, neutropenia (absolute neutrophil count (ANC) <500 cells/m 3 ), or increased liver enzymes, LFTs (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) following TCZ. We evaluated specifically for an elevation resulting a doubling of baseline liver enzymes or an increase to >5 times upper limit normal following the TCZ dose. Hypertension following TCZ was identified by evaluating progress notes noting new onset hypertension at any point after the TCZ dose. Many patients had hypertension at baseline, in these patients we evaluated whether additional interventions where needed to maintain control of patient blood pressures following TCZ. Progress notes and nursing notes were also reviewed to assess if any allergic reaction or infusion related reaction occurred.

Baseline characteristics and comorbidities known to be associated with more severe COVID-19 (hypertension, cardiovascular disease, diabetes, obesity, chronic kidney disease or end stage renal disease, asthma or chronic obstructive pulmonary disease, HIV regardless of CD4 count and any other immune-deficiency) [11] [12] [13] [14] [15] [16] were evaluated on all included patients in the TCZ evaluation as well as the non-TCZ comparator group for the post-TCZ infection analysis. Immune-deficiency included any of the following: leukemia, lymphoma, solid tumor if recent chemotherapy or radiation therapy (past 3 months), HIV with CD4 < 200/mm 3 , neutropenia < 1,000/mm 3 , primary immune deficiency, autoimmune or idiopathic condition requiring a biological agent or steroids, equivalent of ≥ prednisone 20 mg daily for > 30 days. To characterize the patients' clinical presentation, course, and outcomes in the group that received TCZ, we also evaluated time to TCZ from symptom onset, intensive care unit (ICU) admission at the time of the TCZ dose, the TCZ weight based dose, mechanical ventilation at the time of the TCZ dose, whether they also received remdesivir or a hydroxychloroquine based regimen, time to defervesce following TCZ (if the patient was febrile prior to the dose), time to positive culture (if they had positive cultures post TCZ), length of hospital stay (LOS), and mortality (all-cause). We also reviewed mean baseline and daily (for 5 days following the initial TCZ dose) C-reactive protein (CRP), ferritin, and D-Dimer trends.

Descriptive statistics were used to summarize the observed infectious and toxicity analysis for TCZ. For the post-TCZ infection analysis, Chi-squared or Fisher's exact test were used to compare the categorical baseline characteristics, comorbidities and identified infections among those that received TCZ versus those in the control group that This article is protected by copyright. All rights reserved.

did not receive TCZ. For age, as a continuous variable that was determined to be normally distributed a Student's t-test was performed. LOS was not normally distributed and evaluated using Mann Whitney U. All statistical analyses were performed using STATA®, version 16, College Station, TX.

A total of 74 patients received TCZ for COVID-19-associated CRS consistent with our protocol. The majority of patients (89%) in the TCZ group received only 1 dose. The mean follow-up period for all patients reviewed was 58 days. The baseline characteristics and comorbidities among those that received TCZ in addition to the control group are noted in Table 1 . There were no statistically significant differences between groups for the comorbidities assessed. A higher proportion of patients were male (42% versus 33% control) and were immune-compromised (12% versus 4% control) in the TCZ group. Of the 25 TCZ patients that required mechanical ventilation, 24 (96%) received their dose after intubation. The Late onset infection rate compared to that in the control group is shown in Table 2 The mean time for the TCZ administration from symptom onset was 9 days, with mean weight-based dose of 4.5 milligrams per kilogram. The mean time for patients that were febrile prior to the TCZ dose (n=15) to defervesce was 6.3 hours, and mean time to culture positivity (from the date of the first TCZ dose) among those with a culture positive infection was 11 days. The overall mean LOS was 15.5 days versus 10.3 days in the TCZ and control groups, respectively (p=0.04). The mortality rate among those that received TCZ was 39% (n=29) versus 23% (n=17) in the control group, p=0.03. The inflammatory marker trends following TCZ are shown in Figure 1 , 2, and 3. At 5 days following the TCZ dose, the mean CRP decreased by 80% and mean ferritin by 30%. D-Dimer levels did not decrease following TCZ.

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The rate of infections following TCZ administration among patients with COVID-19 related CRS observed in this study, both overall and late onset, is similar to the findings of recently published studies evaluating the use of TCZ for this indication reporting an infection rate ranging between 0-27%. 3, [6] [7] [8] 10 One retrospective study comparing rates of infections among patients with COVID-19 between those that received TCZ versus a standard of care (SOC) control group, found no difference in the rates of infections between these groups (13% TCZ and 12% SOC). 8 In our analysis however, we identified that while overall infection rate was similar between groups, late on-set infections occurred in significantly more patients that received TCZ compared to the control (23% vs. 8%, p=0.013). This is not surprising given the long half-life of the drug (11 days with 4mg/kg doses). 17 And while not significantly different between groups, of interest, culture confirmed invasive fungal infections were present in 3 patients that received TCZ in our study and 1 additional patient had invasive fungal sinusitis diagnosed by CT imaging, no culture data could be obtained; however, this additional patient was not included in our analysis. A recent report found that among 43 patients that received TCZ, 3 (6.9%) were later diagnosed with candidemia. 10 This is of concern in that previous studies have shown that mice deficient in IL-6 were more susceptible to candida infections and had increased fungal burdens, compared to non-deficient controls. 18 As far as the other toxicities evaluated, the observed rate of LFT elevations (51%) is higher compared to other studies findings reporting a rate of 15-29%, however the rate of neutropenia (1.4%) is much lower than reported elsewhere (16%). 8 GI perforation, diverticulitis, infusion reactions, and severe allergic reactions are rarely reported in the This article is protected by copyright. All rights reserved.

literature evaluating use of TCZ for COVID-19, congruent with the fact that we did not observe any of these toxicities in our study. 3, [6] [7] [8] The observed mortality rate in our study was 39%, higher than the control group (23%), and what has been reported in other studies evaluating the use of TCZ for COVID-19 CRS (15-27%). [5] [6] [7] [8] While the reason for this is unclear, it should be considered that our protocol required both rapidly progressing hypoxemia and presence of elevated inflammatory markers, and among the patients that required mechanical ventilation in the TCZ group, the majority received their TCZ after intubation. The required parameters for patients to be considered for TCZ and the fact that 32% of patients in the TCZ group received their dose after being placed on mechanical ventilation resulted in us reserving use only in patients where poor outcomes may already be imminent, hence contributing to a higher rate of mortality and possibly to the longer length of stay as well. It also pertinent to consider that we implemented a lower flat dose (average dose 4.5 mg/kg), some recommend dosing 8 mg/kg per dose for COVID-19 related CRS, which could have had an impact on the outcomes observed in our study. 7 The mean time to dose the TCZ in our study was 9 days following symptom onset. While the optimal timing of TCZ for COVID-19 is not established, this could have potentially contributed to our observed mortality rate as well. Additionally, while the differences were not statistically significant, a larger proportion of patients in the TCZ group were male (42% TCZ versus 33% control), and were immune-compromised at baseline (12% TCZ versus 4% control).

This could have contributed to higher mortality as well. Both male gender, and immunecompromise have been identified as factors that may be associated with more severe disease or mortality among COVID-19 patients. 19, 20 Finally, a larger proportion of This article is protected by copyright. All rights reserved.

patients in the TCZ group also received hydroxychloroquine (57% versus 20%, p=0.001) which could also could contribute to increased mortality, however studies have not consistently demonstrated whether use of this agent increases mortality among patients with COVID-19. [21] [22] [23] We also observed an evident decline in CRP and ferritin following the administration of TCZ, consistent with other studies evaluating the use of TCZ in the setting of COVID-19 CRS. 5, 7 However, the D-Dimer levels continued to increase following TCZ, also consistent with observations of a previous study. 7 The discrepancy in the effect on the levels of these inflammatory markers highlight the fact that TCZ is only acting partially on the inflammatory response cascade.

There are several limitations with this study to consider. As a retrospective analysis, bias and confounders may influence the observed outcomes, including differences in baseline characteristics and length of stay. All TCZ use for the indication of COVID-19 CRS was overseen by our Infectious Diseases consult service, following the criteria that had been outlined in a clinical protocol, which promoted consistent usage of TCZ among those meeting outlined criteria. Though this may also have contributed to selection bias, including the difference in early-onset infection, as patients who presented with infection were less likely to receive TCZ based on our protocol. To avoid potential bias in the control group, we matched the patients to the TCZ group according to requirement of intensive care unit admission and mechanical ventilation. While matching according to clinical scores that may be applicable to the critically-ill patient population (e.g. SOFA or APACHE II) could also help to establish a more evenly matched control group, the applicability of these scales among COVID-19 patients with suspected CRS are lacking. This article is protected by copyright. All rights reserved.

We feel that matching according to requiring ICU admission and mechanical ventilation are more clinically relevant in day-to-day practice. Evaluating toxicities related to a drug retrospectively is also a limitation in that we cannot establish a true causality, many of these patients already had hypertension and elevated LFTs at baseline, and COVID-19

itself may cause LFTs to be elevated as well. 24 More patients in the TCZ group also received hydroxychloroquine which also could have contributed to the observed rates of hepatotoxicity in this group as this agent can be associated with hepatotoxicity, although rare. 25 We also did not have a control arm for the safety analysis. Additionally, while we had a clinical protocol outlining when to consider TCZ based on progressive hypoxia and elevated inflammatory markers, the criteria to use for the diagnosis of COVID-19 related CRS and whether it requires the administration of TCZ is not well established. Our criteria is based on observations from direct patient care and studies identifying inflammatory marker thresholds for more severe disease. 19 IL-6 levels are not included in this analysis as it was not consistently available on all patients, and the sample had to be sent-out to an external laboratory for it to be performed at our medical center; therefore, the clinical utility of an IL-6 level was limited in our cohort of patients.

Forty-five (61%) patients that received TCZ had at least one of the evaluated complications and we observed a 39% mortality rate, higher than our control group and other studies. 3, 5-8 Based on these findings, infection risk (considering the higher rate of late-onset infections and invasive fungal infections observed) and other drug-related toxicities should be factored in when considering the use of TCZ for COVID-19associated CRS. Until results from randomized and controlled prospective clinical trials evaluating TCZ for this indication are available, there remain limited data to definitively This article is protected by copyright. All rights reserved.

establish efficacy or safety in this setting. With the potential for harm, and unclear evidence to support efficacy, clinicians should consider limiting off-label use of TCZ for COVID-19 CRS and only using in the setting of a clinical trials.

The data that support the findings of this study are available from the corresponding author upon reasonable request. 

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HCQ based regimen 42 (57)* 15 (20)** 0.001 * HCQ HCQ alone (17) , HCQ + ribavirin (5) , HCQ +lopinavir/ritonavir (20)** HCQ alone (3), HCQ + ribavirin (2), HCQ + lopinavir/ritonavir (10) EUA: Emergency use authorization, HCQ: hydroxychloroquine Coagulase negative Staphylococcus 

* All pathogens isolated in relevant cultures are listed, some patients may have grown more than 1 organism, only organisms specifically requiring treatment are included **Total number of patients with an infection, some had more than 1 following TCZ (or during admission at any point for controls). 17 total infections were identified in 12 patients the TCZ group and 6 infections were identified in 3 patients in the control group. † For patients that received TCZ; time from TCZ to first culture positive, for patients in the control group; time from date of admission to date of first culture positive