IL-6 Inhibition in Critically Ill COVID-19 Patients Is Associated With Increased Secondary Infections

Abstract

Background: 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 pre-dispose to secondary infections. Methods: We retrospectively reviewed the medical record of critically ill COVID-19 patients during an 8-week span and compared the prevalence of secondary infection and outcomes in patients who did and did not receive tocilizumab. Additionally, we included representative histopathologic post-mortem findings from several COVID-19 cases that underwent autopsy at our institution. Results: One hundred eleven patients were identified, of which 54 had received tocilizumab while 57 had not. Receiving tocilizumab was associated with a higher risk of secondary bacterial (48.1 vs. 28.1%; p = 0.029 and fungal (5.6 vs. 0%; p = 0.112) infections. Consistent with higher number of infections, patients who received tocilizumab had higher mortality (35.2 vs. 19.3%; p = 0.020). Seven cases underwent autopsy. In three cases who received tocilizumab, there was evidence of pneumonia on pathology. Of the four cases that had not been given tocilizumab, two showed evidence of aspiration pneumonia and two exhibited diffuse alveolar damage. Conclusions: 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, pre-dispose 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.

Keywords: COVID-19; SARS-CoV-2; cytokine release syndrome; immunosuppression; tocilizumab.

Figure 1

Laboratory data in tocilizumab and non-tocilizumab groups. (A) White blood cell (WBC) count, (B) percent lymphocyte, (C) absolute lymphocyte count, (D) D-dimer, (E) C-reactive protein, and (F) ferritin levels on day 1 of admission to the ICU. There was no difference between non-tocilizumab (non-toci) and tocilizumab (toci) groups in laboratory data except for absolute lymphocyte count, which was lower in the tocilizumab group. ns, not significant.

Figure 2

Post-mortem histopathology of lungs from COVID-19 patients. Low- (×100) and high-power (×200) 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 (×100). Higher power shows fibrin, fibroblasts, and mononuclear cells incorporated into the alveolar walls (×200). (B) There is diffuse alveolar damage with hyaline membranes lining alveoli (×100). Higher power shows minimal inflammation with only a few mononuclear cells (×200). (C) There is extensive intra-alveolar inflammation (neutrophils) in an otherwise normal lung (×100). On higher power, there is minimal alveolar wall thickening by inflammatory cells (also mainly neutrophils on myeloperoxidase staining and only rare lymphocytes) (×200). (D) Majority of the sections from this case show organizing intra-alveolar fibrin (×100). Several foci of acute inflammation with alveolar filling are present, as seen here on higher power (200x).