Results from an Italian study published in The Lancet Rheumatology have demonstrated a significant reduction in the risk of invasive mechanical ventilation or death in patients with severe coronavirus disease 2019 (COVID-19) pneumonia who were treated with the IL-6 inhibitor tocilizumab, either intravenously or subcutaneously, when compared with standard care. The authors said the association with tocilizumab was even stronger when overall mortality risk was analysed alone.
“Our results are consistent with those of a smaller, retrospective, case-controlled French study by Klopfenstein and colleagues, in which death or intensive care unit (ICU) admissions were higher in patients who did not receive tocilizumab than those who did (72% vs 25%; p=0.002),” noted Giovanni Guaraldi, MD, Azienda Ospedaliero-Universitaria Policlinico of Modena, Modena, Italy, and colleagues.
Their retrospective cohort study included 544 adults with severe COVID-19 pneumonia who were admitted to tertiary-care centres in Bologna and Reggio Emilia, Italy, between February 21 and March 24, 2020, and a tertiary-care centre in Modena, Italy, between February 21 and April 30, 2020. Overall, 359 (66%) of the patients were male, with a median age of 67 years, and all were experiencing clinical deterioration, with a median Subsequent Organ Failure Assessment (SOFA) score of 2 (IQR 1–4).
At the time of hospital admission, all patients received standard treatment, including supplemental oxygen, hydroxychloroquine, azithromycin at the physician’s discretion, lopinavir–ritonavir or darunavir–cobicistat for 14 days, and heparin for prophylaxis of deep vein thrombosis.
A non-randomly selected subset also received tocilizumab, which was given either intravenously (up to a maximum of 800 mg) in two infusions, 12 hours apart, or subcutaneously at 162 mg administered in two simultaneous doses, one in each thigh, when the intravenous formulation was unavailable. Patients were excluded from tocilizumab use if they had coexisting infections other than COVID-19, a PaO2/FiO2 ratio > 300 mm Hg, chronic or current glucocorticoid use, and severe haematological, renal, or liver function impairment, among other criteria.
Researchers noted that the standard care group included older patients with less severe disease, and the group given intravenous tocilizumab had the most compromised patients. Comorbidities data were only available for patients in the Modena cohort, which accounted for 354 (65%) of all patients. Among these, patients given tocilizumab had a higher burden of hypertension and diabetes, and more had symptoms such as headache and cough. Biochemical markers, available for 304 of the Modena patients, showed that those in the tocilizumab group had higher lactate dehydrogenase and worse inflammatory profiles at baseline, with higher C-reactive protein and IL-6 concentrations.
The primary endpoint assessed a composite of invasive mechanical ventilation or death. Results showed that 57 (16%) of 365 patients in the standard care group needed invasive mechanical ventilation, compared with 33 (18%) of 179 patients treated with tocilizumab (p=0.41; 16 [18%] of 88 patients treated intravenously and 17 [19%] of 91 patients treated subcutaneously). In addition, 73 (20%) patients treated with standard care only died, versus 13 (7%; p<0·0001) patients in the tocilizumab arm (six [7%] treated intravenously and seven [8%] treated subcutaneously). After adjusting for sex, age, recruiting centre, duration of symptoms, and SOFA score, tocilizumab was associated with a lower risk of invasive mechanical ventilation or death (adjusted hazard ratio 0.61, 95% CI 0.40–0.92; p=0.020).
In regards to mortality, a significant reduction in risk of death was found for tocilizumab over standard care alone after controlling for sex, age, SOFA score, recruiting centre, and duration of symptoms (aHR 0.38, 95% CI 0.17–0.83; p=0.015).
Researchers also paid attention to new episodes of infections in the tocilizumab and standard care groups, including bloodstream infections (three vs four), bacterial pneumonia (eight vs six), candidemia (two vs two), urinary tract infection (one vs one), Pneumocistis jirovecii pneumonia (one vs one), invasive aspergillosis, (four vs none), hepatitis B virus reactivation (one vs none), and herpes simplex virus 1 reactivation (four vs none). Overall, 24 (13%) of 179 patients treated with tocilizumab were diagnosed with new infections, versus 14 (4%) of 365 patients treated with standard of care alone (p<0.0001).
“Current recommendations do not include any immunologically active drug in routine clinical practice, and use of glucocorticoids is controversial. Tocilizumab, administered intravenously or subcutaneously, can be considered together with anakinra as one of the immunomodulatory drugs that have been tested in clinical care for the treatment of severe COVID-19 pneumonia,” the authors said.
Adverse events were a major concern, and the authors stated that “the case of severe herpes simplex virus 1 hepatitis in the tocilizumab group suggests the importance of screening for herpes virus reactivation, especially if glucocorticoids are added.”
Some limitations include the non-randomised and open-label nature of the study, as well as the lack of confounder measurements for some of the biomarkers of inflammation and coagulation, which were available for only the participants in Modena.
However, the authors said “our study also has strengths. First, it was a large study that included patients from a real-life hospital setting. Second, key confounding factors were collected daily in a standardised way for a minimum of 14 days and were linked to the electronic charts of blood counts and clinical data. Although these results are encouraging, they should be confirmed in ongoing randomised studies.”