Biomarker variation in patients successfully treated with tocilizumab for severe coronavirus disease 2019 (COVID-19): results of a multidisciplinary collaboration.

OBJECTIVES: Acute respiratory distress syndrome (ARDS) related to SARS-CoV-2 is likely due to a cytokine storm characterised by a major release of pro-inflammatory cytokines, including interleukin-6 (IL-6). Blocking excessive IL-6 production might be the key to the COVID-19-ARDS treatment. Beneficial effects of IL-6 blockade using a humanised anti-IL-6 receptor antibody, tocilizumab (TCZ) were previously reported in patients with COVID-19 related ARDS. The aim of the study was to study the variation over time of several biomarkers, demonstrated to be predictors of poor prognostic, in subjects successfully treated with TCZ for severe COVID-19. METHODS: Retrospective analysis of a case series of patients with COVID-19-ARDS, evidenced by RT-PCR and lung CT-scan. Patients with increasing O2 requirements, within the window of opportunity for TCZ treatment (Day 7 to Day 17 after onset of symptoms) were treated with TCZ (2 infusions of 8 mg/kg). Demographic, biological and clinical data were collected from the patients' files. Serum levels of CRP, ferritin, fibrinogen, lymphocytes, platelets, creatinine, D-dimer and liver enzymes were assayed at the time of the first TCZ administration, then every two days for 8 days. RESULTS: 40 patients were treated with TCZ. Most of them had several comorbidities, and all had multiple biological abnormalities (lymphopenia, increased CRP, ferritin, fibrinogen, D-dimer, liver enzymes). 30 patients (75%) benefited from TCZ and 10 patients died. In the survivors, following TCZ administration CRP decreased dramatically as early as day 4 (-86.7%, p<0.0001) and returned to normal at day 6. Fibrinogen and lymphocyte count returned to normal values at day 6. Ferritin also decreased significantly. No significant change was observed for D-dimer (p=0.68) and other studied biomarkers (haemoglobin, leucocyte count, AST). CONCLUSIONS: In patients with COVID-19 acute respiratory distress syndrome, treatment with TCZ resulted in favourable evolution in 75% of the cases. Biomarkers of inflammation (CRP, ferritin, fibrinogen) decreased dramatically as early as the 4th day after TCZ injection. Lymphopenia, a predictor of poor prognostic, was reversed 6 days after TCZ injection.

Predictive factors of mortality in patients treated with tocilizumab for acute respiratory distress syndrome related to coronavirus disease 2019 (COVID-19).

COVID-19 patients (n = 34) suffering from ARDS were treated with tocilizumab (TCZ). Outcome was classified in two groups: "Death" and "Recovery". Predictive factors of mortality were studied. Mean age was 75.3, mean oxygen (O2) requirements 10.4 l/min. At baseline, all patients had multiple biological abnormalities (lymphopenia, increased CRP, ferritin, fibrinogen, D-dimer and liver enzymes). 24 patients (70.5%) recovered after TCZ therapy and 10 died (29.5%). Deceased subjects differed from patients in whom treatment was effective with regard to more pronounced lymphopenia (0.6 vs 1.0 G/l; p = 0.037), lower platelet number (156 vs 314 G/l; p = 0.0001), lower fibrinogen serum level (0.6 vs 1.0 G/l; p = 0.03), higher aspartate-amino-transferase (108 vs 57 UI/l; p = 0.05) and greater O2 requirements (11 vs 8 l/min; p = 0.003).

Standardized Follow-up of Patients with Symptomatic Knee Osteoarthritis Treated with a Single Intra-articular Injection of a Combination of Cross-Linked Hyaluronic Acid and Mannitol.

OBJECTIVES: The objective of this study is to obtain pilot data from daily practice conditions of a viscosupplement made of a cross-linked high-molecular-weight hyaluronic acid (HA) combined with mannitol in patients with knee osteoarthritis (KOA). METHODS: The data of 40 consecutive patients, 29 women and 11 men, who were prospectively followed up for 6 months, using a standardized procedure, were retrospectively analyzed. All patients have received a single intra-articular injection of HAnox-M-XL (4.4 mL), viscosupplement made of a cross-linked HA (16 mg/mL) + mannitol (35 mg/mL), in the target knee. The primary outcome was safety. The secondary end points included 3- and 6-month change in the WOMAC pain (0-50) and WOMAC total (0-240) and patient's global assessment (PGA). Patient's self-assessment of treatment efficacy (0-3) and analgesic consumption were obtained at months 3 and 6. An intent-to-treat analysis was performed. RESULTS: Mean (SD) age was 60.7 (13.9) years, and mean BMI was 28.6 (5.0). Kellgren-Lawrence radiological grade was I/II and III/IV in 13 and 27 of the subjects, respectively. The average WOMAC pain and WOMAC total scores at baseline were 21.5 (9.8) and 89.9 (42.8), respectively. Thirty-nine patients completed the follow-up. HAnox-M-XL was well tolerated; two patients experienced knee pain after injection, which resolved within three days. No treatment-related severe adverse event was reported. Mean (SD) variations in WOMAC pain and WOMAC total scores were -8.2 (8.9) and -38.4 (35.6), respectively, at month 6 (P = 0.001). PGA decreased from 5.5 (2.0) to 3.0 (2.2) (P = 0.006). Efficacy was rated as good or very good in 76.9% of the cases. Most of the regular analgesics users decreased their consumption. CONCLUSION: Treatment with one injection of 4.4 mL HAnox-M-XL is effective to alleviate KOA symptoms over six months, without safety concern. Controlled trials are needed to confirm these pilot data.

Imaging Guidance Improves the Results of Viscosupplementation with HANOX-M-XL in Patients with Ankle Osteoarthritis: Results of a Clinical Survey in 50 Patients Treated in Daily Practice.

BACKGROUND: The objective of this survey was to assess retrospectively the interest of performing viscosupplementation using imaging guidance in patients suffering from ankle osteoarthritis (OA). PATIENTS AND METHODS: This is a multicenter retrospective survey using a standardized questionnaire. Fifty patients suffering from ankle OA and treated, in daily clinical practice, with a single intra-articular injection of a novel viscosupplement made of a combination of a non-animal cross-linked hyaluronan and mannitol, HANOX M-XL, were included in the survey. The injection procedure (imaging or landmark guidance), demographic data, patient's self-evaluation of pain, satisfaction, treatment efficacy, and tolerability were collected. Predictive factors of both efficacy and patient's satisfaction were investigated. RESULTS: The percentages of patients very satisfied/satisfied and not really satisfied/dissatisfied with the treatment were 68% and 32%, respectively. Efficacy was rated as very good, good, moderate, and poor by 38%, 30%, 12%, and 20% of the cases, respectively. Efficacy was unrelated to gender and age and was highly correlated with pain score (P < 0.0001). In satisfied patients, the decrease in consumption of analgesics/non-steroidal anti-inflammatory drugs was >75% in 64% of the cases. Efficacy was significantly different with regard to imaging guidance. There was a statistically significant difference in efficacy and satisfaction between landmark-guided and imaging-guided injections (P = 0.02). The success rate was 2.3 times higher in the imaging-guided group than in the landmark-guided group. No significant difference was found between patients injected under fluoroscopy or ultrasound guidance, despite a trend favoring ultrasound (P = 0.09). Tolerability was rated as very good/good in 47 patients, moderate in two, and poor in one and was unrelated to the type of guidance. CONCLUSION: This preliminary study suggests that the use of imaging guidance significantly optimizes the success rate of ankle viscosupplementation. No safety concern was observed. LEVEL OF EVIDENCE: III.