Introduction
The burden of adjunctive treatment
Impact of viral elimination on the outcome of severe COVID-19
Reference | Study design | N of patients | Intervention | Outcome |
---|---|---|---|---|
[8] | Retrospective observational | SARS-CoV‑2 infection (n = 30) HIV infection (n = 25) | Darunavir, IL‑6 interaction | Circulating danunavir lower when IL-6 > 18 pg/ml (p < 0.0001) |
[9] | RCT | – TCZ (n = 295) – Placebo (n = 143) | Viral load measurement daily in nasopharyngeal swab and blood | AUC of viral load (as copies/μl.hour-1) in swab: 4.07 (range 2.07–7.41)/TCZ and 4.61 (range 1.68–11.04)/placebo HR for negative viral load in serum by day 14 with TCZ 1.17 (0.82–1.68) |
[10] | Prospective, non-randomized | – Non-TCZ (n = 62) – TCZ (n = 76) | Serial viral load measurements | Initial viral load was related to viral clearance (HR 0.56; p = 0.01) Median time to seropositivity 14 days in TCZ vs. 17 days in non-TCZ (p = 0.017) |
[11] | Prospective | – CD14 monocytes from 8 infected patients – Six treated patients | – Ex vivo treatment of CD14 monocytes with TCZ (n = 8) – IV treatment with TCZ (n = 6) | – Increase of HLA-DR expression on CD14 monocytes – Increase of absolute lymphocyte count |
[12] | Prospective | – SARS-CoV‑2 infection (n = 30) | TCZ treatment (n = 5) | Decrease of NK and NKT-cells compared to healthy controls; increase of perforin(+) and granzyme(+) NK cells after TCZ |
Bacterial elimination and sepsis outcome
Transfering the success of immunotherapy for COVID-19 to bacterial sepsis
Adjunctive immunotherapy assists pathogen elimination
Trials need to be appropriately powered
The proper patient population need to be selected
-
Strategy 1: treat patients with an infection at risk for progression to organ dysfunction through a specific mechanism which is activated. Organ dysfunction has not become apparent and a biomarker which indicates the activation of the specific inflammatory cascade to be inhibited is required. One such example is the on-going INSPIRE trial (Clinicaltrials.gov NCT05785442). This a double-blind RCT in which patients with community-acquired pneumonia (CAP) or hospital-acquired pneumonia (HAP) and circulating presepsin levels of more than 350 pg/ml are randomized to treatment with SoC and placebo or SoC and anakinra for 10 days. The primary endpoint is the progression of the patient to organ dysfunction or death. Organ dysfunction if defined as an increase of the total admission sequential organ failure assessment (SOFA) score by two or more during treatment [28].
-
Strategy 2: treat patients with full-blown sepsis and overt organ dysfunction according to the prevailing pathophysiology. One such example is the on-going ImmunoSep trial (Clinicaltrials.gov NCT01990232) in six European countries (Germany, Greece, Italy, the Netherlands, Romania, Switzerland). This a double-blind, double-dummy RCT in which patients with CAP or HAP or ventilator-associated pneumonia or primary bacteremia are randomized to one arm of SoC and placebo immunotherapy or one arm of SoC and precision immunotherapy. Before randomized patients are screened for the level of immune activation by measurement of blood ferritin and of the expression of HLA-DR on CD14 monocytes. When ferritin is more than 4420 ng/ml, participants are classified into macrophage activation-like syndrome. When ferritin is 4420 ng/ml or less and the absolute count of HLA-DR receptors on CD14 monocytes is less than 5000/cell patients are classified into sepsis-induced immunoparalysis. Patients with MALS (macrophage activation-like syndrome) receive intravenous treatment three times daily with anakinra for 15 days and subcutaneous dummy placebo. Patients with sepsis-induced immunoparalysis receive subcutaneous treatment with rhIFNγ every 48 h for 15 days and intravenous dummy placebo treatment. Patients who cannot be categorized into MALS or sepsis-induced immunoparalysis cannot participate in the study [29]. The used cut-offs of ferritin and HLA-DR for patient classification have been developed by a previous phase IIa trial [30].