Immune Therapy, or Antiviral Therapy, or Both for COVID-19: A Systematic Review

Abstract

Background: Based on current evidence, recent guidelines of the National Institute of Health, USA indicated the use of remdesivir and dexamethasone for the treatment of COVID-19 patients with mild-moderate disease, not requiring high-flow oxygen. No therapeutic agent directed against the immunologic pathogenic mechanisms related to the cytokine release syndrome complicating the disease was indicated.

Objectives: The purpose of this review was to assess the clinical impact of different therapies for COVID-19; thus, helping to identify the optimal management of the disease. To explain the rationale for the different therapeutic approaches, the characteristics of SARS-CoV-2, the pathogenesis of COVID-19, and the immune response triggered by SARS-CoV-2 infection were reported.

Methods: The efficacy assessment of the different treatments was performed by a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Available English language published articles including randomised controlled trials, open-label trials of antivirals and immune therapies extracted from Medline, Google Scholar, and MedRxiv databases were analysed. For inclusion, the primary end point of the trials had to be the efficacy as measured by the improvement of clinical features, or mortality, or the Intensive Care Unit Admission rate, or the discharge number. Case reports, paediatric studies, and studies without control group were excluded. The literature search was extended up to August 15, 2020.

Results: After the removal of duplicate articles, and the exclusion of studies not meeting the eligibility criteria, 2 trials of lopinavir/ritonavir, 1 of favipiravir, 3 of remdesivir, 1 of dexamethasone, 3 of hydroxychloroquine, 2 of colchicine, 6 of tocilizumab, 1 of sarilumab, 1 of siltuximab, 2 of anakinra, 3 of baricitinib, 1 of ruxolitinib, 1 of mavrilimumab, and 1 of itolizumab were suitable for the review. Among antivirals, only remdesivir significantly reduced the time to recovery, and mortality. Data for chloroquine and hydroxychloroquine were largely inconclusive. In a large trial, dexamethasone 6 mg/day reduced mortality by one-third. Trials of tocilizumab and sarilumab did not definitively demonstrate efficacy. Anakinra significantly reduced the mortality in 2 trials. Three retrospective trials on a cumulative number of 145 patients, reported the efficacy of baricitinib, with significant reduction of intensive care unit admission, and deaths. These results were recently confirmed by the ACTT-2 trial. Due to paucity of studies and to the small size clinical series, the results of other immune therapies were not conclusive.

Conclusions: Beyond the supportive therapy, up to now the best therapeutic approach for COVID-19 may be a three-step combination therapy, including remdesivir 100 mg/day (200 mg loading dose on first day) in the first stage of the disease, and combined dexamethasone 6 mg/day plus baricitinib 4 mg/day to target the immune dysregulation triggered by the SARS-CoV-2 infection. The promising results of anakinra should be confirmed by the ongoing RCTs.

Fig. 1

Most of SARS-CoV-2-infected individuals are asymptomatic or present mild symptoms. According to the CDC, people with the following symptoms may have COVID-19: fever, cough, dyspnoea, repeated chills, muscle pain, sore pain head, sore throat, loss of smell (anosmia) and/or taste (ageusia) and diarrhoea. About 25% percent of these patients will have a seriously ill disease. A small proportion may develop a very severe pneumonia, which may progress to acute respiratory distress syndrome (ARDS) or end-organ failure that may be associated with a cytokine storm syndrome. ESR erythrocyte sedimentation rate, CRP C-reactive protein, LDH lactate dehydrogenase, G-CSF granulocyte colony-stimulating factor, MIP-1a macrophage inflammatory protein 1-a, PT prolonged prothrombin time, TNF-α tumour necrosis factor-α

Fig. 2

SARS-CoV-2 infects mucous membranes expressing high levels of ACE2 as nasal and larynx mucosa, then may pass into the lungs through the respiratory tract. After receptor recognition and viral entry into the ciliated epithelial cells, SARS-CoV-2 replicates the viral genome and encodes structural and non-structural viral proteins. Therefore, new virions are assembled, and released. Active viral replication leads to production of type I interferon (IFN) and influx of neutrophils and macrophages. These cells are the major cell sources of pro-inflammatory cytokines and chemokines as interleukin (IL)-1β, IFN-γ, inducible protein-10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1), which may result in activation of T-helper-1 (Th1) cells. Moreover, IL-17, produced by Th17 cells recruits monocytes and neutrophils to the site of infection contributing to the inflammation. Finally, Th2 cytokines such as IL-4 and IL-10 are also produced with the attempt to suppress the hyper-inflammation. This cytokine storm, as well as the several stages of viral replication, are the target of the current therapies for COVID-19

Fig. 3

Systematic review of efficacy of antivirals in COVID-19: PRISMA flow diagram. All extracted trials, and the reasons for exclusion, are reported in the supplementary material file

Fig. 4

Systematic review of efficacy of anti-inflammatory and immune therapies in COVID-19: PRISMA flow diagram*. *All extracted trials, and the reason for exclusion, are reported in the supplementary material file