The leading role of allergists and clinical immunologists in the fight against SARS CoV-2
There is no doubt that allergists and clinical immunologists should be on the front line in the fight against SARS CoV-2, for different reasons. First, the host immune response is the main mechanism to block the viral infection and attenuate or prevent symptoms6. Second, there is a wide consensus that the progression of the disease to the most severe life-threatening forms is associated with an intense inflammatory process and a cytokine storm5. Third, beyond plasma-based therapy and vaccines, several candidate drugs against SARS CoV-2 are part of the current therapeutic armamentarium of the clinical immunologist and require the expertise of our specialty7.
So far, 26 clinical trials explore the efficacy of Tocilizumab, an anti-IL-6R (sIL-6R and mIL-6R) monoclonal approved for rheumatoid arthritis, giant cell arteritis and the CAR-T induced Cytokine Release Syndrome II-V. Some other monoclonal antibodies targeting IL-1, IL-17A, growth factors, complement factors are listed in Table I.
Beside monoclonal antibodies, several other immunosuppressants and immunomodulators are under investigation. Interferon beta 1a – both intravenously and in an inhaled formulation -, interferon alfa 2a and peginterferon lamda 1A are object of 31 clinical studies. Immunoglobulin and convalescent plasma-based therapy are investigated in 35 trials.
Fifteen registered studiesV are evaluating the use of systemic corticosteroids in COVID-19. Despite concern about possible detrimental effects8,9, there is yet no evidence for or against their use in COVID-19 patients. There is rational to speculate that their safety and efficacy may be different in the early viral phase compared to the late inflammatory phase. Conversely, there is no evidence to withdraw an ongoing treatment with inhaled steroids in subjects with asthma and rhinitis10,11.
Other non-steroid anti-inflammatory drugs and the effect of cytokine filtration devices are also under investigation, particularly in COVID-19 subjects with pneumonia and a severe inflammatory disease7.
More studies on anti-TNF drugs have also been recommended12. Among cell-based therapies, 24 studies plan to investigate the immunomodulatory role of mesenchymal stem cells7. In an in-silico molecular modelling screening of 2000 FDA approved drugs for potential inhibitory effect on SARS CoV-2 main protease enzyme (Mpro), the top hits bound to the central site of Mpro substrate-binding pocket include antiviral drugs such as Darunavir, Nelfinavir and Saquinavir. Interestingly, the top hits bound to the terminal site of Mpro substrate-binding pocket included Montelukast and Fexofenadine13. Independently from the practical impact of the above observation, this strategy appears promising in repositioning available drugs , until novel targeted treatments for COVID-19 are available.
However, despite this intense clinical research and 177 papers (including 4 systematic reviews) on COVID-19 treatment listed by PubMed, evidence available for safe and effective drugs has not progressed at the same speed of the pandemic14. In fact, to our knowledge only very few clinical trials have been published.
The randomized, open-label trial with Lopinavir/Ritonavir in 199 patients with severe COVID-19 failed to meet the primary end-point (time to clinical improvement)15. However, 53 additional studies are investigating the efficacy of Lopinavir/Ritonavir in various severity stages of the diseaseV.
Following the more promising results of a cohort study of patients treated with Redemsivir on a compassionate-use16, both FDA and EMA have permitted the use of this drug in COVID-19. While a randomized double-blind placebo-controlled trial could not confirm a significant benefit of Redemsivir in a cohort of 236 patients – possibly because of the failure to recruit its target of 453 patients17 -, Anthony Fauci anticipated that a larger multi-center trial in over 1000 subjects showed a high significant (<0.001) effect on the primary outcome of the study (i.e. time to recovery, which was reduced from 15 to 11 days)VI. Eleven more trials on Redemsivir are still ongoingV. A few additional published studies with hydroxichloroquine vs best supportive care, favipiravir vs umifenovir, and lopinavir/ritonavir vs umifenovir are reported by Thorlund and co-workers18.