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.