Differences in immune responses to emerging corona viruses and the difficulties of developping vaccines contribute to a surge in ARDS in vulnerable populations, leading to acute shortages and disruptions in health care logistics and delivery, notabily in technical and human resources for intensive care (mechanical ventilation and extracorporeal oxygenation). It would therefore interesting to know which pharmacological interventions in early stages of corona virus infections could modulate the immune response in a way to reduce the number of cases with progression to ARDS or mitigate the respiratory complications related to COVID-19, in order to maintain functioning of the health care system and to avoid irrational allocations of resources (e.g.purchasing hundreds of ventilators by institutions which are unable to provide the medical and nursing staff needed to use them). Does anybody know of recent observations that hint at a role of pharmacological interventions which could contribute to improved outcomes?
Lit.
Gralinski LE, Sheahan TP, Morrison TE, et al. Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis. mBio. 2018;9(5):e01753-18. Published 2018 Oct 9. doi:10.1128/mBio.01753-18
Frieman M, Baric R. Mechanisms of severe acute respiratory syndrome pathogenesis and innate immunomodulation. Microbiol Mol Biol Rev. 2008;72(4):672–685. doi:10.1128/MMBR.00015-08
Early/middle stage:
In the middle stage, where symptoms start occurring, fever activates the innate immune system (whereas Covid-19 suppresses it). Furthermore, fever suppresses immune-overreactions via HSP's & NF-kB regulation. Therefore, fever might help fight off the virus, preventing severe complications.
In this stage of the infection, fever should not be mitigated. Therefore, drugs such as paracetamol, aspirin, NSAID's, or any other COX-2-inhibitor, should not be taken. However, individual circumstances might require these kinds of medication anyway. For instance: Amlodipine could be prescribed as BP-lowering medication. Amlodipine also inhibits COX-2, and therefore mitigates fever. If Amlodipine is prescribed, it should not be stopped. Another example would be someone who takes something like Warfarin. Fever might change INR.
Preprint Fever & COVID-19-Complications
Preprint Core warming of coronavirus disease 2019 (COVID-19) patients...
Vitamin D is already mentioned.
Preprint The Role of Vitamin D in Suppressing Cytokine Storm in COVID...
Preprint Vitamin D deficiency: a factor in COVID-19, progression, sev...
Article Evidence that Vitamin D Supplementation Could Reduce Risk of...
severe complication-stage, with Pulmpnary Edema:
- Anti-viral medication (Chloroquine, Remdesivir)
Anti-viral medication, such as (hydroxy)Chloroquin & Remdesivir, has shown some potential. However, I believe that anti-viral medication could potentially have more beneficial effects earlier on, when complications are not yet present. During severe complications, it is mostly the immune-overreaction that needs to be mitigated. Except from some promising preliminary studies, I do not have any hard data regarding viral inhibitors yet. I believe the side effects of Chloroquine were already mentioned.
Ciclesonide has potentially a double beneficial effects on both inflammation & viral inhibition. I believe a preliminary studie was done in Korea, with promising results. However, to my knowledge there is no hard data yet.
Article Remdesivir and chloroquine effectively inhibit the recently ...
Article Hydroxychloroquine and azithromycin as a treatment of COVID-...
Article Chloroquine in COVID-19 the evidence
Article ECG QT interval prolongation in rheumatic patients using ant...
https://academic.oup.com/jmcb/article/doi/10.1093/jmcb/mjaa015/5814654
https://academic.oup.com/jmcb/article/doi/10.1093/jmcb/mjaa014/5814655
- IL-6-inhibitors (Tocilizumab):
IL-6-mediated endothelial cell contraction increases capillary permeability, causing interstitial pulmonary edema (imaging: ground-glass opacity), parenchymal infiltration & alveolar collapse (imaging: consolidations). Therefore, inhibiting IL-6 could possibly mitigate these severe complications. Preliminary research shows the effect of Tocilizumab on pulmonary edema (visible on imaging as decreasing ground-glass opacity). This research is far from perfect, however, and there are serious side effects of IL-6 inhibitors (such as increased risk of secondary infections). There are multiple studies (phase-3-trials) ongoing at the moment, but other than the results from Xu (2020), and anecdotal reports, there is no hard data yet.
Article Interleukin-6 Causes Endothelial Barrier Dysfunction via the...
Preprint Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis
Article Tocilizumab, an anti-IL-6 receptor antibody, to treat COVID-...
Article Tocilizumab treatment in COVID-19: A single center experience
https://www.biorxiv.org/content/10.1101/2020.04.08.029769v1
http://www.chinaxiv.org/abs/202003.00026
- B2R blockers (Icatibant):
Bradykinin (BK), formed by Kallikrein, also increases capillary permeability, and therefore contributes to pulmonary edema . BK-dependent pulmonary edema is resistant to corticosteroids (or adrenaline). ACE-2, next to its role in RAAS, also inactivates a BK-variant (that acts mostly on B1R in the lungs). Therefore, Ace-2 mitigates pulmonary edema . Covid-19 reduces ACE-2, thereby increasing BK, which subsequently increases pulmonary edema (linking the virus directly to pulmonary edema ). Comorbidities (such as diabetes) also reduce ACE-2, thereby contributing to pulmonary edema . Blocking the B1R and B2R receptors (or the upstream Kallikrein-process) might mitigate severe complications. Icatibant is a selective B2R-inhibitor (Firazyr). There have been some preliminary good results using Icatibant on covid-19 patients. However, once again, there is no hard data yet (that I know of).
Preprint Kinins and Cytokines in COVID-19: A Comprehensive Pathophysi...
Article Attenuation of pulmonary ACE2 activity impairs inactivation ...
http://www.journalrip.com/Files/Inpress/jrip-18698.pdf
- C5-blockers (Eculizimab)
The complement-system activation possibly plays a role in this stage of the disease as well, and C5 blockade (with Eculizimab) might also help (studies are ongoing at the moment).
Preprint Highly pathogenic coronavirus N protein aggravates lung inju...
Article Will Complement Inhibition be the New Target in Treating COV...
https://hudsonmedical.com/articles/soliris-stop-death-covid-19/
https://www.medrxiv.org/content/10.1101/2020.03.29.20041962v2
- C1-blockers (Ruconest)
C1-blockers not only downregulate the complement system, but also downregulate BK through inhibition of the upstream Kallikrein-process. I believe there are some preliminary good results using Ruconest on covid-19 patients. A clinical trial is ongoing at the moment.
https://www.perssupport.nl/persbericht/210420022/pharming-reports-encouraging-results-from-use-of-ruconest-r-in-covid-19-patients
Article C1-esterase inhibitor: An anti-inflammatory agent and its po...
Article The Influence of ACE Inhibition on C1-Inhibitor: A Biomarker...
So, in short, there are a lot of potential mitigating factors, and even though some preliminary studies have been done (with promising results), there is no hard data available (that I know of). I am probably still missing a lot though...
Dear Hans,
unfortunately I don´t have any suggestion for modulating immune response in COVID-19; however, past few days I really think about treatment of ARDS by exogenous surfactant. It seems that SARS-CoV-2 uses ACE2 as a portal of entry into the lungs and I have found that more than 80% of pulmonary ACE2 are situated on type II alveolar epithelial cells - those producing pulmonary surfactant. Regarding our research, strong inflammation impairs pulmonary surfactant function seriously in many many ways and if there are no functioning pneumocytes to produce new, this can cause respiratory failure which is hardly manageable only by ventilatory support.
I try to spread this idea to suggest exogenous surfactant treatment in those seriously ill. Maybe it could help.
Jana
Stellate ganglion block in order to prevent sympathetic nervous system hyperactivity?
This is an interesting question. COVID-19 is associated with ARDS and septic shock. However, there is some suggestion that beta-blockade may improve outcomes in patients with septic shock and reduce the incidence of ARDS. This is currently being investigated in the STRESS L trial which uses an infusion of the short acting beta blocker landiolol.
Rajkumar Rajendram Thanks for the hint. Here ist the link to the trial you mentionned: https://doi.org/10.1186/ISRCTN12600919
Thank you Hans-Ulrich Iselin
When considering the use of betablockers in patients with respiratory disease it is important to recognise that the lungs predominantly have B2 receptors whilst the heart predominantly has B1 receptors.
So, B1 selective beta-blockade is not contra-indicated in patients at risk of bronchospasm. However it is recommended that PEF and symptoms are monitored of patients with asthma and COPD started on beta-blockers. In critically ill patients on invasive mechanical ventilation changes in airway compliance can be monitored.
Thanks for this important question
I agree with the protocol of the combination of:
hydroxychloroquine + azithromycine
which is actually applied in our country MOH and university hospitals
Hesham A Abdelhalim Dear colleague, thank you for your answer which confirms the special interest of the association of hydrochloroquine and azithromycine in the ongoing clinical trials. While clear concepts of the mechanisms of immunomodulation induced by chloroquin and hydrochloroquin are emerging in the literatur, the role of azithromycin remains unclear. To efficiently combat new coronarviruses, we need a world-wide comprehensice efforts to understand the molecular pathways we act on. The attitude of the scientific community - even in the midst of the pandemic - must be guided by the will not only by the quest for efficacy in terms of health economics, but by the will to understand the mechanisms through which the effect ist achieved. That might sound old-fashioned but it has been a cornerstone for medical thinking since Hippocrates, Ibn Rushd, Andreas Vesalius, William Harvey, Claude Bernard and so many others.
Dear researchers, in N. Italy there is an incredible violent outbreak of this new disease, but now with traits very similar to SARS-2002 and MERS that the current COVID19 sensu Wuhan-Hubei, particularly for death rate and severity. This RG open question aim to recognize some of the underlying causes of this aberrant phenomenon https://www.researchgate.net/post/The_novel_Coronavirus_in_N_Italy_Lombardia_COVID19_2019nCoV_SARSCoV2_shows_a_fatality_rate_compatible_with_SARS_Why2
Variations of Vit D status could be interesting and at least partially explain tremendous variations in clinical picture and outcome. In the last decade we also have global vit d deficiency pandemic, while vit D is known as a immunomodulatory agent. Some studies suggested and direct antiviral effect. Recent study on animal model of ARDS (induced by LPS and mediated by cytokine storm) showed protective effect of vit D treatment, reducing lung permeability and modulating RAS. Metha analyses also showed increased risk of respiratory infections among vit d deficient subjects.
Vit D is pretty safe (some clinical trials gave 40000 IU for two weeks without adverse effects), and, in my opinion, intense supplementation (even without finished clinical trials ; one is ongoing with single dose of 25000)would be reasonable. Up to 25000 IU / day, in my opinion, is safe and complies primum non nocere principle.
Early/middle stage:
In the middle stage, where symptoms start occurring, fever activates the innate immune system (whereas Covid-19 suppresses it). Furthermore, fever suppresses immune-overreactions via HSP's & NF-kB regulation. Therefore, fever might help fight off the virus, preventing severe complications.
In this stage of the infection, fever should not be mitigated. Therefore, drugs such as paracetamol, aspirin, NSAID's, or any other COX-2-inhibitor, should not be taken. However, individual circumstances might require these kinds of medication anyway. For instance: Amlodipine could be prescribed as BP-lowering medication. Amlodipine also inhibits COX-2, and therefore mitigates fever. If Amlodipine is prescribed, it should not be stopped. Another example would be someone who takes something like Warfarin. Fever might change INR.
Preprint Fever & COVID-19-Complications
Preprint Core warming of coronavirus disease 2019 (COVID-19) patients...
Vitamin D is already mentioned.
Preprint The Role of Vitamin D in Suppressing Cytokine Storm in COVID...
Preprint Vitamin D deficiency: a factor in COVID-19, progression, sev...
Article Evidence that Vitamin D Supplementation Could Reduce Risk of...
severe complication-stage, with Pulmpnary Edema:
- Anti-viral medication (Chloroquine, Remdesivir)
Anti-viral medication, such as (hydroxy)Chloroquin & Remdesivir, has shown some potential. However, I believe that anti-viral medication could potentially have more beneficial effects earlier on, when complications are not yet present. During severe complications, it is mostly the immune-overreaction that needs to be mitigated. Except from some promising preliminary studies, I do not have any hard data regarding viral inhibitors yet. I believe the side effects of Chloroquine were already mentioned.
Ciclesonide has potentially a double beneficial effects on both inflammation & viral inhibition. I believe a preliminary studie was done in Korea, with promising results. However, to my knowledge there is no hard data yet.
Article Remdesivir and chloroquine effectively inhibit the recently ...
Article Hydroxychloroquine and azithromycin as a treatment of COVID-...
Article Chloroquine in COVID-19 the evidence
Article ECG QT interval prolongation in rheumatic patients using ant...
https://academic.oup.com/jmcb/article/doi/10.1093/jmcb/mjaa015/5814654
https://academic.oup.com/jmcb/article/doi/10.1093/jmcb/mjaa014/5814655
- IL-6-inhibitors (Tocilizumab):
IL-6-mediated endothelial cell contraction increases capillary permeability, causing interstitial pulmonary edema (imaging: ground-glass opacity), parenchymal infiltration & alveolar collapse (imaging: consolidations). Therefore, inhibiting IL-6 could possibly mitigate these severe complications. Preliminary research shows the effect of Tocilizumab on pulmonary edema (visible on imaging as decreasing ground-glass opacity). This research is far from perfect, however, and there are serious side effects of IL-6 inhibitors (such as increased risk of secondary infections). There are multiple studies (phase-3-trials) ongoing at the moment, but other than the results from Xu (2020), and anecdotal reports, there is no hard data yet.
Article Interleukin-6 Causes Endothelial Barrier Dysfunction via the...
Preprint Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis
Article Tocilizumab, an anti-IL-6 receptor antibody, to treat COVID-...
Article Tocilizumab treatment in COVID-19: A single center experience
https://www.biorxiv.org/content/10.1101/2020.04.08.029769v1
http://www.chinaxiv.org/abs/202003.00026
- B2R blockers (Icatibant):
Bradykinin (BK), formed by Kallikrein, also increases capillary permeability, and therefore contributes to pulmonary edema . BK-dependent pulmonary edema is resistant to corticosteroids (or adrenaline). ACE-2, next to its role in RAAS, also inactivates a BK-variant (that acts mostly on B1R in the lungs). Therefore, Ace-2 mitigates pulmonary edema . Covid-19 reduces ACE-2, thereby increasing BK, which subsequently increases pulmonary edema (linking the virus directly to pulmonary edema ). Comorbidities (such as diabetes) also reduce ACE-2, thereby contributing to pulmonary edema . Blocking the B1R and B2R receptors (or the upstream Kallikrein-process) might mitigate severe complications. Icatibant is a selective B2R-inhibitor (Firazyr). There have been some preliminary good results using Icatibant on covid-19 patients. However, once again, there is no hard data yet (that I know of).
Preprint Kinins and Cytokines in COVID-19: A Comprehensive Pathophysi...
Article Attenuation of pulmonary ACE2 activity impairs inactivation ...
http://www.journalrip.com/Files/Inpress/jrip-18698.pdf
- C5-blockers (Eculizimab)
The complement-system activation possibly plays a role in this stage of the disease as well, and C5 blockade (with Eculizimab) might also help (studies are ongoing at the moment).
Preprint Highly pathogenic coronavirus N protein aggravates lung inju...
Article Will Complement Inhibition be the New Target in Treating COV...
https://hudsonmedical.com/articles/soliris-stop-death-covid-19/
https://www.medrxiv.org/content/10.1101/2020.03.29.20041962v2
- C1-blockers (Ruconest)
C1-blockers not only downregulate the complement system, but also downregulate BK through inhibition of the upstream Kallikrein-process. I believe there are some preliminary good results using Ruconest on covid-19 patients. A clinical trial is ongoing at the moment.
https://www.perssupport.nl/persbericht/210420022/pharming-reports-encouraging-results-from-use-of-ruconest-r-in-covid-19-patients
Article C1-esterase inhibitor: An anti-inflammatory agent and its po...
Article The Influence of ACE Inhibition on C1-Inhibitor: A Biomarker...
So, in short, there are a lot of potential mitigating factors, and even though some preliminary studies have been done (with promising results), there is no hard data available (that I know of). I am probably still missing a lot though...
Martijn, thans so much. I did not tell you but I have been reading each of the cites you put up here. I am very interested in the first part: how to augment our defenses. Shall give a talk on that in 4 days, and your tips helped me quite a lot. thanks!! keep safe
This may be obvious, but it is necessary to investigate our severe patients with D-dimer dosage and spiral angioscan rather than non-injected CT. Heparin may improve them.
Denis Boutry thanks for this interesting contribution. Direct endothelial damage by the virus may be at the origin of the hypercoagulation observed in certain COVID-19 patients.
In order to answer your question more directly, 2 drugs seem to be distinguishable, ivermectin and tocilizumab.
Traci L Testerman Thank you very much for your answer to my question. If I understand you well, you recommend to look for the "window of opportunity" antiinflammatory action between reigning in viral replication and inflammatory response. This window of opportunity might have been played a role in the benign course described by Valentina Spezzani et al in https://smw.ch/article/doi/smw.2020.20246
It would be a pleasure and an honour for the authors of the case report if you would comment directly on your recommendation concerning abemaciclid effects on Swiss Medical Weekly's online discussion forum. The simplistic clinical concept of "immunosuppression" based on granulocytopenia has to be questionned. While it has proved useful for the management of bacterial infections, it seems to be completely inappropriate for viral infections of the type we are discussing here.
Sorry, I forgot the DOI. Here it is: Article Benign COVID-19 in an immunocompromised cancer patient - The...
Broadly speaking COVID-19 is more severe if either
1: immune deficiency significantly reduces host response to the virus
OR
2: hyperimmune response results in a 'cytokine storm'
In the first scenario patients may benefit from antivirals and convalescent plasma.
In the second scenario patients may benefit from immune suppression with steroid or tocilizumab.
Rajkumar Rajendram Thanks for this concise answer. The central problem will remain the identification of the individual tuning of the immune system during the incubation period (innate immune response plus the various drugs that are used - and may interact with the immune system - during this clinically silent phase).
Corticosteroids. Given their effective anti-inflammatory properties, there has been extensive interest in the potential role of corticosteroids in both the prevention and treatment of ARDS. Different regimens have been investigated, varying from short courses of high-dose steroids to prolonged courses of lower doses
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