Immune responses to infections with by a corona virus vary widely and are appear to be related to the development of most severe complication, acute respiratory distress syndrome. Since survival of patients respondingto the virus in this way depends on respirators support, mechanical ventilation and extracorporeal oxygenation, therapeutic methods which demand highly specialized medical and nursing staff, human resources which become scarce in an epidemic or pandemic. Since vaccination are not available in newly emerging corona virus epidemics it would be interesting to know if and which targeted pharmacological modulation of immune response early in the course of an infection could help to reduce the need for intensive care and/or improve the outcome of respiratory support.
Hi,
Is interesting to raise a question:
Why is impossible until now to create a vaccine anti COVID-19, or vaccine anti SARS or Vaccine anti MERS or vaccine anti HIV.
WHY???
Is known vaccines anti Gripp.
Only an element is known:
Scientists can create vaccines counter viruses because they have DNA, BUT, to create a vaccines counter retroviruses that have RNA is impposible until now.
Where is problem in these cases?
Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility
Article Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 ...
Trial assesses tissue plasminogen activator as a treatment for COVID-19-related respiratory failure
https://www.news-medical.net/news/20200408/Trial-assesses-tissue-plasminogen-activator-as-a-treatment-for-COVID-19-related-respiratory-failure.aspx
Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility
Article Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 ...
Trial assesses tissue plasminogen activator as a treatment for COVID-19-related respiratory failure
https://www.news-medical.net/news/20200408/Trial-assesses-tissue-plasminogen-activator-as-a-treatment-for-COVID-19-related-respiratory-failure.aspx
Covid-19 is generally a mild, self-limiting illness.
In a small percentage of cases it is severe (i.e. causes respiratory failure) or critical (i.e. causes multi-organ failure).
The availability of healthcare in general and specifically critical care will affect the case fatality rate of these patients. In China and Italy where large numbers of healthcare professionals were infected the capacity to deliver healthcare was substantially reduced. So excess deaths occurred.
The cause of respiratory failure has not, at present, been fully elucidated. There are several theories currently under investigation. However a systemic inflammatory response results in the progression to multi-organ failure.
The patients who are dying are generally those with impaired immunity. These patients are dying because of the damage the virus is causing to their bodies.
These patients may benefit from improved immunity.
However, some apparently normal patients are dying. I suspect that these
patients are dying from an exaggerated immune response (i.e. cytokine storm and other pathological immune responses). Boosting the immunity of these patients may actually exacerbate the disease!!
This is a very dynamic situation and the answers to this question may be completely different tomorrow.
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 clinical trials finished; one is ongoing with single dose of 25000)would be reasonable.
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.
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
Ciclesonide has potentially a double beneficial effect 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.
Preprint The inhaled corticosteroid ciclesonide blocks coronavirus RN...
Article A Case of Coronavirus Disease 2019 Treated With Ciclesonide
Preprint Identification of antiviral drug candidates against SARS-CoV...
http://www.koreabiomed.com/news/articleView.html?idxno=7807
- 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 PE 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...
What if we could lower down the rate of mitosis for some time, would it lower down the virus expansion and allow the immune system to cope with it and follow up? Maybe the greater benefits than damage?
Patients on chemotherapy are on "lowered mitotic rate", but prognosis for them is poor.
@ Martijn, HSPs could be possible double-sword, because effect on immune system can depend on dose (induced level), especially for HSP90 (gp96), which is one of the most potent immunomodulator. The right amount at the right time is crucial.
Recombinant HSPs could be noteworthy as adjuvans in the context of vaccine development.
What about slowing down the metabolism? We need to find a way to slow down the division - expansion of virus count and it can be done only by affecting our cells, I believe. I am thinking about something that should be done at this moment. The vaccine is a ''long way from home'' for the time being. Thinking about people being at the edge of life right now...
Look for this articlehttps://www.thegreenjournal.com/article/S0167-8140(20)30185-7/fulltext
I have contacted a Head of one of the departments of an oncology clinic in Belgrade and sent the article. She said that even at that dose the immune response would be compromised too much and allow virus to progress. And as it was pointed out the fear of bringing an infected person and the risk for those patients that are treated for cancer diseases is far too great... All the best...
Who are specific imunoglobulins that in reased during a RNA virus infection?
Who are specific immunoglobulins that are increased during and after an RNA virus inection?
Detection of Immunoglobulin M (IgM), IgA, and IgG Norwalk Virus-Specific Antibodies by Indirect Enzyme-Linked Immunosorbent Assay With Baculovirus-Expressed Norwalk Virus Capsid Antigen in Adult Volunteers Challenged With Norwalk Virus
Thanks Mr. Pirro. I still have no answer from the Oncologist so I cannot say anything. Yet we are speaking about pneumonia with different factors that might have cause it. When we speak about the one caused by Corona virus we don't have any information on how or at which progression would the virus stop its reproduction radiated by 30 - 100 cGy or if it could make any changes in its structure but rather progress the failure of the immune system as I was told. The bacteria may show signs of reduction in number growth or total eradication as their structure and replication ids different. I see in the research the viral pneumonia was treated yet which kind of virus was it and what was the health status and age of those treated. Personally I would recommend to those deciding on the faith of people on ventilators with bad prognosis to try this treatment. All the best and thanks once again.
Pirro Prifti: interesting suggestion. It reminds me of the interest of my grandfather, the surgeon Hans Iselin (1878-1953), for the use of X-ray in treatment of inflammatory processes and neoplasms, which led to 2 publications ins 1910 and 1927:
1) ISELIN, H. (1910) Von der Behandlung der Knochen- und Gelenkstuberkulose mit Röntgenlicht. Deutsche Zeitschrift f. Chirurgie 103, 483–515 (1910). https://doi.org/10.1007/BF02866615,
2) ISELIN, H.(1927) The Treatment of Cancer of the Breast by X-rays after Operation. Proceedings of the Royal Society of Medicine. 1927 Nov;21(1):53-61.PMID: 19986151 PMCID: PMC2101800
look this interesting article:
https://www.europeanscientist.com/en/big-data/no-sars-cov-2-does-not-contain-hiv-genetic-code/
Look this article about lack of vitamin D and grave cases with covid-19:
https://www.gismeteo.ru/news/coronavirus/uchenye-svyazali-smertnost-ot-koronavirusa-i-nedostatok-vitamina-d/?utm_medium=referral&utm_source=lentainform&utm_campaign=l.gismeteo.ru&utm_term=1280476&utm_content=1