Preprint Hypothesis Version 1 Preserved in Portico This version is not peer-reviewed

Kinins and Cytokines in COVID-19: A Comprehensive Pathophysiological Approach

Version 1 : Received: 1 April 2020 / Approved: 3 April 2020 / Online: 3 April 2020 (04:13:43 CEST)

How to cite: van de Veerdonk, F.; Netea, M.G.; van Deuren, M.; van der Meer, J.W.; de Mast, Q.; Bruggemann, R.J.; van der Hoeven, H. Kinins and Cytokines in COVID-19: A Comprehensive Pathophysiological Approach. Preprints 2020, 2020040023 (doi: 10.20944/preprints202004.0023.v1). van de Veerdonk, F.; Netea, M.G.; van Deuren, M.; van der Meer, J.W.; de Mast, Q.; Bruggemann, R.J.; van der Hoeven, H. Kinins and Cytokines in COVID-19: A Comprehensive Pathophysiological Approach. Preprints 2020, 2020040023 (doi: 10.20944/preprints202004.0023.v1).

Abstract

Most striking observations in COVID-19 patients are the hints on pulmonary edema (also seen on CT scans as ground glass opacities), dry cough, fluid restrictions to prevent more severe hypoxia, the huge PEEP that is needed while lungs are compliant, and the fact that anti-inflammatory therapies are not powerful enough to counter the severity of the disease. We propose that the severity of the disease and many deaths are due to a local vascular problem due to activation of B1 receptors on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2, a cell membrane bound molecule with enzymatic activity that next to its role in RAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the bradykinin receptor type 1 (B1). In contrast to bradykinin receptor 2 (B2), the B1 receptor on endothelial cells is upregulated by proinflammatory cytokines. Without ACE2 acting as a guardian to inactivate the ligands of B1, the lung environment is prone for local vascular leakage leading to angioedema. Angioedema is likely a feature already early in disease, and might explain the typical CT scans and the feeling of people that they drown. In some patients, this is followed by a clinical worsening of disease around day 9 due to the formation antibodies directed against the spike (S)-antigen of the corona-virus that binds to ACE2 that could contribute to disease by enhancement of local immune cell influx and proinflammatory cytokines leading to damage. In parallel, inflammation induces more B1 expression, and possibly via antibody-dependent enhancement of viral infection leading to continued ACE2 dysfunction in the lung because of persistence of the virus. In this viewpoint we propose that a bradykinin-dependent local lung angioedema via B1 and B2 receptors is an important feature of COVID-19, resulting in a very high number of ICU admissions. We propose that blocking the B1 and B2 receptors might have an ameliorating effect on disease caused by COVID-19. This kinin-dependent pulmonary edema is resistant to corticosteroids or adrenaline and should be targeted as long as the virus is present. In addition, this pathway might indirectly be responsive to anti-inflammatory agents or neutralizing strategies for the anti-S-antibody induced effects, but by itself is likely to be insufficient to reverse all the pulmonary edema. Moreover, we provide a suggestion of how to ventilate in the ICU in the context of this hypothesis.

Subject Areas

COVID-19; bradykinin; ACE2; pulmonary angioedema; ARDS; icatibant

Comments (43)

Comment 1
Received: 5 April 2020
Commenter: Paolo Madeddu
The commenter has declared there is no conflict of interests.
Comment: The hypothesis suggested by the paper is sound but several other considerations should be made on the use of receptor blockade 1. Many patients manifest severe complication associated with DIC which could be caused by activation of the plasma kallikerin coagulation system. Upstream blockade of tissue and plasma kallikrein could be a more effective way to inhibit angiooedema and DIC than kinin antagonists 2. Our articles in Circulation 2002 -2004 showed that both B1 and B2 receptors are indispensable in tissue healing during ischemia. Blocking them could worsen the recovery during ischemia and vascular damage. Therefore the indiscriminate use of antagonists is not justified until guidelines are put in place 3. Chemokines and cytokines other than kinins could be involved and they could act also after lining blockade 4. All the scientific community should be encouraged to generate hypothesis like the one here and expert in kallikrein kinin should participate - I am keen to help having published before on this topic Best regards Paolo Madeddu
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Response 1 to Comment 1
Received: 9 April 2020
Commenter: Frank van de Veerdonk
The commenter has declared there is no conflict of interests.
Comment: Indeed, there is more to it. Plasma leakage sets the main stage for further complications It is alo becoming apparent that later in the disease especially on ICU patients will start to develop microthrombosis of the small vessels and eventually some will progress to fibrosis, which are predominantly men and cardiovascular, and eventually die. These thrombotic angiopathy is also accompanied by an endothelitis which has been observed in autopsies. The local plasma leakage and inflammation will trigger the contact system and release of tissue factor (TF), this occurs in the first phase of disease in the subendothelial compartment. However, with longer presence of plasma and fibrin formation there will ultimately be more extensive fibrin formation and clot formation obstructing the small bloodvessels in the lung. Together with the local endothelitis this can progress to larger vessels. This is a unique situation of a thrombotic angiopathy due long standing angioedema and activation of the contact system and TF release, which has overlaps but is not a classical DIC nor it is like TTP/HUS (we measured haptoglobin and they are all high). The next stage is around 3-5 weeks of illness where there is extensive damage to the lung, plasma leakage continues, thrombo-microangiopathy is present and finally fibrotic reaction is triggered and progresses to true fibrosis. I agree we should target kallikrein-activity instead of blocking only B2R or B1R.
Response 2 to Comment 1
Received: 11 April 2020
Commenter: Mark Bosman
The commenter has declared there is no conflict of interests.
Comment: Hello Doctors, not being a doctor but a chemist. I was promoting Chloroquine and Hydrochloroquine begin Jan already because it raises the pH of the virus cells and breaks the protein (ordinary denaturation process of proteins). But the now identified bradykinine is also family of the kinines and CQ and HCQ are also kinine derivatives ( look to the tail amine structure is the same as in all kinine derivatives, actually you can synthesise all starting from the same amine). being theory but as being a strong believer in "first kill" it than cure it, you should apply multiple strategy to prevent the virus to infect too much healthy cells before this " bradykinine" effect starts in. So it is all centered around the ACE2 receptor mechanisms. 1) Lung/liver have a lot of these receptors 2) fat cells have a lot of these receptors. Funny enough , I read all scienetific reports about SARS,SARS2,SARS2-19 and all of them report that these virusses are extremely good at attaching to the ACE2 receptors. Another mechanism which lowers the amount of ACE2 receptors in cells is the Day-Night rythum which is reported in several studies in US in 2015 when researcher investigated SARS2 and even changed the virus into actually what is today and they reported severe lung problems in the mice they injected with this "new" virus. They also autopted these mice and found the bleeding of lung cells and vains what you see now today in your patients. So in my view we see happening what we already had in front of us in 2015. This research was blocked in US and proceeded in the University of WUHAN !....their they continued the mechanism of ACE2 and effects and actually reported treatment of the mice with CQ/HCQ/Virus blockers etc. One of these was also MELATONINE !....It reduces the amount of ACE2 proteins in cells and so they found it reduces the ability of the virus to attached to any cell espcially the targeted lung cells. So assume you all believe it comes from BATS....what do bats have...They are BLIND and live at night so BATS have natural protection to ACE2 attacking virusses !!!....PANGOLINS are night animals so have natural protection against ACE2 attacking virusses.. WHAT are humans...DAY animals so we have to low MELATONINE during the day......My suggestion is to apply ASAP the following medication strategy on patient who still have chance to get the medication : 1) CQ or HCQ ( monitor glucose level, just give them SUGAR) 2) MELATONINE 3) KEEP THEM ALL IN THE DARK instead of the BLUE light of HOSPITALS which actiually reduces MELATONINE 4) START THIS MEDICATION NOT WHEN THEY GO FROM normal to IC...Give it the moment somebody enters the hospital. I believe all doctors in hospital are trained to save lives and do whatever it takes to save a life so please START ACTING NOW and dont wait till the RIVM or any other goverment controlled institution tells you.....In groningen they didnt listend to RIVM and see what happens !!!!....So again KILL THE VIRUS FIRST...THE CURE WILL COME LATER
Response 3 to Comment 1
Received: 12 April 2020
Commenter: Zev Waldman
The commenter has declared there is no conflict of interests.
Comment: I would be curious about the authors' thoughts on use of ecallantide, a kallikrein inhibitor also sometimes used for hereditary angioedema. Also, could there potentially be a role for endotracheal (or nebulized) installation of any of the proposed therapies (e.g., icatibant or recombinant ACE2)?
Response 4 to Comment 1
Received: 17 April 2020
Commenter: Peter CM van de Kerkhof
The commenter has declared there is no conflict of interests.
Comment: The paper describes a valuable integration of scientific data , clinical observations in the care of patients with COVID-19 and analogies with other diseases, such as angiooedema and the cough by ACE inhibitors. The discussion in the journal is productive and the interaction helps in scientific communication. What is needed is a research agenda, integrating various ideas and have a robust scientific approach. The WHO has set a research agenda for COVID-19. Are your insights part of this agenda and what are the next steps of your great hypothesis in the international context?
Response 5 to Comment 1
Received: 23 April 2020
Commenter: Cerdan
The commenter has declared there is no conflict of interests.
Comment: Hello from France i m à membre of reacting inserm France Last monday i told the same hypothesis In havé some measurements of bradykinin wich are normal so to confirm it we need to havé some measurements of des arg9 bradykinin If you have this measurements could you transfer to me the results please See you soon
Comment 2
Received: 5 April 2020
Commenter: nicole boxer
The commenter has declared there is no conflict of interests.
Comment: There is some theoretical basis that this might work. There are illustrative cases where ace inhibitors cause angioedema and can be treated with icatibant as well as hereditary angioedema. We should be testing this on Covid 19 patients who would otherwise be made do not resuscitate due to health worker or ventilator shortage.
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Response 1 to Comment 2
Received: 9 April 2020
Commenter: Frank van de Veerdonk
The commenter has declared there is no conflict of interests.
Comment: We thank you for his comment. This is exactly what we have been doing since we formulated the hypothesis. We are performing a explorative clinical trial with icatibant in COFID19 patients who are in need of oxygen therapy and have pulmonary edema.
Response 2 to Comment 2
Received: 17 April 2020
The commenter has declared there is no conflict of interests.
Comment: Treating patients with 2019 n-coronavirus disease.

The report by Huang and colleagues documents the severity of the acute lung injury that affects hospitalized patients infected with a new coronavirus (2019-nCoV)1. All of their 41 patients had pneumonia and abnormalities on chest CT scans, and more than half had no underlying disease. The clinical spectrum of nCoV illness will eventually be determined, but in the meantime, could anything be done to reduce its severity, especially its case fatality rate? The answer may be hidden in plain sight. ACE2 is the tissue receptor for nCoV, as it is for the SARS virus2. Importantly, inexpensive generic drugs like angiotensin receptor blockers3 and statins4 are known to up regulate ACE2 and surprisingly this can reduce the severity of acute respiratory distress syndrome (ARDS). Both drugs improve the host response to infection by targeting, among other things, the ACE2/angiotensin-(1-7)/Mas signaling axis that underlies the endothelial dysfunction seen experimentally and clinically in ARDS and other forms of acute critical illness. In 2014, combination statin/ARB treatment appeared to lead to “remarkable improvement” in patients with Ebola virus disease in Sierra Leone5. Unfortunately, these findings were incompletely and unconventionally documented and they have been ignored or dismissed by investigators and health officials. Nonetheless, if convincing evidence could be obtained for the effectiveness of this treatment in nCoV-infected patients, it would not only improve their prospects for survival, it might also suggest a syndromic approach to treating patients with pandemic influenza and other emerging infectious diseases.

We declare no competing interests.

David Fedson, Steven Opal, Ole Martin Rordam.

Sergy Haut, France (DF), Alpert School of Medicine of Brown University (SO), Trondheim Norway (OMR)


1. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2019, doi.org/10.1016/50140-6736(20)30183-5.

2. Kuba K, Imai Y, Penninger JM. Angiotensin-converting enzyme 2 in lung diseases. Curr Opin Pharmacol 2006; 6: 271-76.

3. Wösten-van Asperen RM, Lutter R, Specht PA, et al. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist. J Pathol 2011; 225: 618-27.

4. Tikoo K, Patel G, Kumar S, et al. Tissue specific up regulation of ACE2 in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications. Biochem Pharmacol 2015; 93: 343-51.

5. Fedson DS. Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola. Ann Transl Med 2016; 4: 421.
Comment 3
Received: 9 April 2020
Commenter: Katrien Grünberg
The commenter has declared there is no conflict of interests.
Comment: In addition to the hypothesized direct vasoactive role of bradykinin I would like to point at a second effect of bradykinin, which is stimulating unmyelinated sensory nerves, thereby driving neurogenic inflammation (excellent review by Groneberg et al.1). Such sensory nerves, abundant in the lungs, in turn release tachykinins which are then modified into various neuropeptides. Several of these are vasoactive (e.g. substance P; activity similar to bradykinin), and/or pro-inflammatory. Another neuropeptide, CGRP produces vasodilation in a concentration-dependent manner; an effect that has been shown to be inhibited by an NSAID. Neuropeptides bind to NK receptors 1,2, or 3. Both bradykinin and tachykinins are degraded by ACE and by neutral endopeptidase (NEP). Hence, the hypothesis of COVID-19 increasing bradykinin levels would also apply to tachykinins. NEP is present in epithelium, and epithelial damage has been shown to reduce NEP and, hence, enhance neurogenic inflammation. An alternative approach would be to inhibit the release of tachykinins at the pre-junctional level, for example by targeting for example the inhibitory opiod (OP3)- or histamin (H3) receptors. And finally, based on research in RS virus, one could hypothesize that SARS CoV2, similar to RS-virus, has a direct effect enhancing neurogenic inflammation by a viral protein causing posttranscriptional modification of tachykinins, resulting in the formation of a proinflammatory so-called “virokine”(2). Taken together neurogenic inflammation and its downstream targets should be taken into account when investigating the role of ACE2 and bradykinin in COVID19.
1: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1398-9995.2004.00665.x
2: https://www.jbc.org/content/278/47/46854.long
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Response 1 to Comment 3
Received: 20 April 2020
Commenter: Dernis van Eenennaam
The commenter has declared there is no conflict of interests.
Comment: I express my respect for the posting of this article and the opportunity to comment on it.
Very interesting if there is a comparability with RS, there is also a comparability with BRSV (RS in cattle). Veterinary medicine is far ahead in some areas because it does not have the same ethics as humans. In the event of an outbreak of BRSV, vaccination (intramuscularly) with a vaccine drastically reduced the health of the animals.
A vaccination of the vaccine in the trachea improved within hours and stopped the outbreak.
I practiced this more than 20 years ago. Recently, research in humans has shown that airway vaccination may be more effective.

Is it possible that a vaccine occupies the ACE2 receptors and the process interrupts the circle?

I am well aware that there is no vaccine available. My line of thought is based on "infection" with patient's own viruses that have been killed by, for example, microwaves and are placed back in the airways or a kind of dialysis of the air. In a hospital and certainly with corona contamination, equipment must be available to do this.
I apologize for thinking far beyond all limits
Comment 4
Received: 11 April 2020
The commenter has declared there is no conflict of interests.
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Comment 5
Received: 11 April 2020
Commenter: Tim Young
The commenter has declared there is no conflict of interests.
Comment: I have just read about your research in Financial Times comments: https://www.ft.com/content/c59a385f-62e1-42a2-b8ac-2ecb44305e4e?commentID=c0ed3be3-21ee-42fd-aa19-2b90770f8205

And, finding it interesting, looked up bradykinin in Wikipedia, which says that a sign of excess bradykinin is a "dry cough", which is what those infected by COVID-19 commonly report, which may suggest that you are onto something. Well done!

Moreover, Wikipedia also states that green tea is a bradykinin inhibitor, and, while I have no idea about how powerful the effect of green tea may be, I would note that Japan's reported deaths from COVID-19 are remarkably low, and that green tea, including very strong types like matcha, is heavily consumed in Japan, especially by older people.
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Comment 6
Received: 11 April 2020
Commenter: Eddy Risseeuw
The commenter has declared there is no conflict of interests.
Comment: I am wondering whether patients who are on an ACE inhibitor medication to lower their blood pressure are at a higher risk of developing pulmonary edema with Covid-19 than patients who take other medications.
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Comment 7
Received: 12 April 2020
Commenter: Sylvia van Manen
The commenter has declared there is no conflict of interests.
Comment: One of the related articles is that of Constanza Emanueli et al, about the bradykinin B1 receptor in spontaneously hypertensive rats (SHR).
In 1992 an article has been published titled 'The effect of treatment with Vitamin D3 on the responses of the duodenum of SHR on bradykinin and to potassium', in which is concluded that vitamin D treatment of SHR has an effect on the duodenum smooth muscle which might be due to calmodulin-dependent activation of calcium-dependent potassium channels. 1)
Should we not start with a high dose of Vitamin D3 for all Covid-19 patients, taken into account the higher probability of vitamin D deficiency in obese patients, and the beneficial results of vitamin D supplementation for IC patients as seen in a RTC in Iran? 2)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1908699/pdf/brjpharm00227-0125.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610782/
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Comment 8
Received: 12 April 2020
Commenter: Hans Bakker
The commenter has declared there is no conflict of interests.
Comment: Dear Frank et all, wonderful hypothesis though I think there is more to it like Paolo Maddedu suggested. Other mechanisms in the oedema problem besides Bradykine may worsen the angio leakage equilibrium and for that may be treated in multiple ways. Like f.e. higher levels of adenosin and Histamin.
If there is a shortness in ACE to control Bradykinin are people with ACE inhibitors than at higher risk? And could treatment with adrenalin at a certain stage and histamin inhibitor be a helpful suggestion?
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Comment 9
Received: 13 April 2020
Commenter: Krystyn Podgajski
The commenter has declared there is no conflict of interests.
Comment: Since zinc increases ACE2 activity, why are you not interested in zinc deficiency or zinc supplementation?

And couldn't zinc entry to the cell take place when the protein is brought into the cell along with its' zinc finger? No only will zinc activation of ACE2 get rid of the ANGII but it will also help with immunity by stimulating NfKB. Zinc on its' own has been shown to inhibit the cytokines storm as well.

It is not a new idea that zinc lowers bradykinin!

https://academic.oup.com/jn/article-abstract/117/3/490/4763354

Has there been any effort to track zinc deficiency with infection outcomes?
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Response 1 to Comment 9
Received: 12 May 2020
Commenter: J. Ramakers
The commenter has declared there is no conflict of interests.
Comment: Probably said everywhere, but, hey, can't read or watch everything :-) In this video a theory is explored that links chloroquine to help zinc get into the cells were the zinc makes it hard for the virus to make copies of itself: "chloroquine is a zinc ionophore": https://www.youtube.com/watch?v=U7F1cnWup9M (Coronavirus (COVID-19) Update 34 with pulmonologist & critical care specialist Roger Seheult, MD of https://www.MedCram.com )
Comment 10
Received: 14 April 2020
Commenter: Frank Conijn
The commenter has declared there is no conflict of interests.
Comment: Very interesting research, but I would have a few questions:

1. The abstract says: "This kinin-dependent pulmonary edema is resistant to corticosteroids." That's a very worrisome statement! It's not that I don't believe it, but can you substantiate that here? There are several trials running that use steroids in covid-19 patients with ARDS, so a quick reply may be important.

2. Would that steroid resistance also count for patients who do not yet have ARDS but who do have (biomarker signs of) upcoming cytokine storm syndrome? (One might want to give them steroids to prevent ARDS.)

3. Would the (type of) drug you suggest also prevent or cure the damage to other organs than the lungs, damage as stated by immunology prof. Savelkoul on https://www.youtube.com/watch?v=wzI_SKNF6YI&t=125 (video in Dutch)?
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Comment 11
Received: 14 April 2020
Commenter: Gina Lemmen
The commenter has declared there is no conflict of interests.
Comment: So there are a few players involved:
-ACE2
-Furin enzym
-NLRP3 inflammasome
-Bradykinin
If you block one of them it will have an effect on the whole proces.
Covid19 enters the body true ACE2, furin will activate it in the lungs, bradykinin will cause leakage in the lungs because there is no break anymore because ACE2 loses it's function, and if the patiënt has a high level of nlrp3 inflammasome it will cause an overreaction to the immunesystem which will lead to complications (in the lungs).

So I think maybe we can find the answer in this question: children around the world are almost not infected by covid19. What do they have - or not have - to defend themselves from covid19?
Is it that they have less ACE2? Or a low level of NLRP3 Inflammasome? It can not be that only their immunesystem is so much different so there must be another chemical reason.

Many patients are overweight, older or have another disease. In my research I find ACE2 and nlrp3 the mean reason why these people get so sick of covid19. Bradykinin and furin are also big players. But a high level of nlrp3 causes a chemical reaction so the immunesystem will overreact which also causes more problems in the lungs. Not only ACE2 acts as a guardian, nlrp3 is a guardian too.
So my questions are:
What do children have or don't have worldwide to protect themselves from Covid19?
What is your opinion about the nlrp3?
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Response 1 to Comment 11
Received: 19 April 2020
Commenter: Harm Olthoff
The commenter has declared there is no conflict of interests.
Comment: One age-dependent influencer for the lower resistance to corona type virusses like SARS has been discussed in [1], i.e. a higher PGD2 expression as occurs upon aging correlates with a progressive impairment in rDC migration to DLNs, so diminishing T cell response.

References:
1. Zhao J., Zhao J., Legge K., Perlman S. Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J Clin Invest. 2011;121:4921–4930. [PMC free article] [PubMed] [Google Scholar]
Comment 12
Received: 15 April 2020
Commenter: Frank Conijn
The commenter has declared there is no conflict of interests.
Comment: Very interesting research, but I would have a few questions:

1. The abstract says: "This kinin-dependent pulmonary edema is resistant to corticosteroids." That would be very worrisome. Can you substantiate that here? There are several trials running that use steroids in covid-19 patients with ARDS, so a quick reply may be important.

2. Would that steroid resistance also count for patients who do not yet have ARDS but who do have (biomarker signs of) upcoming cytokine storm syndrome? (One might want to give them steroids to prevent ARDS.)

3. Would the (type of) drug you suggest also prevent or cure the damage to other organs than the lungs, damage as stated by immunology prof. Savelkoul on https://www.youtube.com/watch?v=wzI_SKNF6YI&t=125 (video in Dutch)?
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Response 1 to Comment 12
Received: 15 April 2020
Commenter: Frank van de Veerdonk
The commenter has declared there is no conflict of interests.
Comment: Thank you for your questions

1. This pathway might indirectly be influenced via anti-inflammatory agents (such as porticos) that lower the expression of B1R. There will however be no direct effect and for this we need to target the kinin-kallikrein system.

2. Same as 2.

3. When the pathogenesis in the other organs would be similar (such as kidney) then yes.
Comment 13
Received: 15 April 2020
Commenter: Ali
The commenter has declared there is no conflict of interests.
Comment: Linseed or flaxseed oil may decrease inflammation caused by bradykinin and histamine. Linseed oil contains a very high percentage of alpha-linolenic acid, an omega-3 fatty acid, which acted against bradykinin and histamine in rodents.

Ginger may decrease some of bradykinin’s negative effects. One component of ginger, 6-shogaol, blocks the production of inositol triphosphate in tissue studies. Bradykinin normally stimulates the production of inositol triphosphate, so this effect suggests that 6-shogaol may decrease bradykinin.
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Comment 14
Received: 15 April 2020
Commenter: Elroy Brakel
The commenter has declared there is no conflict of interests.
Comment: I remembered reading about ciclesonide and wondered if there was a connection to bradykinin.

The drug called Ciclesonide is a a steroid inhalant that suppresses the immune system. Ciclesonide reaches the lungs where it can reduce inflammation.

https://www.zmescience.com/medicine/asthma-drug-covid-19-06264/
According to the results released from Kanagawa Prefectural Ashigarakami Hospital, among the three patients treated with Alvesco, one woman was relieved from fever and pneumonia symptoms and discharged virus-free after eight days. The other two patients are free from respirators. Currently, there are 10 more patients receiving the drug.

https://geneonline.news/en/2020/03/28/japan-trials-asthma-drug-alvesco-to-fight-covid-19/
In vivo, ciclesonide (intratracheal administration), des-CIC, and budesonide inhibited antigen-induced accumulation of eosinophils, protein, and tumor necrosis factor-alpha into the bronchoalveolar lavage fluid of ovalbumin-sensitized and -challenged Brown Norway rats with an ED(50) value ranging from 0.4 to 1.3 mg/kg, indicating similar potency, which suggests in vivo activation of the parent compound. Ciclesonide and budesonide inhibited the bradykinin-induced protein leakage into the rat trachea.

https://www.ncbi.nlm.nih.gov/pubmed/14718604
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Response 1 to Comment 14
Received: 26 April 2020
Commenter: Knuijver
The commenter has declared there is no conflict of interests.
Comment: Elroy Brakel? That is the e-mail I sent out and the exact reference and quote I used to link it to Ciclesonide.
Comment 15
Received: 15 April 2020
Commenter: Dr.Mohammad Sultan
The commenter has declared there is no conflict of interests.
Comment: Firstly i'd like to thank the research group for their efforts, but i do not think your theory is 100% correct .
in my point of view i think we should depend on Autopsy results to get the correct answers to this situation. Lab tests are needed as you we are practicing science , but the data should gathered from many sources and filtered to relevant and irrelevant , then processed and used to get a correct answer.
Dear colleagues in the research group i'd like to share with you the results of An autopsy took place in china which contradict your theory 100% , and the Chinese results showed that the T-cells are 100% responsible for the pathology of the disease , the results and the link is below:

According to chinese autopsy reports there was an insight on the pathology of the disease and i quote the following

"Biopsy samples were taken from lung, liver, and heart tissue of the patient. Histological examination showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates (figure 2A, B). The right lung showed evident desquamation of pneumocytes and hyaline membrane formation, indicating acute respiratory distress syndrome (ARDS; figure 2A). The left lung tissue displayed pulmonary oedema with hyaline membrane formation, suggestive of early-phase ARDS (figure 2B). Interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were seen in both lungs. Multinucleated syncytial cells with atypical enlarged pneumocytes characterised by large nuclei, amphophilic granular cytoplasm, and prominent nucleoli were identified in the intra-alveolar spaces, showing viral cytopathic-like changes. No obvious intranuclear or intracytoplasmic viral inclusions were identified.

The pathological features of COVID-19 greatly resemble those seen in SARS and Middle Eastern respiratory syndrome (MERS) coronavirus infection.4, 5 In addition, the liver biopsy specimens of the patient with COVID-19 showed moderate microvesicular steatosis and mild lobular and portal activity (figure 2C), indicating the injury could have been caused by either SARS-CoV-2 infection or drug-induced liver injury. There were a few interstitial mononuclear inflammatory infiltrates, but no other substantial damage in the heart tissue (figure 2D).
Peripheral blood was prepared for flow cytometric analysis. We found that the counts of peripheral CD4 and CD8 T cells were substantially reduced, while their status was hyperactivated, as evidenced by the high proportions of HLA-DR (CD4 3·47%) and CD38 (CD8 39·4%) double-positive fractions (appendix p 3). Moreover, there was an increased concentration of highly proinflammatory CCR6+ Th17 in CD4 T cells (appendix p 3). Additionally, CD8 T cells were found to harbour high concentrations of cytotoxic granules, in which 31·6% cells were perforin positive, 64·2% cells were granulysin positive, and 30·5% cells were granulysin and perforin double-positive (appendix p 3). Our results imply that overactivation of T cells, manifested by increase of Th17 and high cytotoxicity of CD8 T cells, accounts for, in part, the severe immune injury in this patient."
from the (https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30076-X/fulltext?rss=yes&utm_campaign=update-lanres&utm_source=hs_email&utm_medium=email&utm_content=83570178&_hsenc=p2ANqtz-9uESUXj_Lm4iXDmvI7dkxjM6zR338P5y63h6v-10exFeWJ3NmnEemsd0SL_ftH9EkPEZ3SiWrzL7vAIGVMdFVtzj32qQ&_hsmi=83570178)

My personal opinion is to use the following regimen ( infliximab and Novilumab) or one agent.
as clearly mentioned the above Immune mediators play a major role in inducing the ARDS and the destruction of the Alveolie , and the same above mentioned can be controlled with already existing forms of specific immunosuppressors for example mixing (Infliximab and Novilumab) which are well known to target the T-cell and its immune mediators.?
Thier side effects are well known , and the patients who are infected with covoid-19 also suffer from marrow suppression
in my point of view the risk of using TNF-alfa blocker with PD1 inhibitor as the regimen was used together in treating colitis
https://www.cghjournal.org/article/S1542-3565(16)30675-9/pdf
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Comment 16
Received: 15 April 2020
Commenter: Frank Conijn
The commenter has declared there is no conflict of interests.
Comment: In comment 12, I asked:

[question]
1. The abstract says: "This kinin-dependent pulmonary edema is resistant to corticosteroids." That would be very worrisome. Can you substantiate that here? There are several trials running that use steroids in covid-19 patients with ARDS, so a quick reply may be important.
[/question]

You responded with:

[response]
1. This pathway might indirectly be influenced via anti-inflammatory agents (such as porticos) that lower the expression of B1R. There will however be no direct effect and for this we need to target the kinin-kallikrein system.
[/response]

That describes the mechanism. That's beyond my expertise, but what I would like to know is whether there are any controlled trials (published or not yet) that found that corticosteroids do not significantly improve the condition of corona-infected patients with ARDS (doesn't have to be SARS CoV-2, may be SARS CoV or MERS CoV, too).

And/or whether there are any controlled trials that found that corticosteroids do not prevent ARDS in patients with serious covid-19 symptoms (actually: lab-proved cytokine storm syndrome) but who do not yet have ARDS.
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Response 1 to Comment 16
Received: 15 April 2020
Commenter: Frank Conijn
The commenter has declared there is no conflict of interests.
Comment: Because what you're describing would be in vitro evidence. I would need in vivo evidence.
Response 2 to Comment 16
Received: 16 April 2020
Commenter: Frank Conijn
The commenter has declared there is no conflict of interests.
Comment: I will rephrase that: I would need endpoint evidence.
Response 3 to Comment 16
Received: 16 April 2020
Commenter: Frank Conijn
The commenter has declared there is no conflict of interests.
Comment: Through a (further) scrutiny of the Dutch overall guideline on the treatment of Covid-19, it appeared that there is (rather) strong endpoint evidence, through meta-analyses, that corticosteroids do improve the condition of patients with ARDS (1-3). [But if given indiscriminately (without lab-checking whether the immune system is in overdrive), increase the chance of getting it (3).]

Clinically, the first finding is good news. But my question now becomes: Do you still uphold the sentence "This kinin-dependent pulmonary edema is resistant to corticosteroids"? And if so, on the basis of what evidence?

Possibly, your therapy works better, maybe even much better. Please don't get me wrong on that. But the said sentence must worry clinicians and researchers using corticosteroids to a great extent. So it would really need substantiation or withdrawal, in my opinion.

And then there's the matter of the other organs. They get injured, too, in severe Covid-19; the literature list would be too long to post here. But is their pathogenesis similar (vascular leakage)?

1. Meduri GU, et al. Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: Analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature. Intensive Care Med. 2016;42(5):829-840.
2. Yang Z, et al. Early application of low-dose glucocorticoid improves acute respiratory distress syndrome: A meta-analysis of randomized controlled trials. Experimental and therapeutic medicine. 2017;13(4):1215-1224.
3. Peter JV, et al. Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: Meta-analysis. BMJ. 2008;336(7651):1006-1009.
Response 4 to Comment 16
Received: 18 April 2020
Commenter: Frank van de Veerdonk
The commenter has declared there is no conflict of interests.
Comment: Thank you for your comments.

Indeed we do not know the impact of corticosteroids, and the situation is far more complex in the setting of COVID-19 compared to the situation of angioedema, such as in ACE inhibition and HAE, where we know corticosteroids will not have a dramatic impact on angioedema. It is good to change this sentence into "it might be resistant to ...." Agree?
and I thank you for your nuance and suggestion.

Others and we are currently investigating cortico's in REMAP-CAP/REMAP-COVID. The latter will even have the capacity to study the effects of corticosteroids and kinin-kallikrein interventions in combination.
So I think these studies will eventually answer your questions.
Response 5 to Comment 16
Received: 18 April 2020
Commenter: Frank Conijn
The commenter has declared there is no conflict of interests.
Comment: I'd suggest to change the sentence to "This kinin-dependent pulmonary edema may be more responsive to B1/B2 receptor blockers than to corticosteroids and adrenaline."

Regarding the REMAP-CAP study, I didn't want to go off-topic. But now that you mention it, I would like to comment on it. The problem I have with it is twofold. Firstly, it's done with patients that already require ICU care. Secondly, the estimated primary completion date is December 2021! By that time, with the current lockdown, the economy will have collapsed so much that only the very rich can still afford a hospital stay, if you catch my drift. So, that's taking way too long.

I think a speedy RCT should be done with hospitalized patients who do not yet require mechanical ventilation but who do have a lab-proven immune system in overdrive. With one arm treated with a biological such as tocilizumab, and one with a placebo (blinded) or no immunosuppression (open label). With the aim to see whether it can prevent ARDS.

I find the cytokine-related explanation for why children rarely get seriously ill from SARS-CoV-2, by prof. Savelkoul, too compelling to not do such a study. (Children make much less cytokines.) And immunosuppression in select patients may have a better a chance of protecting the other organs as well.

See https://gezondezorg.org/c19-richtlijn.php#is for a substantiated and detailed proposal (article in Dutch).
Comment 17
Received: 18 April 2020
Commenter: Avner Reshef MD
The commenter has declared there is no conflict of interests.
Comment: Thank you for the excellent review of the hypothetical patho-mechanisms of COVID19 lung injury. As for the involvement of the Kalikrein-Kinin System (KKS) and your reference to the bradykinin (BK)-induced vascular hyperpermeability and Angioedema, the situation is a bit more complex:
1. HAE Patients with either C1-Inhibitor deficiency (C1-INH-HAE), acquired AE, ACE-I induced, or normal C1-INH (nC1-INH, FXII, AngPT1, PLN mutations) never experience pulmonary edema. Why? Conceivably because the lungs are the major source of ACE enzyme and normally BK is degraded in the lungs within 4 seconds (and lasts longer in other tissues). ACE (Kininase II) is the main (95%) degradation enzyme of BK (into des9-arg BK that is further degraded by Carboxypeptidase N). Perhaps SARS-COV2 virus destroys the capability of the lungs to make ACE enzyme and therefore locally formed BK is increased? This is yet to be proven.
2. A rapid spillage of chemical mediators into the blood circulation may occur during inflammation, infectious tissue injury and hyper-permeability situations (i.e. HAE, Clarckson's Syndrome). This may explain the elevation in plasma cytokines observed in COVID19-induced interstitial pneumonia, but not necessarily prove its involvement in the destructive process.
3. Elevation of D-dimers was indeed observed during attacks of HAE, without evidence for increased thrombotic propensity (we and others have reported it). Theoretically, equilibrium between thrombosis and fibrinolysis is obtained during repeated HAE attacks. Additionally there are no long-term consequences, such as fibrosis in the edematous tissues.
4. Icatibant is a highly selective BKB2 antagonist, and to the best of my knowledge cannot inhibit BKB1 receptors.
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Comment 18
Received: 20 April 2020
Commenter: Markus Koller
The commenter has declared there is no conflict of interests.
Comment: As a non-scientist I read this very interesting discussion and wondered how it releates to the findings described in: Endothelial cell infection and endotheliitis in COVID-19, Zsuzsanna Varga et.al. The Lancet. ?
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2820%2930937-5/fulltext
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Comment 19
Received: 24 April 2020
Commenter: Joost Ramakers
The commenter has declared there is no conflict of interests.
Comment: Correct me if I'm wrong but I noticed that similar insight including the potential therapy with icatibant has already been published in the Journal of Renal Injury Prevention (Article History: Received: 20 March 2020, Accepted: 28 March 2020, Published online: 30 March 2020 at http://www.journalrip.com/Files/Inpress/jrip-18698.pdf )
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Comment 20
Received: 26 April 2020
Commenter: Ronald Portegies
The commenter has declared there is no conflict of interests.
Comment: I think there's a lot of interesting and usefull things said in this topic. However, there is something I'd like to add as a patient. I don't have edema, fever, or cough, but I do however have a vasoconstrictive blockage of the lungs. Luckily after 7 weeks, it's slowly receding now, and it feels like it's clearing. (I can still feel my kidneys though, they're not happy)

I have not been hospitalized because I've been able to counter this blockage effect by focusing my efforts on 3 parts:
1) lowering homocysteine levels
2) increasing the efficiency of the endothelial Nitric Oxide Synthase system
3) countering the loss of Potassium

I have done all three through supplementation. I found trying to boost my immune system had little to no effect whatsoever. Then again I already have a pretty good immune system, I never get a cold, ever, and I only get a mild flu maybe once a year. I am, however, nutritionally exhausted from a very stressfull 2019, and in january my blood pressure was slightly raised, for the first time ever.

I think the underlying problem in this disease (and quite possibly, SARS and MERS as well) is the reduced function of the endothelial NOS system. Arteries, Veins and the Lymphatic system al have in common that eNOS is required for their correct function. Lose eNOS function in he arteries, and you get blockage. Lose it in the veins, and you get edema. Losing it in the lymphatic system can create or worsen either. Which way it goes, blockage or edema, will probably be due to patient variation. So by focusing either on the vasoconstrictive OR the vasodilatory aspect of the disease, might detract us from the underlying aspect that will affect all patients.

And it will lead to conflicting theories, with one theory working for one set of patients, and another theory working for another set of patients, and neither theory working for all of them. (With the resulting controversies and taking-sides that is usual in the scientific community both not helping our understanding of the problem OR save more lives)

Also, loss of effectiveness/efficiency of eNOS is also one thing that all 'pre-existing conditions' all have in common.

Furthermore, it can explain why young people might get infected but not sick, because they will still have an optimal eNOS system. Even if their ACE2 cells are affected, they will have enough robust redundancy in the eNOS system that they can clear the infection without symptoms. Older people generally lose redundancy in their biochemistry, that is in essence what aging is all about.

Easy enough to check: some young people DO get ill; go check their eNOS system. If you find that in some way they've lost some redundancy in there, you've hit paydirt.

Plus, the interdependencies of the eNOS system, both micronutrient and hormonal-wise, are as complex as a directory tree, and in fact some of the most complicated I have ever seen in biochemistry. Complexity in biochemistry always garantuees obscurity in medicine. The more complex something is, the less likely it is to be understood, and the more likely it is that it's relevance will be overlooked.

So, it might be, that by looking at angiotensin II, aldosterone, bradykinin, etc. we are in fact only scratching the surface of the problem. And that the underlying explanation for 'why do some people get very sick and/or die?" is the fact that they've lost too much redundancy in the whole vasoconstrictive/vasodilatory system to counter the effects the virus has on this weakend system.

And because reduced redundancy is naturally unique to each patient, whether the action of the virus is mostly constrictive or dilatory in a patient is bound to be equally unique in each patient. So it will be more important to quickly diagnose the difference, and treat accordingly, than to stick to one side of the coin, and risk losing half your patients.

For the vast majority of patients, loss of redundancy will be based on loss of micronutrients. This will be FAR more prevalent than any genetic influence. In fact I loathe to use the 'G'-word, because once that's out of the bag, scientists all over the world tend to jump en masse on that bandwagon running around like a bunch of headless chicken, all with dollar-signs in the eyes of their chopped-off heads...and making no progress whatsoever in true understanding of the causality.

Micronutrients come first, help the body. They've kept me out of the hospital so far, (although a bit too much of vitamin C might still get me into it, kidney-wise), and focusing on restoring the redundancy will help ANY other treatment that anyone can think off. Regardless of theory, restoration of proper endothelial function will help all patients.

The B vitamins are nearly all important in eNOS/homocysteine biochemistry, and their interactions are highly complex.
I found out that trying to supplement with one of them, I quickly ran into the law of diminishing returns, after which another helped, also to be rewarded with diminishing returns. This can really be only explained by one depleting the others. So, a B-complex is probably the safest bet at this point. Also, the omega-3 fatty acid DHA turns out to be an essential co-factor for folate in the methylation pathway, so it should be on the list. It would certainly help to explain the much lower CFR's in asian countries; their diet contains a lot more fish than the west.

Anyway, hope this helps. Now if you'd excuse me, I need to go get my kidneys some flowers and a box of chocolate...
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Comment 21
Received: 26 April 2020
Commenter: Knuijver
The commenter has declared there is no conflict of interests.
Comment: This may also explain why asthma sufferers in China do not appear in the Covid-19 statistics.

I also read in The Lancet that asthma seems to immunize:
https://www.thelancet.com/action/showPdf?pii=S2213-2600%2820%2930167-3
And this is how that goes back to black people:
https://doi.org/10.1016%2FS0009-9236%2896%2990161-7
Then you see that in the statistics:
- in China (where statistically no blacks live) you see 1500 Covid-19 patients without asthma (asthma patients have an inhaler)
- in the UK, blacks are hit extremely hard by Covid-19 (but there are no asthma statistics, I emailed the NHS about that.) https://www.icnarc.org/About/Latest-News/2020/04/04 / Report-On-2249-Patients-Critically-Ill-With-Covid-19
- in Italy you see the same as in China, no asthma Covid-19 patients (who have an inhaler) but also no statistics for blacks and therefore not for RAS X ASTMA https://www.epicentro.iss.it/en/ coronavirus / bollettino / Report-COVID-2019_23_april_2020.pdf
- this is also known in the US, but there is a threat of stigmatisation of blacks, a politically very sensitive issue (there, inhalers do happen to be low on stock)
- The ASTMA X INHALER X COVID-19 statistics are probably available in the Netherlands and Belgium.

The ethnicity issue aside, it is more important that the "" "hypothesis is that an inhaler immunizes" "".

That would not be enough for blacks to overcome their predisposition to more severe angioedema. But that's another hypothesis I'm working on. In case it is true, black healthcare workers should be informed.

It is difficult to get the statistics clear. In connection with co-morbidity I need ASTMA X INHALER X COVID-19 X CO-MORBIDITY statistics. Who can help me with that?
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Response 1 to Comment 21
Received: 9 May 2020
Commenter: Alexander Jan Mulder
The commenter has declared there is no conflict of interests.
Comment: Thank you.
On the subject of the impact of COVID-19 on people with dark skins.
In some researches (Sweden, UK) the possibility was mentioned that low Vitamin D-3, caused by a dark skin and living in a region with low sun hours could reduce the effectiveness of the immune system.
Many dark coloured people there also lack the means to get an extra 20-30 mcg Vitamin D-3 per day (1000 IU).
Eating fat fish for that purpose does not work. Sweden: many Somali's in "Refugee-camps".

On the subject of the Immune System itself.
Some reports of virologists mention the appearance of 4 regions in the virus' RNA of 4 strings that are exact copies of parts of HIV-1 (AIDS). They say that this causes the Virus to be able to also attack T1-cells, like in AIDS, preventing them to destroy the infected cells and viruses in it. I heard of children dying from strange effects after a short illness. Maybe that is connected.

I hope this info from the Internet could be of some help to any of you..
I have worked as IT systems integrator for 40 years and i have experience with working with specialists of different disciplines and get them to understand each other.

I wish you all good luck in together finding some way to stop the Pandemic.
Alex Mulder,
Schagen, The Netherlands.
Comment 22
Received: 28 April 2020
Commenter: Nancy Tarrand
The commenter has declared there is no conflict of interests.
Comment: To the authors, do you have any data yet from the Covid-19 patients to whom icatibant has been given?
Thank you.
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Comment 23
Received: 3 May 2020
Commenter: Letizia Baas
The commenter has declared there is no conflict of interests.
Comment: The discussion on the lung problems occurring during COVID-19 infection is very interesting. I’m not a physician, nor (so far) a COVID-19 patient. But as a former member of the HAE patients organisation in the Netherlands, I know that some HAE patients besides e.g. Ruconest or Icatibant use some times Tranexamic Acid in tablet form. They use it when the swelling is minor, e.g. a swelling on their hand. Also little children suffering from HAE get Tranexamic Acid in tablet form or grinded in some drink. This solely when the symptoms are mild.
Important during this pandemic is to try to keep patients as fit as possible in order to avoid hospitalization. Tranexamic Acid is available as oral tablets. Therefore it is suitable for use at home. Could the prophylactic use of Tranexamic Acid in severe patients who are still at home, be of any relief so that hospitalization may be avoided?
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Comment 24
Received: 5 May 2020
Commenter: Letizia Baas
The commenter has declared there is no conflict of interests.
Comment: The discussion on the lung problems occurring during COVID-19 infection is very interesting. I’m not a physician, nor a COVID-19 patient (yet). But as a former member of the HAE patients organisation in the Netherlands, I know that some HAE patients besides e.g. Cynrize, Ruconest or Icatibant use some times Tranexamic Acid in tablet form. They use it when the swelling is minor, e.g. a swelling on their hand. Also little children suffering from HAE get Tranexamic Acid in tablet form or grinded in some drink. This solely when the symptoms are mild.

Important during this pandemic is to try to keep patients as fit as possible in order to avoid hospitalization. Tranexamic Acid is available as oral tablets. Therefore it is suitable for use at home. Could the prophylactic use of Tranexamic Acid in severe patients who are still at home, be of any relief so that hospitalization may be avoided?
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Comment 25
Received: 12 May 2020
Commenter: J. Ramakers
Commenter's Conflict of Interests: I am a patient of one of the authors
Comment: I want to repeat the question above in comment 22, Received: 28 April 2020, Commenter: Nancy Tarrand, as I am too daily watching this website 3 times a day being so curious if there are already any updates or results on the hopefully still (?) ongoing "explorative clinical trial with icatibant in COFID19 patients who are in need of oxygen therapy and have pulmonary edema." as formulated in Response 1 to Comment 2 by Frank van de Veerdonk

Comment: To the authors, do you have any data yet from the Covid-19 patients to whom icatibant has been given?
Thank you.

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