Hello, dear Jana,

This morning I woke up with the same idea that surfactant could be a track. I'm not a virologist or pulmonologist, I'm a geneticist. I observed strong selection signatures (in small ruminants in different parts of the world) on a solute carrier gene that acts on surfactant recycling...the idea popped into my head. Are there any studies comparing the composition of surfactant in adults and children? I can't find any....

Kind regards,

Anne

Dear Anne,

neither could I. Actually, there are some differences in surfactant composition in premature newborns and mature newborns but I really don´t know about changes later in life.

I only know that if there is strong inflammation (and in serious patients there is), inflammatory mediators are able to impair endogenous surfactant in many many ways (this was part of my recent research). In case there are no functioning type II cells to produce new one - or in case there is some alteration in recycling as you suggested - there can be problem, respiratory failure.

I don´t think that therapeutic exogenous surfactant is given to adults nowadays; however, I think it would really help! But I can´t find way how to point this to the responsible. That was why I started this discussion.

Iam neonatologist in iran isay it 1minth ago

and i suggest it

seem it is can be used i think

Dear Jana and Morteza, This is what I see on the Internet: "In adult acute respiratory distress syndrome, there is also a surfactant deficiency, but this time secondary to damage to the alveolar epithelium. However, the administration of exogenous surfactant is not practised in adult respiratory distress, because the quantities to be administered would be too large, and therefore extremely expensive, for a benefit that is not demonstrated." ...I guess it hasn't been tested because of the cost... I don't know who we should go to for specific information concerning the feasibility of such a protocol....

Dear Mortiza and Anne, thank you, that is true it would be expensive, I knew that as I work with surfactant.

The dose which is used for newborns comes really high if recalculated to an adult. However, there are many ways - using lower dose or diluting surfactant to reach at least some improvement, use synthetic surfactant which is cheaper although less effective.. moreover, Chiesi corporation, the biggest producer of surfactant, is an Italian corporation, so I hope they would notice this idea.. Obviously it is not used, but we are not in obvious situation.. I don´t know.. I just try to think up something..

Jana....thank you all these elements are really interesting....We have to go for it....who to contact?

Dear Jana, Anne and Morteza I have had this idea in my mind and today looking for some information about it I have found your conversations from 3 days ago. Have you gone on with this question? Have you found any research about it since then?

I appreciate your feedback

I'm myself I' m a neonatologist and so I am first-line witness of the wonderful effects of surfactant not only in Preterm Distress Syndrome but in older children when ARDS

Dear Ana,

Thank you very much for your message, it gives us energy to do even more!! With Jana we contacted French doctors and a Chinese doctor who is the author of this article:"Clinical characteristics of novel coronavirusdisease 2019 (COVID-19) in newborns, infants and children". In this paper, authors are proposing the use of surfactant for children ("administrationof high-dose pulmonary surfactant").

Right now we don't have any answers...we feel a little helpless...

Apparently there is a trial underway in Italy/UK. Can we discuss the feasibility of aerosolized surfactant to potentially decrease the volume required in adults? The early trials of surfactant in adult ARDS used aerosols. I’m told its been tried in neonatal RDS but is not yet FDA approved in babies. The Aerogen nebulizer and Pari eFlow have been cited as potential devices to deliver. I’m keen to try this.

Dear Stephen, there is a trial about surfactant in COVID-19 adults? That´s great!

Unfortunately I have only experiences with a bolus-given surfactant treatment and not the aerosolized one. But that just makes me more interested!

May be Ana Concheiro will know more about nebulizers?

Aerosol therapy is still not approved in newborns. Although there are some promising results. One way to administer surfactant can be with using diluted surfactant by bronchoalviolar lavage, like we do in meconium aspiration syndrome, or pure as we do in SDR and in old children with ARDS. Intratracheal instilation can be done with a thin catheter through the endotracheal tube

Thanks for your answers and interest

We´ll continue to share information

To Stephen M Robert ,

Prof. Carlo Dani wrote response to Anne and me about surfactant nebulisation for adults.

He believes that the problem is the time for the delivery of the effective dose.

"Currently, the dose of 200 mg/kg in preterm infants needs about 20 min for delivering. Considering that Curosurf has a concentration of 80 mg/ml you could delivery 7.5 mL/h corresponding to about 600 mg/h. Therefore,  in a human being of 70 kg we could give about 8.6 mg/kg.

I have no idea if this dose could be effective in adults nor if eFlow can be adapted: in preterm infants eFlow is connected to small nasal prongs.

Another problem is that surfactant nebulization allows a 5-45% lung deposition.

I think that endotracheal administration in mechanically ventilated adults could be  a better option."

Is there any trial about aurfactant in COVID-19?

The VPS network has a listserv (email covid19myvps.org) where I asked about experience and someone said there is a trial of patients from Italy and UK. I don’t know their delivery method. Thanks to everyone. I really want to find a way to do this. Jana Kopincova

Thank you Stephen, this is really very interesting! Please keep us updated. On my end I'm forwarding your answer to Professor Carlo Dani.

See you soon...

Did you see that?

https://www.prnewswire.com/news-releases/windtree-to-pursue-clinical-study-of-lung-injury-treatment-in-covid-19-patients-with-its-kl4-surfactant-therapy-301028739.html

I am glad I found this thread. This idea came to me as well last night and I am hopeful surfactant will be helpful in the management of this terrible virus.

To everybody who is interested: please help us to spread this idea wherever you can.

Me and Anne are not clinicians; we tried to contact some important people by mail but it seems that there is just low clinical impact of our thoughts. Prof. Dani suggested bolus administration of exogenous surfactant to intubated adults rather than nebulised; but we don't actually know how to inform those respinsible.

There is some research on KL4 surfactant for COVID-19 in link above, but please, if possible, inform people in your country, in your hospital.

I’m pushing the idea at my institution, and there us some interest. Will keep you updated. I don’t always get notification on this thread. If anyone wants to discuss for fun, clinically, or for research collaboration, feel free to contact me at [email protected]. Could correspond or arrange a teleconference. Will try to keep up on this thread too.

I have reviewed all clinical trials going on about COVID-19 (almost 150 studies around the world). None concerned surfactant therapies.

As a spanish clinician I have contact our ICU doctors to report about and ask if they know any information but they have not. We keep in touch and report any information.

You don’t need surfactant! I’m glad more than one person around the world had this idea. Look at my write-up here: https://www.reddit.com/r/medicine/comments/fmlitp/are_we_treating_covid19_the_wrong_way_a_deep_dive/?utm_source=share&utm_medium=ios_app&utm_name=iossmf

Thank you, Jonathan, we appreciate every idea which can be helpful!

Called CMO of Windtree Thetapeutics and left voicemail message RE: their trial of Aerosurf for COVID. Will update you all if I get a call back.

Jonathan, I can’t upload your pdf. Mind emailing it to me or sharing tye punchline? [email protected]

Thanks!

According to this article , Article It’s all about sex: gender, lung development and lung disease

The main difference between female and male lungs during early stages of lung development is in the production of pulmonary surfactants. '' The

earlier appearance of surfactant in female neonatal lungs

favors patency of small airways and airspaces and might

contribute to their higher airflow rate and lower airway

resistance compared with neonatal males.

In addition it has been revealed that androgens inhibit fetal pulmonary surfuctant production in a variety of species.''

Now , has anyone seen the mortality rates of women vs men in Italy and China ? If no, please do :

1. https://www.epicentro.iss.it/coronavirus/bollettino/Report-COVID-2019_20_marzo_eng.pdf

2. https://www.worldometers.info/coronavirus/coronavirus-age-sex-demographics/

If the lower death rates in women can be correlated with pulmonary surfactant production/availability, then it could support the idea that pulmonary surfactants can indeed help, if not cure, then sustain patients without having to rely on mechanical breathing support

Thank you dear Panayiotis, it's really very very interesting...!

Here is an article that looks at the gender issue, notably on the side of hormones: https://www.latimes.com/science/story/2020-03-21/why-is-the-coronavirus-more-deadly-for-men-than-for-women

I was really writing a proposal on this the day before yesterday to see how would be the effects since COVID-19 patinrs are really challenging when they have ARDS

Just to explain our thoughts about the surfactant need in COVID-19

1. SARS-CoV-2 (similarly to SARS virus) uses ACE2 as a portal of entry into the lungs; the enzyme is expressed predominantly in type 2 pneumocytes (e.g. doi.org/10.3390/jcm9030841); this interferes with surfactant re-uptake and synthesis de novo

2. serious COVID-19 is associated with exceeding lung inflammation and intensive host immune reaction; the presence of inflammatory and oxidative agents in lungs has high potency to deactivate endogenous surfactant which then hampers ventilation support;  we think this is at least a part of ARDS pathogenesis

3. hyaline mambranes formation was found post mortem in human patients and in COVID-19 primates suggesting surfactant depletion

Please, correct me if there is anything incorrect or you have some newer knowledge. Good luck in fight to all!

Correct:@ https://doi.org/10.1038/s41418-020-0530-3

Thank you, Ali, very detailed paper! So, could be surfactant helpful when we know all this? Should we try to contact those people with our ideas?

I have started a research as I said. I wish YES!

I mailed to Prof. Shi who wrote that paper. I wish YES, too!

Hi Jana

I have gone through all your discussions, I have read in more paper all have shown that SARS family and Covid-19 Using ACE2 receptor to Entry in alveolar cells. However, I have written a proposal to prevent the entry of Covid-19 by blacking ACE2, Since the reviewer of the proposal refused my hypothesis as he sais that virus entry into lung cells carry out by phagocytosis of macrophages.

Would you please if you or someone has the comment write to me.

Hello!

I am glad I found thus thread. Any updates on the topic since March 3rd? I am trying to push surfactant idea at my institution but have no success so far.

Sorry guys. I didn't realize the PDF didn't upload. I'll share the link below.

Bottom line is we are all right, its a T2P infection problem. The issue isn't just peep, it's also dynamic airway obstruction from the small airways from the exudative phase in ARDS causing air trapping. I'd be happy to discuss with you all, maybe we can have a little brainstorming meeting on zoom? I had it and learned alot through my experience!

Hello.. i have same idea.. i hypotesize that surfactant could be against against covid 19. i would like to use a biosurfactant that have membran lipid destruction of virus.. how about your ideas?

if you all do a conference call, I’d like to join. My only request would be someone take the lead as moderator and give a little thought to goals of discussion. Not me! 😆

There's a little known Survanta study from >25 years ago that showed a reduction in mortality in ARDS from 50% to 15% with surfactant administration. The company could not upscale production from the pediatric market to the adult market because of prions and needing to use clean cows in New Zealand to produce the drug. I worked on Surfaxin back when it was KL4-Surfactant and our main goal was ARDS, not IRDS. It is being "restudied" as Aerosurf by Windtree Therapeutics https://www.windtreetx.com.

**Conflict of interest statement: I do own a very little stock in Windtree (diluted by multiple reverse splits over the years). I personally think the company has been terribly mismanaged, but the surfactant that Charles Chochrane and Susan Revak developed is still a good one.

Thank you

Jonathan thank you for your pdf! I would like to know your opinion on paper sent by Ali: doi: 10.1038/s41418-020-0530-3

Could be the air trapping caused by hyaluronan accumulation in lungs?

Thank you all guys for your effort. As to me, I will have no space to join zoom-conference :( However, I am not a clinician so I don´t think I could contribute too much to your knowledge. But I will be really glad if you meet and discuss whatever can help and whatever you can use in your practice and please keep me then updated!

It is great to be part of this virtual "lab"! I hope that early our vision will move to the practice. I preassume than one case report of surfactant saving COVID-19 patient would be enough to change all the resistance of responsive ones.

Jana Kopincova thanks for that article! it was a very informative read! I also shared my data with the study author of the first article on the clinical characteristics of Covid-19 in china, and one of the critical care doctors in italy.

I would say this, i'm not sure if it is hyaluronan accumulation. It would be difficult to prove, especially since there is lack of specimens and autopsy because of infectious risk. One of my sources did have two autopsy cases from china done on patients who had lobectomies before their diagnosis with covid-19. I'd recommend reaching out to them and asking if the proteinaceous fluid they saw was consistent with hyaluronan, usually the study has primary author contact information.

I have also attached a video my lovely wife took of me demonstrating the clearance of the airflow obstruction between huff cough maneuvers. There is no other disease to my knowledge that does this! This is my own video and you have permission to share fully.

the pathology on those cases showed diffuse alveolar damage, so I still believe that the underlying cause for air trapping is debris from the inflammatory/exudative phase of ARDS. This could include NETS from neutrophils and DNAse (dornase) might be helpful as a treatment.

Thank you guys so much for this avenue of communication. This pandemic has isolated us all socially and physically, and it gives me great hope that we will survive when i see such a strong international community not sheltering their ideas, but sharing with complete and open interactions.

I used myself as a lab rat while sick, knowing what we know, and came up with ideas because of that. It may have been foolhardy to do so, but I survived and gained new insights and great appreciation for this disease.

You are real heroes and scientists!

and here comes the disclaimer that my employer requires:

I am a pulmonary and critical care fellow at Mount Sinai Morningside/West/Beth Israel. The views expressed on this research gate account are my own and do not reflect the views of my employer

Great idea....

Coronavirus = COVID-19 = pneumonie virale pouvant dégénérer en SDRA pouvant se compliquer en sepsis et défaillance multiviscérale (dûe à une tempête inflammatoire).

surfactant = un tensioactif (phospholipides + protéines dont certaines hydrophobes) = stabilisation alvéolaire = s'oppose à l'atélectasie (collapsus alvéolaire).

surfactant = tensioactif comme le savon = phospholipides : activité virucide en dégradant physiquement la membrane phospholipidique virale + protéines SP-A et SP-D (collectines) intervenant dans l’opsonisation et la modulation des lymphocytes T et des cellules dendrititiques = détérioration du surfactant augmenterait la susceptibilité du poumon à l’infection ou à l’inflammation.

concentration en surfactant chez les individus sains : plus élevée chez le nouveau-né (100 mg/kg) et diminue chez adulte (40 mg/kg).

coronavirus = atteinte alvéolaire = destruction du parenchyme et donc des pneumocytes de type II = diminution du surfactant = sévère détresse ventilatoire

Traitement des patients COVID-19 = lavages bronchiques avec du surfactant dilué ou l’instillation de bolus de surfactant surfactant naturels issus de broyat à partir de poumons animaux ou synthétiques = diminution de la détresse ventilatoire lors de la destruction du parenchyme pulmonaire + correction de la défense du poumon attaqué par l’action tensioactive virucide.

merci pour votre intérêt, exactement le protocole auquel je pensais. suffit de gérer le risque d'aérosol pour les prestataires et le coût du surfactant

I was thinking how to eliminate fluids from alveoli, then I realize that surfactant could even kill virus by disrupt its lipids, and I reach here and found information about T2P involvement. I think this is a valid aproach as coadyuvant of therapy.

But, what about administration? should be intratracheal? I think, it must use nanocarriers not only to reduce de dose, and hence the cost, but targetting in a better way. So, inhalatory administration of surfactant in nanocarriers should be considered.

I was interested in this as a rescue therapy for mechanically ventilated patients with COVID, but the experience seems to be patients’ lungs aren’t so terribly sick and are not difficult to manage if one has access to critical care.

Perhaps there will be a role in a fraction of patients with severe lung inflammation and poor compliance, or perhaps aerosolized surfactant could be useful to prevent need for intubation.

Somebody is doing that. See the product AT-100

https://www.bioworld.com/COVID19products

Stephen M Robert exactly! the amount of positive pressure required to just avoid end expiratory collapse may be minimal, to the order of 1-5 cm H2O. That’s why i came up with a low cost CPAP device using a fan. Still haven’t had any takers for the design, but I think it would be perfect as a low cost alternative. Maybe you know someone that can use it. See attached

The primary cause of death among COVID-19 patients is respiratory failure attributed to acute lung injury and ARDS. The leading cause of this is the pro-inflammtory storm mediated by the cytokines released mainly from the macrophages. This storm will cause profound fluid leakage into lung parynchema and many histopathological changes will occur.This will lead to increase the barrier thickness of oxygen exchange and impending proper blood oxygenation. Furthermore, fluid overload will increase the tension within the alveoli which results in collapse that further compromises the oxygenation.

So the key pathophysiology here is the dysregulated or overactive immune response against SARS-Cov2 which itself participates in this over activation of the immune system by activating the inflammasome NLRP by two main pathways. Additionally,the ability of coronavirus to induce apoptosis and even necrosis further exacerbate the immune response and more and more cytokines will be released.

I think finding a drug that has immunomodulatory action that can really mitigate the storm will significantly decrease the mortality rate and decrease the number of patients who need mechanical ventilation.

Dear all,

like most of you I woke up this morning with the idea to use surfactants and it did not take long to find your discussion.

In fact there are biodegradable surfactants available that have a monograph in the Pharm. Eur. and USP. They could move in the clinic in a fast manner. Of course, pulmonary surfactant is a complex mixture of lipids and specific proteins that stabilizes alveoli at the end of expiration and has an important role in innate immune defense. So I would go for simple surfactants such as fatty acids. pH of a for instance 5% solution has to be adjusted to pH 7.2 with NaOH and isotony has to be provided by NaCl. Such a sterile solution can then be inhaled via a nebulizer. Potential might also show surfactants like phosphatidic acid, as it is eliminated once it gets in direct contact with epithelial cells, as the phosphate substructure is cleaved off by a membrane bound phosphatase. Unfortunately this compound has no monograph.

Andreas

I just find this piece of information

https://www.oindpnews.com/2020/03/windtree-therapeutics-to-study-its-kl4-surfactant-for-covid-19/

Abdallah Barjas Qaswal absolutely! That’s probably why we’re having such amazing response to iv steroids in patients. There was a drug finding study from mers that showed an inhaled corticosteroid (ics) inhibited viral replication. That might be why there were NO asthmatics in the chinese data! I think ICS early may prevent progression to respiratory failure, and IV steroids may help mitigate inflammation if disease had already progressed.

iv steroids are used in neonates to help differentiate type 2 pneumocytes!!!

Corticosteroid is not recommended to treat COVID-19 since it has unfavourable short term and long term outcomes. Additionally, what makes hydroxychloroquine favourably recommended from other suggested drugs is that it has both antiviral and immunomodulatory actions.

@Jonathan Stoever

Metanalysis of surfactant in ARDSshows no improvement in mortality morbidity or oxygenation.

https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-018-0761-y

However some studies suggest possibility of reducing viral Load.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418337/

So I am not very optimistic but a small trial on intubated patients early on at day 1of intubationmay be warranted. And not way into ARDS after sever lung damage took place.

Thank you, Ghassan Siblini. I deeply appreciate reviews and meta-analyses. This one boiled down to just 10 studies of very different surfactants. We know that SP-A does not actually confer significant surface tension lowering ability and SP-B is the major hydrophobic protein, followed by SB-C. What we found manufacturing KL4-Surfactant is that it is very fussy. To get the "right" liposomes, we had to be very precise. One of the downfalls when Discovery Labs (now Windtree Therapeutics) took over the project was lack of attention to small details. Their FDA approval was delayed over 2 years just for a slight change in the palmitic acid which adversely affected activity. Their abandonment of Surfaxin for Aerosurf was designed to deliver a lower dose to the adult market using aerosolization, rather than large bolus administration.

With so few good studies, it is difficult to know if a high quality, reliably produced surfactant, administered in a large bolus, would have a better outcome than what is reported here. Sadly, we don't have time to do better studies for COVID-19.

The argument about the complexities of ARDS and MOF is a valid one. Is there a time separation in these patients between respiratory failure and additional organ failure? If so, might surfactant play a role if administered early?

The case isn’t closed on surfactant in ARDS. Intensivists specialize in negative trials. The adequately powered studies invariably enroll heterogenous populations confounded by multiple centers, varying time from onset of illness to treatment, and innumerable unnoticed other variables. In the right patient and at the right time, its effects are dramatic and prettu hard to deny.

Hi, thank you all very much for bring this item to discussion I´m biologist and biotechnologist not virologist but as many of you said the idea of surfactant for COVID 19 is all the day in my head. I was read a lot about it the last 2 days, specially about the possibility of a nebulization as a way of administration. Thank you a lot for the possibility to discuss it.

Aída

file:///C:/Users/Felix/Downloads/1-s2.0-S0005273617300974-main.pdf

2019 study

From bench to bedside: in vitro and in vivo evaluation of a neonate-focused nebulized surfactant delivery strategy

Article From bench to bedside: in vitro and in vivo evaluation of a ...

https://www.windtreetx.com/kl4-surfactant-technology/

Mucolytic agent

N-acetylcysteine is a classic mucolytic agent. The unique hydrosulfuryl(-SH) group breaks the disulfide bond (-SS) between mucin molecular complexes, thereby reducing the viscosity of sputum (18). Also, it can promote ciliary movement, improve mucociliary clearance capacity (19) and increase the secretion and activity of pulmonary surfactant, thus promote mucus discharge. Furthermore, N-acetylcysteine also has a strong antioxidant effect, which can reduce oxidative stress damage in respiratory diseases (20). Recent studies have indicated that N-acetylcysteine can also impair and inhibit the formation of bacterial biological membrane. When used alone or in combination with antibiotics, it can inhibit respiratory infections (21).

May be it would be and indirected way to stimulate the secretion of endogenous pulmonary surfactant in the early stages of the COVID 19, is a conventional approved drug, have not contraindications in this illness

Aída Sterin Prync Thank you for the update on KL4-Surfactant lyophilization and aerosolization. When Sue Revak and I were making the batches for the initial infant trial, we noted that when the solution bubbled going on the lyophilizer, it left a "fluffy" precipitate that dissolved more readily in Tham buffer and had better activity. If it caked on the bottom, the activity was not as good. I've been out of the loop for many years, but I would want Windtree's version to be "fluffy" for bedside reconstitution.

Thank you Monica Sue.

I hope that will be the better version available.

Hi,

thanks for this stimulating thread.

In the "close" future, an alternative to the surfactant replacement therapy might be the up regulation of surfactant production/secretion by pharmacological agents such as micro-RNA. Unfortunalely, it's too late for the COVID-19 patients.

Zhou, J., Fu, Y., Liu, K., Hou, L., & Zhang, W. (2019). miR-206 regulates alveolar type II epithelial cell Cx43 expression in sepsis-induced acute lung injury. Experimental and therapeutic medicine, 18(1), 296–304. https://doi.org/10.3892/etm.2019.7551

I've been wondering about something along these lines for a week or two, but didn't trust my own thoughts enough to slip into the Google rabbit hole. Guess I'm glad I did, because now I feel less crazy (I'm not a biologist, per say) even if still a bit helpless.

From what I've gathered, in the inflammatory process there is an accumulation of HA in the lungs that is absorbing water--I assume this is part of the process that disrupts the lung surfacant.

I am wondering if there is a way to release SOME of this water as part of a potential solution?

Jocelyn Tourtellotte one of the well known Pulmonologists I work with, Dr. Gerard Turino, was working on the opposite effect for chronic obstructive lung disease. see here: https://journal.chestnet.org/article/S0012-3692(17)33284-1/fulltext#sec5

His lab was very involved in this project, I'm sure you could reach out to them to ask if they could potentially look into treatment options of hyaluronidase.

The main researcher he works with (since he's 90 something years old and STILL working!) is Shuren Ma

Jocelyn Petitto,

you are right. Part of the treatment of acute respiratory distress syndrom consists to maintaining a negative fluid balance. "Several small trials have demonstrated improved outcome for ARDS in patients treated with diuretics or dialysis to promote a negative fluid balance in the first few days" .

March 27, 2020

https://emedicine.medscape.com/article/165139-treatment#d8

Laurent Grelot,

Thank you for that! I was feeling a little crazy... I dropped out of vet school after finishing my MPH (dual program) and went into a PhD, so I feel really arrogant to even make suggestions.

Is there a way to release some of the water from the "glass" to provide similar effect?

- Jocelyn

Positive pressure on a ventilator pushes some of the water from the lungs back into the blood, and the rest we get out by forcing the body to dilute the urine and pee out more water

I was about to say "oh, like reducing blood pressure" but it is not "like" it is, as that's what is used as a treatment for high blood pressure.

[You know this, I'm just bemused the CV Epi course I took has any relevance to COVID-19 because I *wanted* to take Infectious Disease Epi but it wasn't offered the year I was finishing my MPH.]

Jocelyn Tourtellotte its not just about blood pressure, it’s the leaky capillaries because of inflammation from the infection. these patients also have very low levels of albumina (either through kidney losses or by inflammation), look up the starling equation to learn more. The revised starling equation is the next step in this journey!

The way I thonk about it is that inflamed lungs with leaky capillaries become edematous and poorly compliant. Surfactant deficiency, when present, increases surface tension and makes distal air spaces more likely to collapse. Opening pressure is higher than closing pressure, so keeping alveoli is open is paramount to prevent hyperinflation of open alveoli during the time it takes to open the closed alveoli. Positive end-expiratory pressure (PEEP) helps keep them open, this decreasingg ventilator-induced lung i hury. Rxogenous surfactant also helps prevent collapse.

Sorry for fat thumbs and typos. Also positive pressure ventilation reduces work of breathing, lowering oxygen consumption, and reduces left ventricular transmural pressure, with is an important part of left ventricular afterload. In this way, PPV with PEEP can improve cardiac output and decrease left atrial pressure, pulmonary venous hypertension, and pulmonary edema.

Stephen M Robert.

hence, do you think that CPAP devices used to prevent-treat obstructive sleep apnea might have some interest for patients at the early stage of respiratory problems (shortness of breath)?

Yes. Physiologically it helps, including in COVID-19, but many centers are avoiding noninvasive mechanical ventilation due to concerns of aersolizing COVID in the room and infecting others. The point at which supplemental oxygen becomes “noninvasive mechanical ventilation” is nebulous, but many centers are concerned about CPAP and BIPAP and prefer early tracheal intubation.

How do you tag people?

Did you mean tag people in your text? write "@" and then start to write the name :) Stephen M Robert

Very interesting and stimulating discussion. As a neonatologist, I have seen the miraculous effects of surfactant replacement first hand in premature infants. Volume required for administration would be an issue in adults with Covid-19 induced ARDS. Definitely worth further research.

Yes, the volume will be the challenge. However, there are some possibilities, e.g. lavage with diluted surfactant to remove jelly hyaluronate stuff which is in lungs produced in COVID-19, as mentioned by prof. Yufang Shi (the paper is somewhere above)..

I was intrigued by this very same issue of whether impairment of surfactant levels in COVID-19 patients could account for some of the lung dysfunction. I do not know anything about the potential for surfactant replacement/administration. I'll be interested to read the other comments!

As covid 19 ultimately lead to ARDS it is possible that surfactant be an effective way.

Great idea. What is your ref. about "more than 80% of pulmonary ACE2 are situated on type II" please.

Benan Bayrakci not sure if you were talking to me, but my source for T2P ace2 expression is here Article Tissue distribution of ACE2 protein, the functional receptor...

• Dear Respected Colleagues, Authors, Editors, and Audiences Journal of Cellular & Molecular Anesthesia has just published its latest issue at http://journals.sbmu.ac.ir/jcma. All articles of this issue deal with COVID-19 and the full issue is cordially dedicated to all Physicians, Nurses, all other Health Care Personnel and those patients who have fought bravely with COVID-19. We invite you to review the Table of Contents here and then visit our web site to review articles and items of interest. Thank you for the continuing interest in JCMA, Ali Dabbagh, MD Professor of Cardiac Anesthesia; Editor in Chief, JCMA Anesthesiology Research Center Shahid Beheshti University of Medical Sciences, Tehran, Iran Journal of Cellular & Molecular Anesthesia Vol 5, No 1 (2020): January 2020 Table of Contents http://journals.sbmu.ac.ir/jcma/issue/view/1889 Editorial -------- COVID-19: Apocalypse Now? (1-2)     Ali Dabbagh Original Articles -------- COVID-19 in pediatric patients: A case series (3-5)     Ahmad Eghbali,    Sedighe Shokrollahi,    Nastaran Sadat Mahdavi,    Seyed Alireza Mahdavi,    Ali Dabbagh Common imaging patterns of COVID-19 on spiral chest CT scan: a diagnostic approach for pulmonary involvement in ICU patients (6-15)     Taraneh Faghihi Langroudi,    Mehdi Khazaei The role of Artificial Intelligence in Management of Critical COVID-19 patients (16-22)     Shahabedin Rahmatizadeh,    Saeideh Valizadeh-Haghi,    Ali Dabbagh Review -------- Insights into the SARS-CoV2 Outbreak; the Great Global Challenge: A Mini Review (23-26)     Behzad Pourhossein,    Ali Dabbagh,    Maryam Fazeli Supplemental Oxygen therapy and Non-Invasive Ventilation in Corona Virus Disease (COVID-19) (27-31)     Soudeh Tabashi,    Alireza Mirkheshti,    Mastaneh Dahi,    Dariush Abtahi,    Maryam Vosoughian,    Shahram Sayyadi,    Mohammadreza Moshari,    Elham Memary,    Shideh Dabir,    Sohrab Salimi,    Ardeshir Tajbakhsh Review of therapeutic agents for the treatment of COVID-19 (32-36)     Shadi Ziaie,    Mehran Koucheck,    MirMohammad Miri,    Sara Salarian,    Seyedpouzhia Shojaei,    Mehrdad Haghighi,    Mohammad Sistanizad The immunologic basis of COVID-19: a clinical approach (37-42)     Samira Rajaei,    Ali Dabbagh Case Report -------- Twin pregnant woman with COVID-19: a case report (43-46)     SeyedPouzhia Shojaei,    Mehran Kouchek,    Mir Mohammad Miri,    Sara Salarian,    Mohammad Sistanizad,    Shideh Ariana,    Maryamsadat Hosseini,    Simindokht Shoaee,    Mehrdad Haghighi,    Mahmood Nabavi,    Mohammad Farahbakhsh,    Padideh Ansar,    Mahsaalsadat Mirhadi,    Fahimeh Hadavand Special Article -------- How to manage perioperative patient flow during COVID-19 pandemic: a narrative review (47-56)     Ghasem Janbabai,    Sajjad Razavi,    Ali Dabbagh Journal of Cellular & Molecular Anesthesia http://journals.sbmu.ac.ir/jcma

9

I truly appreciate. Very informative

The longer you think about it, the more surfactant (actualy phospholipid structures like soap) is likely to play a roll in people getting sick or not. Risk groups could be the ones with less/compromised surfactant in the lungs. Which is the case in older sedentary people, diabetics suffre from glycogenation of the phospholipid structure and mothers have more babies with RDS. Sports and exercise stimulate pneumocytes type II and surfactant secretion. Babies with surfactant RDS souffre from hypertention and so on. The way it works could be hiding the Ace 2 receptors from the lipid corona of the virus or on the other hand maybe killing the virus by destruction of the lipid corona. It could in this case also be interesting to test if this virus COVID19 has a higher resistance to phospholipids and need higher concentration to be neutralised then the less virulent ones. Exogenous administration of surfactant is costly, but could we find other ways of using this in treatment? Are there less costly phospholipids you can inhale, use in respirator or aerosoll? N-acetylcysteine as supportive therapy? GLP1 agonist in diabetics? it surely worth investigating what we have allready on the pharmaceutical marked and find out if any work on the actual cases which are not yet highcare IC, the amount of people affected is astronomical.

I think the correlation between COVID-19 severity, age, and pre-existing conditions has to do with collateral ventilation facilitating viral spread (Channels of Lambert) and destroying surfactant production (Pores of Kohn).

1- The dramatically reduced oxygenation in the presence of reasonable ventilation and increased compliance speak to increased capacity in the face of obstruction. If Sars-2 is destroying the epithelium in Kohn pores (reducing surfactant production) as well as dilating channels of lambert, this makes sense on two levels.

2- children develop collateral ventilation over time. Patients with obstructive pulmonary disease from any reason have 10x collateral ventilation (and much more severe disease). People over 80 have dramatically increase collateral respiration.

This hypothesis suggests using early surfactant, and considering drugs that constrict Channels of Lambert (cholinergics, iso/halofluorane) to stop spread early. Article The Clinical Significance of Collateral Ventilation

When i first saw the structure of covid-19, the first thing that came to my mind is micelle/liposome. Then I ask this question, could surfactants have some association with covid-19? I googled and found this discussion. I am glad many had the same questions.

I would like to ask Amy Baxter if asthma is also associated with collateral ventilation...

Why YES! turns out any obstructive respiratory disorder results in 10x collateral ventilation

Thanks a lot Amy. I was trying to find statistics about covid19 and asthma as comorbidity factor

Jana Kopincova added a reply March 26

Thank you, Ali, very detailed paper! So, could be surfactant helpful when we know all this? Should we try to contact those people with our ideas?

My name is Natalia , I work in surfactant in Hantavirus and Flu infection diseases in Argentina. I totally agree with you, surfactants have a primary role in COVID 19.

Hi, Jana and Natalia,

I even have sent a letter about the topic to any clinician I could know.

ARDS clinical trials of surfactant usually include ARDS from very different etiology, plus specific surfactant preparations and dose are other issues.

COVID-19 is another story. The following is taken from https://emcrit.org/ibcc/covid19/

In the original document, the references to surfactant are labelled as recently added. There is even hyaline membrane formation

pathophysiology

(1) Hypoxemic respiratory failure

• The primary organ failure is hypoxemic respiratory failure.
• COVID-19 can reduce surfactant levels, potentially leading to atelectasis and de-recruitment.
• Pneumocytes with viral cytopathic effect are seen, implying direct virus damage (rather than a purely hyper-inflammatory injury; Xu et al 2/17).
• Autopsy studies show pathologic features of ARDS (diffuse alveolar damage and hyaline membrane formation).  It's unclear whether this is due to viral infection itself, or ventilator-induced lung injury

(2) Cytokine storm is listed in second play

📷ReplyForward

Dear Natalia and Dahis,

thank you so much for your help! Me and Anne Da Silva tried to contact some people whose clinical impact is higher than ours, however, they often agreed completely but did not forward this idea to their colleagues..

I wish so much that surfactant will save lives and shorten the ventilation needs!

Dahis, thank you for the reference, it is really valuable!

I wish the same, on my side I am trying to explain my hypothesis in my country, but I am not a doctor, I am immunologist and it is difficult for them to understand and start a clinical trial.

Look: https://latamisrael.com/english/new-hope-for-coronavirus-patients-with-acute-respiratory-distress-syndrome

Wahouuuuhhhh Wonderful!!! Thank you Natalia!!!

There are a lot of relevant papers showing promising results. Unfortunately there have been extensive studies with disappointing results. The question is what is different when the surfactant works vs when it doesn't work. It may be just a question of how bad the pneumonia is. If the lung is flooded with liquid and highly inflamed it may not be able to do much.

I’ve been reading this thread with much interest. Although I’m not a doctor but an engineer, I spent quite a bit of time dealing with the topic while developing LibAirator, a salt therapy device. The LibAirator produces nanometer-scale salt particles that cover the airways with a super-thin salty layer. From the effect it produces (obviously helps mucus clearance) and the physical amount (micrograms), I came to the conclusion that the underlying phenomenon is that it practically fixes the existing surfactant layer (this makes sense chemically), and maybe, it can even work as a surfactant on its own. When considering external surfactants, you may want to consider such a solution, as it is readily available. Due to nanosized particles, there are no “premature” deposition issues, the particles reach everywhere. Please feel free to ask questions.

What I am mainly concerned with these days is whether getting into the serious stage of COVID-19 can be prevented. All those affected seriously seem to have compromised mucociliary clearance that allows the infection to go deep in a short time, resulting in the known consequences. My idea is that such a scenario could be prevented by improving mucociliary clearance to healthy levels. I have detailed this in a “Call for cooperation” here: https://en.libairator.com/call-for-cooperation-covid-19 . Please look at it as proposal from someone who’s main goal is to make something useful. I’d be interested in hearing your comments.

Call for paper for rapid publication on Covid-19 manuscripts in JSSM issue 2020

Submission is open all year round and must follow the format and guidelines on the website. Submit your articles to https://mc04.manuscriptcentral.com/jsusm

Email: [email protected]

I would appreciate anyone in this discussion to contribute your research findings

The reason you are supposed to wash your hands is "'Surfactants basically pry open coronavirus particles and encapsulate viral molecules within micelles suspended in the lather clinging to your hands,'” says Thomas Gilbert, an associate professor of chemistry and chemical biology at Northeastern." Would pulmonary surfactant, then, kill Covid-19 since it also contains lipids? What about other natural surfactants that the body produces?

Elliot Kennel As a tensioactif compound, the lipidic phase of pulmonary surfactant clearly exhibit a virucid activity. In addition, hydrophilic proteins SP-A and SP-D may have an indispensible role as elements involved in the innate defense system. Both proteins are capable of binding to a multitude of different pathogens including fungi and yeast, Gram-negative and Gram-positive bacteria, mycobacteria, mycoplasma, and viruses.

Article Surfactant and its role in the pathobiology of pulmonary infection