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PostPosted: Tue Sep 15, 2009 1:07 pm 
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I wrote this originally back in June and it was requested I repost it periodically. As this has now been vetted by MKey and others I will put it up and make it a sticky. If any of the admins think it should not be sticky please feel free to remove the flag. The point here is to illustrate, for the layman, why some people who die from flu have very rapid onset of symptoms and progress to death within hours to days versus those who die a week or more after symptoms begin. Please note, the length of time can change based on early treatment with heroic medical care.

If anything is found to be incorrect please let me know.

The original is located here: http://diaryofafluyear.blogspot.com/2009/06/rapid-onset-of-symptoms-and-death.html

Quote:
There was recently a discussion on the Rhizalabs Flutracker message board about the recent (as of mid-June) spate of rapid deaths in young, healthy people. I posted an explanation of why viral pneumonia from influenza seems to cause rapid onset of illness and death (often less than 24 hours) versus more "normal" bacterial pneumonia triggered deaths. This was apparently a well-received explanation as it was requested I repost it periodically. I am posting it here so I can have easy access to it. Note there may be some finer technical details that are off, but I believe this is largely good enough for the layman.

From various things I have read it seems the immune system treats a viral infection of the lungs much differently than it does a bacterial infection. Normally, your immune system has to fight off bacteria by having certain types of immune cells eat (phagocytose) the organism. This can be done without the the extremely lethal parts of the immune system.

But a virus enters the cell and hijacks the internal mechanisms in order to make more virions. The body must kill parts of itself, either by triggering the infected cell to die (apoptosis) or outright killing it. Whena virus infects the lungs the body has to mount an attack with essentially its full arsenal. This leads to a cascade that can result in, as I understand it, the spongy material of the lungs being transformed into scar tissue.

The progression is viral pneumonia -> cytokine storm -> ARDS -> (multiple organ failure) The cytokine storm is a result of the viral pneumonia and ARDS and multiple organ failure are the consequences of the cytokine storm. This all happens very quickly.

Bacterial pneumonia takes advantage of the weakness in the body generated by the viral infection, and typically takes longer to develop. This is the cycle of being sick, getting better, then taking a turn for the worse.

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I am a layman with a background in the physical sciences.


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PostPosted: Tue Sep 15, 2009 5:08 pm 
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wotan wrote:
The progression is viral pneumonia -> cytokine storm -> ARDS -> (multiple organ failure) The cytokine storm is a result of the viral pneumonia and ARDS and multiple organ failure are the consequences of the cytokine storm. This all happens very quickly.


I am not quite sure if cytokine storm is necessarily part of the rapid deaths pathology. I am no specialist, and the following arguments arise from earlier readings, as well as informal discussion with ICU hospital staff.

ARDS – Acute Respiratory Distress Syndrome - requires mechanic ventilation, a frequent hospital issue of S-OIV severe cases. The viral infection induces a controlled and selective destruction of infected cells (from both apoptosis and cell destruction by lymphocytes).

An excess of dead cells degradation products can induce kidneys failure, a frequent onset of MODS – Multiple Organ Distress Syndrome. The concomitant use of mechanical ventilation AND hemodialysis to supplement kidney function saved a number of lifes already. ARDS and MODS can both occur without cytokine storm.

As far as I know, cytokine storm involves loss of regulatory mechanisms by immunologic system, producing an “indiscriminate” cell destruction (i.e. infected or not). Such an overreaction can damage not only healthy lung cells, but other healthy tissues as well. Once triggered, no therapy proved to control and revert such a reaction.

I assume that elevated levels of pro-inflammatory cytokines can be detected by apropriate lab tests. I have no concrete example of cytokine storm events on S-OIV H1N1 patients so far. On the other hand, it is plausible that cytokine storm shows up sometime in the present pandemic.

I am not sure about the sudden deaths! Could a large number of cytokine storm occurrences go on undetected? It is plausible only in the lack of a specific bias by the health staff. I don’t know to what extent monitoring patients’ pro-inflammatory cytokines levels is a standard procedure. As swine H1N1 broadens its pathology spectrum, atypical clinical developments deserve detailed and un-biased characterization.


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PostPosted: Wed Sep 16, 2009 5:37 pm 
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You said: "On the other hand, it is plausible that cytokine storm shows up sometime in the present pandemic."

Happy Scientist says:
Shows up? Look through the CDC press briefing: 05/15/2009

"Stacey Singer: Hi. Thanks for taking my call. My question is in the serious cases where we′re seeing hospitalizations in this country and in Mexico and the deaths as well, has the cytokine storm frequently play a role in the deaths? What are people dying of when they′re trying?

Dan Jernigan: The issue of cytokine storm is one that clearly influenza has been associated with in the past. We have reason to believe that could be a part of the cause here. The numbers of individuals that have died that we actually have appropriate tissues and enough information to study is still pretty small. We have seen that some individuals do appear to have what looks like viral pneumonia. So that is a direct infection of the lower respiratory track by the flu virus. And so as we learn more, I think we′ll be able to say if there are unique features about the H1N1, but what we are seeing so far are the kinds of outcomes that have been previously described for influenza, but that′s something that we are very interested in and we want to learn more about. "


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PostPosted: Wed Sep 16, 2009 5:48 pm 
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Read the FLU then compare the descriptions in that book to this
Report:
http://www.recombinomics.com/News/06270 ... Aires.html


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PostPosted: Thu Sep 17, 2009 1:27 pm 
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TheHappyScientist wrote:
You said: "On the other hand, it is plausible that cytokine storm shows up sometime in the present pandemic."

Happy Scientist says:
Shows up? Look through the CDC press briefing: 05/15/2009

"Stacey Singer: Hi. Thanks for taking my call. My question is in the serious cases where we′re seeing hospitalizations in this country and in Mexico and the deaths as well, has the cytokine storm frequently play a role in the deaths? What are people dying of when they′re trying?

Dan Jernigan: The issue of cytokine storm is one that clearly influenza has been associated with in the past. We have reason to believe that could be a part of the cause here. The numbers of individuals that have died that we actually have appropriate tissues and enough information to study is still pretty small. We have seen that some individuals do appear to have what looks like viral pneumonia. So that is a direct infection of the lower respiratory track by the flu virus. And so as we learn more, I think we′ll be able to say if there are unique features about the H1N1, but what we are seeing so far are the kinds of outcomes that have been previously described for influenza, but that′s something that we are very interested in and we want to learn more about. "


Dan Jernigan statement released May 15, just maintains that cytokine storm “could be a part of the cause here” [Mexico].

Quote:
Read the FLU then compare the descriptions in that book to this
Report:
http://www.recombinomics.com/News/06270%20...%20Aires.html

I essentially agree with the Diary of a Flu Year description typical development of a fatal influenza infection viral attack, followed by an opportunist bacterial infection. The same is true about the condensed description of the cytokine storm event.

On the other hand, I argue an intermediary scenario, (ARDS plus MODS pathology) does occur. This conjunction was actually observed in severe patients on Hospital ICU.

An excess of dead cells degradation products can induce kidneys failure, a frequent onset of MODS – Multiple Organ Distress Syndrome. The concomitant use of mechanical ventilation AND hemodialysis is sometimes required to supplement kidney function. This conjunction of interventions, as was informally told, already controlled a number of severe cases which ultimately recovered.

The unusual transformation of the lungs tissue, from spongy material into scar tissue, describen on the Flu Diary, does indeed occur on severe cases of S-OIV H1N1. As a matter of fact, this lung elasticilty alteration (and concomitant tendency to collapse) is one of the non-standard challenges on H1N1patients [mechanical] ventilation.

It has been proposed that unusual hight positive pressure could be required. This idea was presented in a South American physician meeting (from Chile, as I can recall). I learned this approach from a hospital ICU physician who went to this meeting, so my translation may lack important details. Otherwise, not very complex concepts involved.

Trouble is: non-standard ventilator higher POSITIVE pressure can be necessary to expand the otherwise collapsed lungs, which are fibrous and and thick (inflammation). This effect was first verified by RX checking the actual lung response to different pressures. A number of S-OIV H1N1 young adults responded better to higher positive pressures.

On the other hand, standard respirator pressure settings are mostly designed to ventilate the rather elastic tissue of a secondary bacterial infection. I feel that this positive pressure approach deseve further checking.
----------------------------------

Argentina: There were two issues of Recombinomics Commentary covering Argentina on June 27. Here is the Buenos Aires La Nacion newspaper link on this issue (in Spanish, google translation needed):http://www.lanacion.com.ar/nota.asp?nota_id=1144216
I also quote a couple of translated paragraps from the mentioned Commentary (underlines are mine):

Quote:
"We're seeing the placement of young patients, between 15 and 50 years with pneumonia, some rapidly evolving towards a gravity which for many is unusual, in which the lung is' fire 'in a matter of hours," said Dr. Jorge San Juan, head of the Department of Intensive Care Hospital Muñiz.

"The bodies were viscera, meninges and brain swollen, a little common factor in death from influenza. Additionally, the lungs were in bad shape, with some spots we could not identify. The studies sent pathology, " said the coroner who asked not to publicize his name until the health authorities take note of it found.

The inflammation quick progress on lungs, in aggressive viral pneumonia in young adults. This sudden evolution of otherwise healthy, young people, is atypical and paradoxal to doctors. Bear in mind that last pandemic was in 1968. Very few (if any) members of hospital staff had did experienced last pandemics. It is unexpected response. Hardly seen on influenza young adultspatients! Well, this is ARDS! Not as radical as cytokine storm (many patiend did survived ARDS+MODS!), and yet agressive enough.

Otherwise, [non specified] viscera meninges and brain presents inflammation (not necessarily uncontrolled). The newspaper does not clarify if these unusual occurred at the same time and in all patients. In the cytokine storm scenario, other tisues would show more than inflammation. They would become mushy and tend to liquefy (roughly analogue to Ebola pathology).

Otherwise, I have not seen so far any unambiguous cytokine storm detection on S-OIV H1N1 patients. On the other hand, I still think it is plausible that cytokine storm shows up, and any kind of “early warning” protocol could prove useful.


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PostPosted: Sat Sep 19, 2009 1:11 am 
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Well sometimes when it looks like an orange, smells like an orange, and feels like an orange, it’s just an orange. :blush:

Did you read the study which showed the lungs looking more like H5?
http://www.ctv.ca/servlet/ArticleNews/s ... hub=Health

I personally feel the kidneys are failing because the CO2 levels are extremely high from lack of O2 and the patients are going into severe acidosis, the kidneys work as much as they can to restore the balance but fail and you have a cascade effect. As you are aware renal excretion is the primary means of eliminating acid from the body.

Considering the virus enzymology it wouldn’t surprise me one bit if those with
High anion gap (Ketoacidosis/Diabetic ketoacidosis, Lactic) • Normal anion gap (Hyperchloremic, Renal tubular) and Respiratory acidosis end up with massive viral loads.

We know H5 is associated with "cytokine storm"
26. de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med. 2006;12(10):1203-7.

As far as novel H1N1 you may find this read of interest:
http://www.jidc.org/index.php/journal/a ... wFile/18/9

At this point where Novel H1N1 is concerned it is not what I am seeing that is bothering me, it's what I am not seeing.
Where are the sequences on NCBI from the areas with highest CFRs? PB1 in particular?

And note how the very term "cytokine storm", all but once, has been avoided in all press briefings from the CDC. You would think they would be able to rule that out or note it from what happened this spring. But nothing, just more radio silence.
I have seen the graphs, we know the mortality is peaking in 20-40 year old's at this time. Although I do expect more children to be infected I expect more middle age healthy people to die from this as they have done so all spring and summer but this fall will probably be higher numbers unless by some miracle the peak is after the vaccination campaign. Not likely.



Anymore, It is what I do not see that concerns me. Silence speaks volumes.

Have a nice night:)


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PostPosted: Sat Sep 19, 2009 1:25 am 
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Oh here you go I found it:
http://www.macleans.ca/article.jsp?content=n032240921
Lung damage in fatal swine flu cases more bird flu than seasonal flu: expert
September 3, 2009 - 16:07
Helen Branswell, THE CANADIAN PRESS

Some more links
http://www.taipeitimes.com/News/world/a ... 2003453713
"including damage to the alveol"

And then there is this one
http://content.nejm.org/cgi/content/full/NEJMoa0904252
"Possible mechanisms of damage include direct injury to the respiratory epithelium15 with a secondary cytokine storm."

Note figure 3
Figure 3. Initial Radiograph of the Lung and Lung-Tissue Sample from Patient 3.

"The radiograph (Panel A) shows bilateral alveolar opacities in the base of both lungs that progressed and became confluent. The specimen (Panel B, hematoxylin and eosin) shows necrosis of bronchiolar walls (top arrow), a neutrophilic infiltrate (middle arrow), and diffuse alveolar damage with prominent hyaline membranes (bottom arrow). Bacterial cultures were negative on admission, and no evidence of bacterial infection of the lungs was found. The patient ultimately died."


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PostPosted: Sat Sep 19, 2009 3:01 am 
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TheHappyScientist wrote:
Well sometimes when it looks like an orange, smells like an orange, and feels like an orange, it’s just an orange. :blush:

Did you read the study which showed the lungs looking more like H5?
http://www.ctv.ca/servlet/ArticleNews/s ... hub=Health

I personally feel the kidneys are failing because the CO2 levels are extremely high from lack of O2 and the patients are going into severe acidosis, the kidneys work as much as they can to restore the balance but fail and you have a cascade effect. As you are aware renal excretion is the primary means of eliminating acid from the body.

Considering the virus enzymology it wouldn’t surprise me one bit if those with
High anion gap (Ketoacidosis/Diabetic ketoacidosis, Lactic) • Normal anion gap (Hyperchloremic, Renal tubular) and Respiratory acidosis end up with massive viral loads.

We know H5 is associated with "cytokine storm"
26. de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med. 2006;12(10):1203-7.

As far as novel H1N1 you may find this read of interest:
http://www.jidc.org/index.php/journal/a ... wFile/18/9

At this point where Novel H1N1 is concerned it is not what I am seeing that is bothering me, it's what I am not seeing.
Where are the sequences on NCBI from the areas with highest CFRs? PB1 in particular?

And note how the very term "cytokine storm", all but once, has been avoided in all press briefings from the CDC. You would think they would be able to rule that out or note it from what happened this spring. But nothing, just more radio silence.
I have seen the graphs, we know the mortality is peaking in 20-40 year old's at this time. Although I do expect more children to be infected I expect more middle age healthy people to die from this as they have done so all spring and summer but this fall will probably be higher numbers unless by some miracle the peak is after the vaccination campaign. Not likely.



Anymore, It is what I do not see that concerns me. Silence speaks volumes.

Have a nice night:)

Hey, Happy, take it easy! I just can't read all those papers at once!

Othervise, take a look on the link next door in this forum, and see the last post! As you see, I am also seeking for cytokine storm in H1N1! I just didn’t find any concrete case yet!
http://fluboard.rhizalabs.com/forum/viewtopic.php?f=5&t=1260&sid=bed069adfb47483a83d1e05463a9a5d1
_____________________________

About the good links you posted:

http://www.ctv.ca/servlet/ArticleNews/s%20...%20hub=Health
Quote:
TORONTO -- The lungs of people who have died from swine flu look more like those of the victims of H5N1 avian influenza than those of people who succumb to regular flu, the chief of infectious diseases pathology at the U.S. Centers for Disease Control says.


Agree!
- Regular flu: viral infection>>bacterian infection.>> Moderate lung inflammation.
- H1N1 severe cases: aggressive viral infection >> ARDS >> Acute lung inflammation

Otherwise, News doesnt not even mention cytokine storm!!!


http://www.jidc.org/index.php/journal/a%20...%20wFile/18/9
My view:
Cytokine storm is mentioned as a hypothesis, in the context of an alternative therapy via immunomodulators.

Quote:
The cytokine hypothesis proposes that the host immune system and autoinflammation is the main cause underlying respiratory distress in severe cases of influenza. The “cytokine storm” is a consequence of disregulated immune responses to the virus [2]. Influenza virus employs human signaling pathways to replicate, interfering with normal cell physiology and leading to undesired effects such as overinduction of cytokines and chemokines. Host intracellular signaling pathways or host immune mediators, blocked by immunomodulatory drugs, are not affected by viral mutations and therefore may be suitable targets for treating severe influenza patients.


http://www.macleans.ca/article.jsp?content=n032240921
Was already in my logbook.
Quite interesting discussion, again comparison with H5N1; However, not a single mention of cytokine storm yet!

http://www.taipeitimes.com/News/world/a%20...%202003453713My view:
again comparison with H5N1; again not a single mention of cytokine storm!
Quote:
“This is almost exactly what we see with avian flu,”


http://content.nejm.org/cgi/content/full/NEJMoa0904252
Excelent paper!!!; I already posted this NEJM in the topic “A new “strange disease…”, last Sep 15, 2009 8:40. http://fluboard.rhizalabs.com/forum/viewtopic.php?f=5&t=1260&sid=bed069adfb47483a83d1e05463a9a5d1
It is the best H1H1 patology description I have sees so far.

As you see, we are tracking this flu and parts of our trails do overlap.
I am not convinced that the H1N1 lung injuries does arise from a cytokine storm.
I still believe that the hard lung inflammation by the virus alone. It is also very different from lung damage by [seasonal] influenza followed by a [secondary]bacterian infection.

I see the cytokine storm as an "avalanche-like" runaway irreversible reaction, which attacks many different types of healty tissue. Perhaps close to ARDS + MODS, but not exactly the same!

I will download the cytokine storm in H5N1 paper you recommended:
Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med. 2006;12(10):1203-7.

Otherwise, I will try to follow closely the rest of your argument latter!


Last edited by neuromedia on Sun Sep 20, 2009 9:13 am, edited 1 time in total.

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PostPosted: Sat Sep 19, 2009 7:11 am 
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Last edited by MtnLife4u on Thu Nov 05, 2009 12:13 pm, edited 1 time in total.

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PostPosted: Sat Sep 19, 2009 7:45 pm 
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TheHappyScientist wrote:
Read the FLU then compare the descriptions in that book to this
Report:
http://www.recombinomics.com/News/06270 ... Aires.html


Back to Argentina fatalities and lung condition, I quote the Buenos Aires Physician description:
Quote:
"We're seeing the placement of young patients, between 15 and 50 years with pneumonia, some rapidly evolving towards a gravity which for many is unusual, in which the lung is' fire 'in a matter of hours," said Dr. Jorge San Juan, head of the Department of Intensive Care Hospital Muñiz.

"The bodies were viscera, meninges and brain swollen, a little common factor in death from influenza. Additionally, the lungs were in bad shape, with some spots we could not identify. The studies sent pathology, " said the coroner who asked not to publicize his name until the health authorities take note of it found.

Soaring Death Rate in Buenos Aires Raises Pandemic Concerns
Recombinomics Commentary 18:03
June 27, 2009
http://www.recombinomics.com/News/06270901/H1N1_Buenos_Aires.html


For the sake of comparison, here is a description of a typical
Spanish flu post-mortem condition, a "pathological nightmare", as a 1918 physician putted:

Quote:

".... why should the sickness affect so many organs of the body normally untouched?

... most often the disease resembled encephalitis, with the patient lapsing into a coma

... a dilation of the heart but even of fatty degeneration ...

... a cough so intense that it ruptured the muscles of a soldier's rectum ...

... retention of urine...puffy faces and swollen ankles of acute nephritis ...

... the lungs were the organs most vitally affected ...

... a patient's face so contorted in death that even close friends couldn't recognize him ...

... and autopsy surgeons were encountering what one doctor termed 'a pathological nightmare' ...

... lungs up to six times their normal weight, looking 'like melted red currant jelly
.'"


Source=
THE PLAGUE OF THE SPANISH LADY: The Influenza Pandemic of 1918-1919 by Richard Collier, Atheneum Publishing, New York, 1974, pp. 220-221.

The very structure of the lungs melts down. I assume the latter picture as a reference for a full developed cytokine storm!

I believe that among the valuable links in the anthology you already posted, I still can’t recognize the 1918 case description. The NEJM description of 18 Mexican cases is quite detailed, and I am unable to identify possible parallels. Is the viral ARDS halfway to the 1918 case description? I am unable to argue further. Otherwise documented H1N1 pathology does not appear to me as the same thing! Is my cytokine storm pathology picture incorrect?


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