Let's the debate begin:coffee:
My question is WHY ?
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http://www.cdc.gov/ncidod/EID/13/1/173_174.htm
Volume 13, Number 1January 2007
Letter
Questioning Aerosol Transmission of Influenza
To the Editor: We have reviewed the literature cited in Tellier's Review of Aerosol Transmission of Influenza A Virus (1 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1a)) and disagree that it supports the conclusions drawn regarding the importance of aerosols in natural influenza infection. In certain cited studies, researchers recovered viable virus from artificially generated aerosols; this is not evidence that aerosol transmission leads to natural human infection (2,3 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1a)). By standard definitions, the rarity of long-range infections supports the conclusion that effective aerosol transmission is absent in the natural state (4 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1a)) (www.cdc.gov/ncidod/dhqp/gl_isolation_hicpac.html (http://www.cdc.gov/ncidod/dhqp/gl_isolation_hicpac.html)). The superior efficacy of inhaled versus intranasal zanamivir is referenced as support for the idea that the lower respiratory tract is the preferred site of influenza infection; however, 1 study cited is insufficiently powered, and the other 2 do not compare the intranasal and inhaled routes (57 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1a)). The major site of deposition of inhaled zanamivir is the oropharynx (77.6%), not the lungs (13.2%) (www.gsk.ca/en/products/prescription/relenza_pm.pdf (http://www.gsk.ca/en/products/prescription/relenza_pm.pdf)). In another flawed study (8 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1a)), study participants naturally infected with wild-type virus are compared with study participants experimentally infected with an attenuated strain.
In a review of such relevance, critical analysis of confounding factors is necessary. The Alaska Airlines outbreak (9 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1a)) is presented as proof of airborne influenza transmission; however, droplet/contact transmission remains plausible because passenger movement was not restricted and the index patient was seated in high-traffic area. In the Livermore Hospital study (10 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1a)), serious confounders such as bed arrangements, number of influenza exposures, patient mix, and ventilation were not accounted for.
We encourage readers of Teller's article to review the relevant primary literature. We believe that the only reasonable conclusion that can be drawn at this time is that aerosol transmission does not play a major role in natural influenza epidemiology. Whether aerosols play any role in the transmission of influenza is a question demanding an answer; it is clear that we do not yet have that answer.
Camille Lemieux,* http://www.cdc.gov/ncidod/EID/images/cdc/icon_email.gif (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#comment) Gabrielle Brankston,*1 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1f) Leah Gitterman,* Zahir Hirji,* and Michael Gardam*
*University Health Network, Toronto, Ontario, Canada; and University of Toronto, Toronto, Ontario, Canada
Suggested citation for this article:
Lemieux C, Brankston G, Gitterman L, Hirji Z, Gardam M. Questioning aerosol transmission of influenza [letter]. Emerg Infect Dis [serial on the Internet]. 2007 Jan [date cited]. Available from http://www.cdc.gov/EID/13/1/173_174.htm
References
Tellier R. Review of aerosol transmission of influenza A virus. Emerg Infect Dis. 2006;12:165762.
Hemmes JH, Winkler K, Kool SM. Virus survival as a seasonal factor in influenza and poliomyelitis. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=13953681&dopt=Abstract) Antonie Van Leeuwenhoek. 1962;28:22133.
Loosli C, Lemon H, Robertson O, Appel E. Experimental air-borne influenza infection. 1. Influence of humidity on survival of virus in air. Proc Soc Exp Biol Med. 1943;53:2056.
Health Canada. Routine practices and additional precautions for preventing the transmission of infection in health care: revision of isolation and precaution techniques. Canadian Communicable Disease Report. 1999;25(Suppl4).
Calfee DP, Peng AW, Cass LM, Lobo M, Hayden FG. Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10390212&dopt=Abstract) Antimicrob Agents Chemother. 1999;43:161620.
Kaiser L, Henry D, Flack NP, Keene O, Hayden FG. Short-term treatment with zanamivir to prevent influenza: results of a placebo-controlled study. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10722450&dopt=Abstract) Clin Infect Dis. 2000;30:5879.
Hayden FG, Gubareva LV, Monto AS, Klein TC, Elliot MJ, Hammond JM, et al. Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11058672&dopt=Abstract) N Engl J Med. 2000;343:12829.
Little JW, Douglas RGJ, Hall WJ, Roth FK. Attenuated influenza produced by experimental intranasal inoculation. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=479857&dopt=Abstract) J Med Virol. 1979;3:17788.
Moser MR, Bender TR, Margolis HS, Noble GR, Kendal AP, Ritter DG. An outbreak of influenza on a commercial airliner. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=463858&dopt=Abstract) Am J Epidemiol. 1979;110:16.
McLean RL. The effect of ultraviolet radiation upon the transmission of epidemic influenza in long-term hospital patients. Am Rev Respir Dis. 1961;83:368.1Current affiliation: Durham Region Health Department, Whitby, Ontario, Canada
In response: Coughing and sneezing during influenza produce virus-containing aerosols. In the laboratory, influenza virus in homogeneous aerosols, free of large droplets, can infect volunteers at very small doses; studies of infectivity decay in aerosols show persistence for hours. These observations required the generation of artificial aerosols but were performed under conditions that do not enhance stability or virulence (1,2 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1b)). Therefore, they have great relevance for natural infections.
The scarcity of infections that are transmitted long range in well-ventilated areas does not rule out infectivity of aerosol-size particles near patients. That only 13% of inhaled zanamivir is deposited in the lungs is not important: after inhalation, the zanamivir concentration throughout the respiratory tract is >10 μmol/L, orders of magnitude above the 50% inhibitory concentration (3 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1b)). Intranasal zanamivir is protective against large droplets (4 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1b)), which are trapped in the nose (5 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1b)). The requirement for inhaled zanamivir in natural infections (6,7 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1b)) points to aerosol contribution and to the lower respiratory tract as the preferred site.
Little et al. (8 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1b)) compared the severity of natural illness caused by H3N2 strains from 1974 and 1975 to that caused by experimental intranasal inoculation from H3N2 strains from 1972, 1974, and 1975. The challenge strains underwent few passages; characterizing them as "attenuated" is incorrect.
Although large droplets probably accounted for some cases in the Alaska Airlines outbreak (9 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1b)), this outbreak was remarkable for its high attack rate (72%) and for deficient ventilation, which would increase transmission by aerosols but not by large droplets. Passengers with influenza are common, yet with proper ventilation such an attack rate is uncommon.
During the Livermore Hospital study (10 (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#1b)), respiratory infections other than influenza occurred in both groups. It was assumed that visitors and staff would provide equivalent introductions of the virus during the several months of the study; 4 study participants in the irradiated building seroconverted, but the virus did not propagate. The concern by Lemieux and colleagues about ventilation is odd because it would affect mostly aerosol transmission.
I concur with encouraging readers to review the original references. They make a compelling case for the importance of aerosol transmission. In contrast, no convincing data rule it out.
Raymond Tellier* http://www.cdc.gov/ncidod/EID/images/cdc/icon_email.gif (http://www.cdc.gov/ncidod/EID/13/1/173_174.htm#comment)
*Hospital for Sick Children, University of Toronto, Toronto, Canada
Suggested citation for this article:
Tellier R. Questioning aerosol transmission of influenza: in response [response]. Emerg Infect Dis [serial on the Internet]. 2007 Jan [date cited]. Available from http://www.cdc.gov/ncidod/EID/13/1/173_174.htm
References
Douglas RG. Influenza in man. In: Kilbourne ED, editor. The influenza viruses and influenza. New York: Academic Press; 1975. p. 375447.
Schaffer FL, Soergel ME, Straube DC. Survival of airborne influenza virus: effects of propagating host, relative humidity, and composition of spray fluids. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=987765&dopt=Abstract) Arch Virol. 1976;51:26373.
Cass LM, Brown J, Pickford M, Fayinka S, Newman SP, Johansson CJ, et al. Pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10429837&dopt=Abstract) Clin Pharmacokinet. 1999;36(Suppl 1):2131.
Calfee DP, Peng AW, Hussey EK, Lobo M, Hayden FG. Safety and efficacy of once daily intranasal zanamivir in preventing experimental human influenza A infection. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12731753&dopt=Abstract) Antivir Ther. 1999;4:1439.
Knight V. Airborne transmission and pulmonary deposition of respiratory viruses. In: Hers JF, Winkles KC, editors. Airborne transmission and airborne infections VIth International Symposium on Aerobiology. New York: Wiley; 1973. p. 17582.
Kaiser L, Henry D, Flack NP, Keene O, Hayden FG. Short-term treatment with zanamivir to prevent influenza: results of a placebo-controlled study. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10722450&dopt=Abstract) Clin Infect Dis. 2000;30:5879.
Hayden FG, Gubareva LV, Monto AS, Klein TC, Elliot MJ, Hammond JM, et al. Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11058672&dopt=Abstract) N Engl J Med. 2000;343:12829.
Little JW, Douglas RG Jr, Hall WJ, Roth FK. Attenuated influenza produced by experimental intranasal inoculation. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=479857&dopt=Abstract) J Med Virol. 1979;3:17788.
Moser MR, Bender TR, Margolis HS, Noble GR, Kendal AP, Ritter DG. An outbreak of influenza aboard a commercial airliner. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=463858&dopt=Abstract) Am J Epidemiol. 1979;110:16.
McLean RL. Discussion after paper: the mechanism of spread of Asian influenza. Am Rev Respir Dis. 1961;83:368.
The data suggests the risk of infection is probably related to the dose of particles: the more the exposure, the more likely it is you will be infected. This relationship obviously can't be reduced to a single number.
As in every infectious disease, the dosis of infectious agent (as well as the site of entry) is the main determinant of the outcome .
As the survivalrate of Influnzaviruses depends in high degree on environmental factors and is related to the subtype, the influence of these factors will be very different from case to case
The dosis necessary for human infection is unknown, but it estimated 6-7 log10 EID50/ml.
and how many viruses are that ?
Yes is is hard to tell & many experimental assessment vary depending on the theoretical basis they are based on.
But there is something I can tell from the clinic data I often see in the laboratory where I work.
The usual detection limit given to the real-time fluorogenic PCR reaction test we did is often recorded in literracy as ranging from 1 to 10 copy per reaction.
We use 140ul of sample witch mean 140ul/1000ul = 0.14ml
so we have around 7 to 70 copy/ml of sample as our detection limit.
The strongest positives samples taken from swine nasal swabs I saw as well as lungs samples where positeve about 15 to 18 cycles(2x) higher than the detection limit.
That mean around 230000 to 1835000 copy of the matrix gene, the gene that we probe in that test for 7c/ml or 2300000 to 18350000 copy if we take the 70copy by ml estimate.
So by theses experimentals data I saw every day in the lab, a strong positive sample of nasal secretion from a sick pig rage from 230000 to 18350000 copy of the matrix gene of the virus...
I think we can grossly round theses numbers to around the 1 to 10 millions copy/ml in our secretion.
Is the matrix gene / total virus stable ???
Is that ratio = 1/1 ?
When we test for viral culture on plate cells we commonly found viral load even ten cycles stronger than thoses strong clinical samples.
That mean around 235millions copy/ml & up to 18,9 billions copy/ml for that viral culture.
But that said, theses calculation are based on too much asumption that are not proven, like the 1 to 10c/reaction limit & the 1/1 matrix gene/total virion ratio etc.
looking up the old Tellier article ... they say that airborne particles are
less than 3 microns in diameter while particles of size >10 micrometers
fall quickly to ground.
If we assume homogenious distribution of viruses in the body
and take the concentration from your strong samples, then there could be
hardly more than 1 virus in an aerosole and less than 1 per thousand
aerosoles would contain a virus.
When we pack them dense however, an aerosole could contain 30000 viruses.
Maybe viruses tend to cluster, I don't know.
With one breath you might inhale many aerosoles, how many ?
Suppose one person produces 1ml of fluid which is then aerosolized and
put into a room, that would be 1 million viruses and 40 billion aerosoles.
A second person who breathes the air in that room might inhale maybe 1%
of these, which would give an initial dose of 10000 viruses.
That's about the amount which you could get from one large droplet
with 1mm diameter. That should be enough to cause infection.
I don't see the reason, why 1 virus shouldn't have a chance of at least
1:10000 then to cause infection.
As I understand you have pig-influenza-A matrix protein (segment 7),
which you replicate.
In the nasal swabs you have 1e10 matrix segments in 1l
you need 140e-3l for your PCR-test, so that's the matrix-genes from 1e9 viruses.
or 1e12 per l in the other calculation, I'm not sure.
1 droplet has 1e-5l and contains 1e7 viruses ?
when you pack viruses dense, you could put 1e18 per l,
so 1e12 would be 1 virus per (10 micon)^3 while one virus is 0.1 micron in diameter
You are right gsgs,
The PCR reaction is an exponential reaction where we control each cycle with the thermocycler.
A choosen & very conserved fragment of the matrix gene is amplify with two primer of DNA oligonucleotide.
Each cycle double the amount of DNA fragment in the reaction.
After some cycle, the PCR machine detect the right fragment with a complementary fluorescent probe.
The sooner the amount of fluorescent signal is detected, the higher the concentration of the original sample was.
With a standard curve made of a viral culture dilution in TCID50/ml we can quantify the virus with a corresponding scale where the amount necessary to cause an infection in an experimental cell plate is "1" in value.
With 1ml of a 4TCID50/ml sample we would inoculate 4 plates with 0.25mleach & 2/4 plate could succesfully replicate the virus.
We sometime try to makes viral culture with some weak samples to facilitate the typing of their surface proteins. Samples that take more than 33-34 cycles don't grow often so I use to think the 1TCID value is around there.
We should try it with a standard curve to confirm it but the project have seen no interest from the lab administration... &%"/$*(" this is just a veterinary private lab so... my frustration.
I suppose that a strong sample would exhibit something like 10^5 TCID50/ml, I expect a highly pathogenic virus like H5N1 to drive 10 to 100 fold more virus is a secretion & I remember having saw data very close to that in a study that niman often cite. It is here in the library too lazy to find the reference tonight :sleep:
debate is good. But why do we all have to do it ?
Do I really have to follow all the debates, read all the long
papers here ? Can't we share that work ?
Just give it to us as a summary in form of the probabilities
as to what is considered current state of knowledge.
I make it: 20% of flu-infections happen by aerosoles.
What's your estimate ? What's those of the authors ?
no, I was wrong. I misread millions for millionth.
let me try again:
1e10 viruses per l in your nasal swabs
1e13 per l in your cultures
I guess, a droplet from sneezing to be breathed would
be 1/10 mm in diameter, that's 10 viruses in that droplet.
And with influenza you cough, not sneeze, (?) does that give droplets
at all ? What size ? Looks to me that we inhale very few viruses,
less than 1000 with one breath, not sure.
1e6 (=1 million) viruses in your initial sample of 140 ul (ul = micro-liter),
that makes 1e10 after 15 cycles, 1e16 after 33 cycles , that would be 1000l with your
concentration of 1e13/l
let's not be pick with factors of 10 or such...
I don't understand "copy/ml"
how long takes one "cycle" ?
Ok that was a "," issue...
copy/ml = One matrix gene/ml if we assume that one matrix gene = one virus it mean one virus/ml
debate is good. But why do we all have to do it ?
Do I really have to follow all the debates, read all the long
papers here ? Can't we share that work ?
Just give it to us as a summary in form of the probabilities
as to what is considered current state of knowledge.
I make it: 20% of flu-infections happen by aerosoles.
What's your estimate ? What's those of the authors ?
No, gsgs, you really must do your own thinking.
No, you can't conclude, based on these articles, that '20% of infections are caused by aerosols.' Particularly, you can't explain the airplane data that way. And the airplane data is consistent with the Karo cluster, where most of those infected had spent hours in a small room with the index case. Also a case in Turkey where the brother was infected after riding (hours) in an ambulance with his ill sister. It would be interesting to find out whether the driver wore a mask. The data suggests the risk of infection is probably related to the dose of particles: the more the exposure, the more likely it is you will be infected. This relationship obviously can't be reduced to a single number.
dose number as for all illnes, individual susceptibility ( number of alpha 2 .3 for example ), immunity, degrιe of nutrition, mode of exposition etc..
multiples parameters
no, I was wrong. I misread millions for millionth.
let me try again:
1e10 viruses per l in your nasal swabs
1e13 per l in your cultures
I guess, a droplet from sneezing to be breathed would
be 1/10 mm in diameter, that's 10 viruses in that droplet.
And with influenza you cough, not sneeze, (?) does that give droplets
at all ? What size ? Looks to me that we inhale very few viruses,
less than 1000 with one breath, not sure.
1e6 (=1 million) viruses in your initial sample of 140 ul (ul = micro-liter),
that makes 1e10 after 15 cycles, 1e16 after 33 cycles , that would be 1000l with your
concentration of 1e13/l
let's not be pick with factors of 10 or such...
I don't understand "copy/ml"
how long takes one "cycle" ?
and how many viruses are that ?
and how many viruses are that ?
For your purposes, the answer is =>1. It is, therefore, prudent to protect yourself from contamination through aerosol transmission.
Seriously, what is your investment in oversimplifying what is an ongoing scientific debate. Clearly the answer is not yet known or even knowable. Given the rapidity with which the influenza virus is incorporating polymorphisms, it may be a long time before any answer based on fact rather than prudence is viable.
As I understand you have pig-influenza-A matrix protein (segment 7),
which you replicate.
In the nasal swabs you have 1e10 matrix segments in 1l
you need 140e-3l for your PCR-test, so that's the matrix-genes from 1e9 viruses.
or 1e12 per l in the other calculation, I'm not sure.
1 droplet has 1e-5l and contains 1e7 viruses ?
when you pack viruses dense, you could put 1e18 per l,
so 1e12 would be 1 virus per (10 micon)^3 while one virus is 0.1 micron in diameter
but I assume that once the first virus has successfully entered a cell,
then it doesn't matter what the initial dose was.
It will replicate 100000-1000000 fold then, which is probably more than
the initial dose, I assume.
So the immune system can prevent a certain number of invading viruses
to enter cells (and replicating) but not too many.
Of course, more viruses entering means more chances that one will
happen to find the entry into a cell, discarding the immune system.
But I assume what is meant here is a larger dependence
on initial load than that. ?
One thing for sure, I don't see why at such dose (1 to 20 millions/ml) why a tinny droplet aerosolised would not be able to cause an infection when breathed by someone else.
thank you mingus ! very interesting
with this new article from NATURE.. don't you think that it would be easier than presume, to be contaminated via dropplets ?
GsGs,
One of the most important data is the infecting dose, normally given as EID50 (Embryo or Egg infectivity dose), TCID (Tissue culture infecting dose) LED 50 or even PFU.
EID50 means the amount of virus needed to infect (and kill) 50 % of inoculated chicken embryos.
PFU means the number of particels which can form a plaque.
The dosis necessary for human infection is unknown, but it estimated 6-7 log10 EID50/ml.
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