Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

Laidback Al · Apr 15, 2013

Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

The first indication of human-to-human transmission (H2H) of a novel disease is the identification of a localized geographic cluster of several individuals with similar symptoms within a short time span. Such clusters can result from infections from a common nonhuman host, so collecting detailed case data is the first step in determining whether humans are infecting each other. Of course, sequence analysis, when available can differentiate infection sources.

So H2H spread will be first recognized in a localized cluster of cases that have a high probability of transmitting the virus between individuals.

So far there have only been three possible localized cluster reported by China for H7N9.

Cluster 1: Lee family, Shanghai (probable)

The first H7N9 case officialy reported from Shanghai, an 87-year-old-man surnamed Lee, was one of three family members admitted to a hospital in mid to late February. Mr Lee died on either February 27 or March 4 (see discussion above). One other relative also died during this period. Of the three hospitalized cases only the 87-year-old family member was confirmed with H7N9.

link: http://www.flutrackers.com/forum/sho...d.php?t=201633

Cluster 2: Gu Family Cluster, Shanghai (confirmed)

The second cluster, this one confirmed, represents a family cluster of a husband and wife from Shanghai. The wife had symptoms starting on March 27, was hospitalized, and died on April 3rd. The husband experienced symptoms on April 1st, was hospitalized on April 4th, and apparently is still being treated.

This cluster could be H2H or infection from a common nonhuman host.

link: http://www.flutrackers.com/forum/sho...d.php?t=203779

Cluster 3: Beijing Neighborhood Cluster (confirmed)

Two children who are neighbors in Houshayu in Shunyi district have been confirmed with H7N9. A 7-year-old girl surnamed Yao, started experiencing symptoms around April 11 and is still being hospitalized (FT link). Today, a neighbor child, a 4-year-old boy surnamed Chuk (?), is reported to be asymptomatic but tested positive for H7N9. Media reports indicate that the parents of the girl were engaged in the poultry business and the parents of boy may have purchased some poultry from the girl's parents (FT link).

There are conflicting reports that one or both parents of the girl, who were keeping her company in the hospital, are exhibiting ILI symptoms.

As of today, the two children, both confirmed cases, could have resulted from infection from a common source. If the parents of the girl are sick and confirmed with H7N9, or if this cluster grows, H2H transmission need to be carefully evaluated.

Conclusion

Sustained H2H transmission is not demonstrated by any of these clusters -- yet. <object style="position:absolute;z-index:1000" type="application/x-dgnria" id="plugin0" height="0" width="0">

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curiosity · Apr 16, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

It would help to have test results from the chicken flocks they were trading. Of course, there is the theory that humans can give the virus to the chickens - so how would one know?

I would like to know:

Is the replication rate of the influenza virus a constant in an individual host;
or does it change based on the host environment?

Is there a pattern to the changes if it does - i.e., as the virus becomes more adapted, it replicates more quickly in the single host?

curiosity · Apr 16, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

Evaluation of Replication and Pathogenicity of Avian Influenza A H7 Subtype Viruses in a Mouse Model

After reviewing the article Jim Oliveros posted (above) I think the answers to my previous questions are that yes, virus replication is host dependent and adaptation will alter the speed by which the virus replicates in the individual.

With that information, my opinion on H2H transmission is:

This disease is transmitting more frequently H2H, albeit inefficiently.

My opinionated theory is:

Known -
Elderly patients account for larger percentage
Young, healthy patients have limited disease and/or asymptomatic disease

Observed -
For ONLY cases listed with onset date and coinciding hospitalization or death date there is a marked decrease in days on average from onset to hospitalization/death.

Initial cases #3-#23 at average of 6.933(denominator = 15) days between onset to hosp. or death.
Cases #24-#72, again where ONLY onset and hospitalization/death date were reported, the average is 4.053(denominator = 19).

Why?

1st thought is the reporting/testing for additional cases happens more quickly and cases are being hospitalized for quarantine or people are going more quickly to the hospital for treatment.

BUT what if ...

The virus has a slow replication rate because it hasn't adapted completely.

A slow replication rate would allow a young, healthy, immune competent, susceptible human to have plenty of time to take care of a "weak" virus. AKA - children and adults with many "sniffles" and/or asymptomatic cases (and likely contagious).

The elderly, susceptible population (as well as persons with immune dysfunction - which might explain the current middle age cases - no epi evidence to work from) would have an immune response, though much slower and less reactive, thereby allowing the slow growing virus to gain ground and eventually overpower the body's defense system and body. AKA - elderly population with extended illness transitioning to severe illness/death.

IF the theory is correct?

The virus is adapting and enhancing it's ability to replicate faster in the human reservoir. Once the rate of replication increases through adaption, even the young immune systems will have a hard time keeping the virus load down to "inconvenience" level. Then, theoretically, there will be more young adult cases, child cases. The virus will spread readily in the susceptible population. The disease will be rapid onset and progress quickly to severe illness and/or death (in some, not all.)

Observations that might indicate this is plausible -

1 - Continuing decline in onset date to hospitalization date average (wish there were more dates to look at).
2 - Decline in ages affected.
Particularly plausible if a cluster is associated with #1 and 2 above.

Hope I am wrong. Fortunately, I usually am.

Giuseppe · Apr 16, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

I think most of the above suggestion are agreeable.

However, we can't say for certainty how the things are going on the ground, for example if there's an increasing workplace absenteism or school closures.

Children have different immune response to viruses, and particularly toward flu because of the well known phenomenon of the 'original sin'. Older people may Mount an immune response much more effective toward distantly encountered strain. Youngsters, instead, may have an heterotypic response toward different strains and lineages.

In addition, distribution of cell receptors may differ between the various classes of age.

Since ongoing h2h seem less likely than previously tought and the regional sporadic human infections seem to be result of distinct animal-to-human passages, the continuing adaptation theory may not be fully correct.

Differences among various animal isolates may explain different clinical pattern and immune response.

Vibrant62 · Apr 16, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

Curiosity: to me your theory sounds very plausible.

I have another element I would like to add, but it may just be a different way of saying what you were trying to!

If the early cases were caused by a less human adapted H7N9, then it could explain the longer time to hospitalisation. It would be expected that multiple mutations would occur within a single host over the course of infection. Natural selection would favour propogation of better adapted viruses within that host as the infection progressed, leading to accelerated replication in that individual host over time - until a critical viral mass/load is reached of better adapted viruses, leading to accelerated disease progression, which then goes on to cause serious disease = hospitalisation.

However, in the later cases, if the virus that infected these individuals had acquired some additional mutation/s at the time of infection, then fewer changes would be needed in a single host for it to acquire efficient replication = shorter time to hospitalisation.

We really need sequence data from all human cases to see how the H7N9 virus is changing, and see if there are any consensus variations that could explain things .. and as soon as possible.

If this theory were true we may continue to see a shortening of time from symptom onset to hospitalisation as new cases appear, and as full adaptation occurs i.e cases where onset to hospitalisation is 1 - 2 days could be a large red flag and herald the onset of a pandemic.

Giuseppe · Apr 16, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

If this theory is right then this virus couldn't fully sustained in its h2h transmission because of the short time from onset to Death. A critical feature suggested previously for H5N1 pandemic threat assessment.

AlaskaDenise · Apr 16, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

Giuseppe Michieli said:
If this theory is right then this virus couldn't fully sustained in its h2h transmission because of the short time from onset to Death. A critical feature suggested previously for H5N1 pandemic threat assessment.

Yes - the prime directive of a virus is to persist, which means it cannot kill the host faster than it can transmit to a new host. The "quicky" strains should be selected out of the gene pool.

.

Vibrant62 · Apr 16, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

That cant be completely accurate, because its what happened in 1918.

What might be more accurate is that there are a percentage of cases where onset to death or hospitalisation is rapid, and a percentage of cases who are asymptomatic or suffer only 'mild' seasonal type infections i.e who are the spreaders and may be ambulatory.

JimO · Apr 16, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

One piece of information we have that is relevent to the virus's adaptation is that all four human isolates had E627K, while none of the bird isolates had this change. More sequences of both human and bird isolates would be very helpful in determining if this difference is persistent. If E627K causes a higher viral load, then that might partially explain why some cases progress more quickly or are more severe. If human isolates are found that do not have E627K and that correlates with milder cases, that would be an important discovery.

If there were human isolates without E627K or bird isolates with it, that would support the theory that this has so far been primarily a bird to human outbreak.

Laidback Al · Apr 16, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

Lets add a graph to the discussion -

Based on 42 cases

Average Number of Days Between Onset and Hospitalization by Week Number

Sample size
week 10 - 1
week 11 - 0
week 12 - 7
week 13 - 10
week 14 - 20
week 15 - 4

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Laidback Al · Apr 16, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

Below is the list of cases and information -

accuracy of the data is not guaranteed

curiosity · Apr 16, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

Great visualization, Laidback Al!

The statistical sample is so small for any conclusions, but the trend is worth examining. Are people going sooner for "the cure?" Are they discovering more because testing is easier? Arghhh...so many variables, not enough info.

Is there any difference in average age by week?

GM》Smallpox is another virus that has a 20-50 % mortality rate and coexisted with humans for a considerable amount of time.

JJackson · Apr 16, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

Jim Oliveros said:
One piece of information we have that is relevent to the virus's adaptation is that all four human isolates had E627K, while none of the bird isolates had this change. More sequences of both human and bird isolates would be very helpful in determining if this difference is persistent. If E627K causes a higher viral load, then that might partially explain why some cases progress more quickly or are more severe. If human isolates are found that do not have E627K and that correlates with milder cases, that would be an important discovery.

If there were human isolates without E627K or bird isolates with it, that would support the theory that this has so far been primarily a bird to human outbreak.

Or this strain is not well adapted to mammals without E627K and when infected from an avian source with E627 those mutation to K627 are strongly selected for so appear as the dominant protein during late stage testing. With only 4 released human and two bird samples it is tricky to say what is going on. If and when they release more of their samples we should be able to say which hypothesis is correct. They must have a lot of sequence data by now which they are hoarding - the last human sequence data was released 12 days ago.

curiosity · Apr 16, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

Why would they hoard sequence data? There is so much talent on this site alone, you would think they would share all the information to get a better understanding from MANY minds.

sharon sanders · Apr 16, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

curiosity said:
Why would they hoard sequence data? There is so much talent on this site alone, you would think they would share all the information to get a better understanding from MANY minds.

I could write a book.

AlaskaDenise · Apr 16, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

Jim Oliveros said:
.......If there were human isolates without E627K or bird isolates with it, that would support the theory that this has so far been primarily a bird to human outbreak.

Don't forget the one Korean wild bird with 627K.

see: http://www.ncbi.nlm.nih.gov/protein/AEK84613

.

NS1 · Apr 17, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

curiosity said:
Why would they hoard sequence data? There is so much talent on this site alone, you would think they would share all the information to get a better understanding from MANY minds.

Privacy
for
Public Health Leaders

The disease is well established as a crisis matter on the world stage; however, detailed statements concerning the causal factors have been slow and incomplete.

Pathways to success are being actively avoided. For example, any transitional disease is understood, even defined, via passage studies with the new host obviously serving as one passage medium. Properly managed serial samples display presence or absence of variation, diversity and perhaps adaptation. Serial samples of human cases may demonstrate actionable data. Calendar time has elapsed that would allow for 50% of the hospitalised cases to have had serial samples sequenced and deposited.

At this moment, exactly zero serial studies have had results discussed and, to be certain, precisely zero serial sequences have been offered.

That's just "Business as Usual".

Perhaps public health leaders would be appreciative if they were allowed to proceed privately.

NS1 · Apr 17, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

Jim Oliveros said:
One piece of information we have that is relevent to the virus's adaptation is that all four human isolates had E627K, while none of the bird isolates had this change. More sequences of both human and bird isolates would be very helpful in determining if this difference is persistent. If E627K causes a higher viral load, then that might partially explain why some cases progress more quickly or are more severe. If human isolates are found that do not have E627K and that correlates with milder cases, that would be an important discovery.

If there were human isolates without E627K or bird isolates with it, that would support the theory that this has so far been primarily a bird to human outbreak.

Primarily Bird->Human, multiple independent introductions. At this time.

Human->Bird reversal is seeding lightly human-adapted Influenza genetics (with step-wise Gain of Function toward alpha2,6 receptor specificity) to the bird strains for the bird strains to reprocess and accumulate. Slowly.

PB2 aa627 is one of many signals and should not be held as the prime determinant in this emergent H7N9.

PB2 aa627 is sensitive to host species, previous passage, sample location, sample incubation, et al. As such, the Lysine may vary at or below the trace threshold indeterminately, even when sampled from a mammal.

100% Correlation of Lysine to Mammal does not exist.

NS1 · Apr 17, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

Vibrant62 said:
Curiosity: to me your theory sounds very plausible.

I have another element I would like to add, but it may just be a different way of saying what you were trying to!

If the early cases were caused by a less human adapted H7N9, then it could explain the longer time to hospitalisation. It would be expected that multiple mutations would occur within a single host over the course of infection. Natural selection would favour propogation of better adapted viruses within that host as the infection progressed, leading to accelerated replication in that individual host over time - until a critical viral mass/load is reached of better adapted viruses, leading to accelerated disease progression, which then goes on to cause serious disease = hospitalisation.

However, in the later cases, if the virus that infected these individuals had acquired some additional mutation/s at the time of infection, then fewer changes would be needed in a single host for it to acquire efficient replication = shorter time to hospitalisation.

We really need sequence data from all human cases to see how the H7N9 virus is changing, and see if there are any consensus variations that could explain things .. and as soon as possible.

If this theory were true we may continue to see a shortening of time from symptom onset to hospitalisation as new cases appear, and as full adaptation occurs i.e cases where onset to hospitalisation is 1 - 2 days could be a large red flag and herald the onset of a pandemic.

Dysfunctional Behaviour
is the Norm

In influenza, a linear relationship does not exist between speed of replication and host adaptation success level. Conversely, the transitional virus (early to mid-stride alternating between host species) may replicate at a distinctly higher rate (50% to 1,000%) causing advanced morbidity in the non-dominant genetic pairing, generally the human host.

At GeneWurx, we use the delightfully simplified term, "confused", to describe a virus moving into a new host before acquiring the necessary tools for a traditional life cycle in that host. This emergent H7N9 HA is genetically confused and emerges from a chain of genetic confusion reaching at least 4 years into the past and spanning more than 2 dozen host species (many mammalian).

Because unusual viral behaviours will occur during host-transition periods, application of equilibrium-based concepts is not generally advised. Dysfunctional behaviour is the norm. You are looking a new organism that may now be partially blind with inaccurate targeting, but H7N9 still has active weapons systems with lytic impact. Expect outlier behaviour and strong punctuation.

Your technique here of examining calendar durations from onset to critical care to recovery / fatality is entirely useful when taken against the specific genetic markers associated with each case and against the individual host pre-infection health status. However, even using the "less" and "more-adapted" terminology promotes the concept that science has previously understood the bounding elements of this particular emergent H7N9 background . . . and we haven't.

We do know that variation at certain positions on certain backgrounds may be associated with a set of viral behaviours. Those studied positions and values are neither exclusive, nor exhaustive. Those positional changes' outcomes are very dependent on the backgrounds (or surrounding genetics) in many cases and are confounding reversed in instances that remain inexplicable.

The standing viral science community has characterised far less than 10% of the functionality for the influenza genome matrix. Cross-referencing of those functional themes remains elusive in most cases. And this emergent H7N9 is novel in many ways. The HA is distant at important residues from all existing H7N9 and all existing H7N7 with the further compounding effects of voluble interaction with human H3N2, human and avian H5N1 including Wet Market surveillance sequences and human pH1N1.

Thoughtful and deliberate data gathering now, as each of you have so adroitly employed yourselves, creates possibility in the future of correlating to the specific fingerprints of each disease-causing organism based on the sequences.

JetStuuby · Apr 17, 2013

Re: Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

Centre of Hong Kong Health announces h7n9 can spread human to human

http://headlineasia.com/2013/04/17/...ion-announced-h7n9-can-be-spread-human-human/

(as if we didn't already know

Reconsidering human-to-human transmission of H7N9 in China, April 15, 2013

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