China - H7N9 Human Isolates on Deposit at GISAID

[sharon sanders]

Re: China - H7N9 Human Isolates on Deposit at GISAID

bump this.

[NS1]

Re: China - H7N9 Human Isolates on Deposit at GISAID

Scalability Questions
Around
Rate of Mild Case Detection

RePublished from BMJ. Detection of mild to moderate influenza A/H7N9 infection by China?s national sentinel surveillance system for influenza-like illness: case series [Thread#207942]:

Post#3
The number of assumptions is skyrocketing as the number of possible cases. And this is not much informative.

554 sentinel points
12.5 swabs per week / point
554*12.5*4 wk=27,700 swabs per month

5 sentinel swabs tested positive for H7N9 from the above paper =

5 / 27,700 = 0.02% positivity rate

If in a 5,000,000 China megacity during the same period of time there was an ILI rate of 14 x 1,000 then:

14 : 1,000 = x : 5,000,000

x = 70,000 ILI cases per week

if these ILI cases should have been swabbed - employing the above positivity rate we should have had:

70,000 * 0.02% = 14 H7N9 cases

Scaling

Scaling statistics using national factors onto discrete (sub-component) populations is not generally held as an ideal mechanism for creating actionable results at the discrete population level. When this type of spreading is undertaken at a giga-scale (i.e. population of China), often additional considerations and cautions must be employed. The types of projections are the purest form of invention.

An inspection of significant digits may be in order for these calculations while keeping at the forefront the fact that averages and assumptions are being multiplied by averages and assumptions. We will examine here the individual factors and the calculation veracity. Projection estimates will be provided at the end of this post for your example population of 5 million and for several actual geographies in China related to emergent H7N9.

You certainly are accurate on the skyrocketing effect of assumptions. One paper that you posted requires a minimum of 15 swabs per week and this paper suggests a quota range of 10 to 15 swabs per week, a ceiling 50% above the floor (substantial variance, ? sqared=6.25). Using actual counts from the earlier study (46,807 swabs from 554 locations over 8 weeks) gives an average of 10.56115 swabs per location per week.

Factor Validity

The authors openly admit that swabbing is not random and then they immediately attempt without any observational evidence to attach the idea that this quota-driven, non-random test is unbiased? They pledge that their system, though structured with a non-randomised collection, is representative of a billion count population? The system begins by missing 97.5% of the hospitals (sampling 2.5%) and then proceeds to require 15 swabs per week, but only gets about 10.56115 across a week's duration. We're not certain if the authors have supplied a supplement denoting the actual geographic collections? If an attempt is being made to differentiate disease epidemiology, then we'll need specific geographic counts rather than obtuse gerrymandering accumulations and averages.

Severity bias is generally present in infectious disease collections that are not intentionally randomised.

Test Duration

Is the test duration for this paper defined or are we to assume that the accumulations take place over the entire emergence period from their first publicly reported case in late February until May 27? If so, then 12 weeks very much dilutes the outcome when used in place of the 4 week estimate to accommodate the 5 mild cases discovered via passive surveillance of ILI reports. Early multipliers reduced by 66.67% dampen results.

Emerg Infect Dis. Monitoring Avian Influenza A(H7N9) Virus through National Influenza-like Illness Surveillance, China [Thread #205425, Post#1] (emphasis mine)

On April 3, 2013, to enhance surveillance for influenza A(H7N9) virus, all network laboratories were required to increase the number of specimens to a minimum of 15/week and to test all specimens collected since March 4, 2013, for influenza A(H7N9) virus by real-time reverse transcription PCR . . .
. . .
During March 4?April 28, CNISN tested 46,807 nasopharyngeal swab samples from 554 sentinel hospitals throughout mainland China.

ReCalculation

Information Quality is very low in the emergent H7N9 discussion though Information Quantity sometimes exceeds necessity.

Using the actual numbers from the previous study (46,807 covering 8 weeks from early March to late April) summed with the mandated 15 swabs per week per hospital (33,240 covering 4 weeks from late April to late May), we estimate the denominator to be a minimum of 80,047 total swabs over 12 weeks. With detection of 5 mild cases, the rate calculates to:

Mild Case Detection Rate for Emergent H7N9 in ILI Cases ~ 0.006246329%.

We carry forward without examination the Influenza-Like-Illness basis from the nominitive Michieli proposal. Holding constant the discussed ILI factor of 0.01400 (14 Reports per 1,000 Population), the following selected geographic projections may be discussed based on the limitations of the incoming factors' veracity. Particularly daunting is the non-applicability of a national Mild Case Detection Rate across disparate, sub-state geographies.

Concentrated City
Population . . . . . 5,000,000
Projected ILI . . . . . .70,000
Projected Mild H7N9 Count___4.4

Beijing
Population . . . . 20,690,000
Projected ILI . . . . .289,660
Projected Mild H7N9 Count__18.1

Shanghai
Population . . . . 23,470,000
Projected ILI . . . . .328,580
Projected Mild H7N9 Count__20.5

Guizhou Province
Population . . . . 34,690,000
Projected ILI . . . . .485,660
Projected Mild H7N9 Count__30.3

Fujian Province
Population . . . . 37,200,000
Projected ILI . . . . .520,800
Projected Mild H7N9 Count__32.5

Zhejiang Province
Population . . . . 54,630,000
Projected ILI . . . . .764,820
Projected Mild H7N9 Count__47.8

Jiangsu Province
Population . . . . 78,990,000
Projected ILI . . . 1,105,860
Projected Mild H7N9 Count__69.1

China
Population . . 1,344,000,000
Projected ILI . . .18,816,000
Projected Mild H7N9 Count__1,175.3

As Chris & Edgar like to say, "Caveat Lector."

Genetic Calibration

We do tend to agree with the authors that cross-referencing the actual disease (gene form) to the statistics is potentially beneficial for the public.

Related Reading

• GeneWurx Cross Serotype Homology Analysis, Open-Access, Full-Text version
• Human Emergent H7N9 from Zhejiang Province
• Environment Emergent H7N9 from Zhejiang
• Fatal H5N1 Homology to Emergent H7N9 from Shanghai in March
• Mammalian Adaptation of Emergent H7N9 Neuraminidase in Jiangsu
• TamiFlu Resistance via NA 292K in Taiwan and Shanghai
• Zhejiang Fatal H7N9 with Divergent NA, PB2 701N and Aberrant PA
• Novel PB2, Divergent PB1 & Novel PA from First Fujian Case
• China - H7N9 Human Isolates on Deposit at GISAID, Comprehensive Genetics Discussion

[NS1]

Re: China - H7N9 Human Isolates on Deposit at GISAID

Remarks on

Re-Marketing
of
Toxic Anti-Virals

Treatment methods that are deemed successful by the practitioner must be vetted by detailed evaluation using statistically significant populations. We have learned that professed practical meaurements are not always the measure of good practice. Modalities based on low count measurements occuring in very transient and particular situations rarely translate to population-level benefits. We undertake an examination of basic facts concerning one treatment modality against emergent H7N9 influenza in pediatric patients.

Of course, we are quite concerned that emergent H7N9, if revised toward pandemic-enabling genetics, will have commensurately new attack groups, clinical presentations, treatment responses, clinical progressions, clinical outcomes and prognoses. What works today, or appears to work, may be ineffective or even dangerous against a revised dynamic.

With those items in mind, we re-publish comments from an earlier thread, Emerg Microbes Infect. Mild infection of a novel H7N9 avian influenza virus in children in Shanghai [Shanghai CDC: FT #503684].

Even in a crisis, some clinicians will exceed groupthink. If you refuse to rely on groupthink, please choose to review our categorical evaluation of this treatment modality.

[FT #503644]
It is also important to note the positive correlation between the influenza polymerase inhibitor ribavirin and the rapid clinical symptoms resolutions in the described cases. The PA inhibitory property is also cited in other paper cit.

Ribavirin is demonstrated to be profoundly toxic.

For 43 years.

Toxicity is a primary evaluation point around which the extensive body of ribavirin research revolves. Human studies, even of short duration, frequently result in subjects leaving the investigation prior to completion due to toxicity or other physiologically-limiting outcomes.

CardioVascular Contra-Indication

Furthermore, the known contra-indications of ribavirin are also common correlators to the subject groups and factors surrounding pandemic influenza or host-transition viral outbreaks. An obvious and prominent concern is that host-transition virus reservoirs dismay us with fatal clinical outcomes correlated with antecedent cardiac muscle failure, vascular musculature failure, disseminated intravascular coagulation (DIC) and organ failure (liver). The contra-indication profile of ribavirin provides direct risk factors in these areas. The thousands of amputations employed on children infected by pH1N1 after DIC allows a rational researcher to steer clear of ribavirin for future pandemic influenza.

Child-Bearing Age Contra-Indication

Citizens of Child-Bearing age (male and female) risk their future child's life and / or deleterious genetic mutation of their child when ribavirin is engaged. We are all familiar with the fact that host-transition viral reservoirs are dangerous to males and females of child-bearing age and that pregnancy creates exceptional risk of high morbidity and fatality with host-transition viral reservoirs. Ribavirin as a standard in an influenza pandemic risks damaging the current and the future generation.

Eye Concerns

Additionally, retinopathy is associated with the more modern combinational therapies employing this toxic pharmaceutical. As we have recently seen, H7 influenza serotypes tend toward ocular involvement. Human H7N7 outbreaks showed conjunctivitis as a common presenting symptom. Emergent H7N9 infection through the eye is demonstrated in the lab to result in mammal respiratory infection [US CDC: FT#503653]. Maintaining eye integrity may feature as a public health recommendation during an H7 pandemic.

Immuno-Suppression

Ribavirin and other inhibitors in the IMPDH group are recognised for immuno-suppressive activity and are often employed for that particular mechanism of action. Like many influenza reservoirs (pH1N1) and individual clades, emergent H7N9 is proposed, even by the authors of this paper, to be microbiologically and clinically immuno-suppressive.

Unintended amplification of immuno-suppression is a risk that may lead to super-infection when treating an emerging pandemic virus with ribavirin. Super-infection, we are told, is a substantial contributor to fatality in pandemic influenza. Considering the extended durations in hospital observed with the first wave of emergent H7N9 human cases, clinicians will be wise to consider the potential gravity of amplified immuno-suppression leading to super-infection and then fatality.

Emerging Microbes & Infections (2013) 2, e41; doi:10.1038/emi.2013.41 - Published online 10 July 2013

Therefore, we propose that the novel H7N9 virus may induce transient immunosuppression that occasionally results in fatal opportunistic infections, especially in patients with underlying diseases.

Revenue Enhancement

Re-Marketing has become a revenue enhancement strategy promoted and economically idealised by medical consultants over the last decade. The failure of corporations to bring us working solutions provides those very same teams the suffering subjects they need to re-market their previous bad ideas (because nothing new is available). This economically beneficial re-cycling of inappropriate and out-dated techniques has recently resulted in medical tragedies.

While we may hold some sympathy for the frustrated clinicians who are influenced by these advising vultures to "throw everything you have at that infection", we also hold those clinicians to the responsibility of providing some semblence of input toward THEIR patient's treatment. Due to the vacuum found where new ideas should be arising, off-label usage is too regularly adopted by leading professors and clinicians for untested, even bizarre, treatment modalities.

Ribavirin as a standard for influenza care surpasses bizarre, however, and moves into the patently absurd. As if the blind being allowed to lead the blind is no longer enough, we are now being asked to allow the blind to create the blind?

Originally published:
Researcher devises drug cocktail for coronavirus [FT Thread #493730]

A primary issue here is that ribivarin - whilst an effective anti-viral agent - is highly toxic. For this reason it was largely discounted as potential treatment for H5N1 human infections.

See http://www.drugs.com/pro/ribavirin.html

The primary clinical toxicity of Ribavirin is hemolytic anemia. The anemia associated with Ribavirin therapy may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with Ribavirin [see Warnings and Precautions (5.2), Adverse Reactions (6.1), and Dosage and Administration (2.3)].

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to Ribavirin. In addition, Ribavirin has a multiple dose half-life of 12 days, and it may persist in non-plasma compartments for as long as 6 months. Therefore, Ribavirin, including Ribavirin tablets, is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy in both female patients and in female partners of male patients who are taking Ribavirin therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6 month post treatment follow-up period

Related Reading

• GeneWurx Cross Serotype Homology Analysis, Open-Access, Full-Text version
• Human Emergent H7N9 from Zhejiang Province
• Environment Emergent H7N9 from Zhejiang
• Fatal H5N1 Homology to Emergent H7N9 from Shanghai in March
• Mammalian Adaptation of Emergent H7N9 Neuraminidase in Jiangsu
• TamiFlu Resistance via NA 292K in Taiwan and Shanghai
• Zhejiang Fatal H7N9 with Divergent NA, PB2 701N and Aberrant PA
• Novel PB2, Divergent PB1 & Novel PA from First Fujian Case
• China - H7N9 Human Isolates on Deposit at GISAID, Comprehensive Genetics Discussion

[NS1]

Re: China - H7N9 Human Isolates on Deposit at GISAID

Remarks on

Host-Transition
Adaptation
in
Transport Vector Species

Ignition v. Spread

Re-published from an earlier thread with one of Al's wonderful maps and curiosity's insightful epidemiology, China - Map of H7N9 hot spots outside of Shanghai [FT #204004].

On another note: the term "hot spots" reminded me of the chronological onset and location map. IMO, the map looked similar to a few wildfire maps I've seen where the larger fire sends burning embers into the atmosphere that start smaller fires around it - often in the same general direction. Some of those surrounding fires light up, others smolder - dependent on fuel source, terrain, atmospheric conditions, etc...

China has a lot of fuel for "hot spots."

Although, depending on which 1918 origination scenario one thinks is most accurate - Haskell, Kansas; Asian source; or France source; etc... - fuel may or may not matter at the beginning.

Adaptation method and rate within the transport vector are the primary effectors at the beginning of a true influenza zoonotic. Reservoir dynamics are paramount to this process of avian-to-mammal bridging. The number and geographic dispersal of vector organisms (Passerines, Anser, Anas, et al) that are able to transport the host-switching virus describes the commonly found geographic outliers during similar times of ignition.

We all know that spread occurs in an arc, but spread is Stage 2, a separate process that begins only after a virus is established in a new host. Stage 1, Ignition, when traced carefully, may be found often as multi-focal and spontaneous.

Non-intuitive ignition may be seen in the recent GeneWurx prediction and validation of non-contiguous human H7N9 spontaneous emergence in land-locked Hunan province: Passerines Fly Higher than Poultry [FT#495364].

Based on a novel mechanism of genetic tracing that cross-references human clinical outcomes, calculations (guided by the recognition of a sub-segment antigen adaptation method) supported Ignition of emergent human cases in Guizhou and Hunan. We understood from the start that cases in Guizhou would not be reported. Non-contiguous emergent H7N9 (no geographic arc) for a human Hunan case was reported on the 27th of April with a case onset of 2013-04-14.

Human re-hosting will always occur when viral particles with the right receptor binding genetics are in proximity. That much is non-bypassable. If the new viral strain is successfully competitive over standing infective influenzas, then Ignition becomes pandemic.

But it all starts at the animal-man interface, at the contact vector that is also frequently the viral transportation. Outside of exceptional situations where innate immunity is improbably high or low in a vector-proximal, ignitable population, mankind as an effector (the fuel) is not so important.


Related Reading

• GeneWurx Cross Serotype Homology Analysis, Open-Access, Full-Text version
• Human Emergent H7N9 from Zhejiang Province
• Environment Emergent H7N9 from Zhejiang
• Fatal H5N1 Homology to Emergent H7N9 from Shanghai in March
• Mammalian Adaptation of Emergent H7N9 Neuraminidase in Jiangsu
• TamiFlu Resistance via NA 292K in Taiwan and Shanghai
• Zhejiang Fatal H7N9 with Divergent NA, PB2 701N and Aberrant PA
• Novel PB2, Divergent PB1 & Novel PA from First Fujian Case
• China - H7N9 Human Isolates on Deposit at GISAID, Comprehensive Genetics Discussion

[NS1]

Re: China - H7N9 Human Isolates on Deposit at GISAID

Ongoing Discussion of Hospital Over-Capacity Situations and UnExplained Pneumonia Cases in China contemporary to the disclosed Emergent H7N9 cases.

[NS1]

Re: China - H7N9 Human Isolates on Deposit at GISAID

Discussion of Alternate Surveillance Methods to protect the public from Pandemic Disease when UnTrustworthy Primary Sources Force Indirect Measurements.

[NS1]

Re: China - H7N9 Human Isolates on Deposit at GISAID

Discussion on the Notable Absence of Mention: Ongoing 2013 H7N3 Outbreak throughout Mexico

Morens DM, Taubenberger JK, Fauci AS. 2013. H7N9 Avian Influenza A Virus and the Perpetual Challenge of Potential Human Pandemicity. mBio 4(4):e00445-13. doi:10.1128/mBio.00445-13.

[NS1]

Re: China - H7N9 Human Isolates on Deposit at GISAID

First Guangdong Human Case Acquires Antigenic H3N2 HA 128A

[NS1]

Re: China - H7N9 Human Isolates on Deposit at GISAID

First Hong Kong Human Case, 36F, Repeats H3N2 Antigenic HA 128A

[NS1]

Re: China - H7N9 Human Isolates on Deposit at GISAID

Emergent H7N9 Vaccine Candidate Manifests Rare Pandemic H1N1 HA 131T

[NS1]

Re: China - H7N9 Human Isolates on Deposit at GISAID

GeneWurx rNr Analytics have been updated to delineate differences between the Antigens (HA & NA) and the Polymerase Complexes for these two recent human Emergent H7N9 sequences.

The two alternate ReAssortments are detailed and contrasted at Emergent H7N9 Genetics.

• First Guangdong Human Case Acquires Antigenic H3N2 HA 128A
  • A/Guangdong/1/2013
  • HA_: Emergent H7N9 Novel
  • NA_: Emergent H7N9 Standard
  • PB2: H9N2
  • PB1: H9N2
  • PA_: Emergent H7N9 Novel

• First Hong Kong Human Case, 36F, Repeats H3N2 Antigenic HA 128A
  • A/Hong Kong/5942/2013
  • HA_: Emergent H7N9, Similar, but NOT Matched, to Guangdong
  • NA_: Emergent H7N9 Novel
  • PB2: H9N2 ReAssort, Similar, but NOT Matched, to Guangdong
  • PB1: H9N2 ReAssort, NOT Similar to Guangdong
  • PA_: H9N2 ReAssort

[NS1]

Re: China - H7N9 Human Isolates on Deposit at GISAID

Human H7N9 Antigen & Polymerase Constellations, Guangdong v. Hong Kong

[sharon sanders]

Re: China - H7N9 Human Isolates on Deposit at GISAID

In plain English, for non-scientific people, can you explain the ramifications of your recent posts please? Thanks!

[NS1]

Re: China - H7N9 Human Isolates on Deposit at GISAID

GeneWurx rNr Analytics have been updated to delineate differences between the Antigens (HA & NA) and the Polymerase Complexes for these two recent human Emergent H7N9 sequences.

The two alternate ReAssortments are detailed and contrasted at Emergent H7N9 Genetics.

• First Guangdong Human Case Acquires Antigenic H3N2 HA 128A
  • A/Guangdong/1/2013
  • HA_: Emergent H7N9 Novel
  • NA_: Emergent H7N9 Standard
  • PB2: H9N2
  • PB1: H9N2
  • PA_: Emergent H7N9 Novel

• First Hong Kong Human Case, 36F, Repeats H3N2 Antigenic HA 128A
  • A/Hong Kong/5942/2013
  • HA_: Emergent H7N9, Similar, but NOT Matched, to Guangdong
  • NA_: Emergent H7N9 Novel
  • PB2: H9N2 ReAssort, Similar, but NOT Matched, to Guangdong
  • PB1: H9N2 ReAssort, NOT Similar to Guangdong
  • PA_: H9N2 ReAssort

In plain English, for non-scientific people, can you explain the ramifications of your recent posts please? Thanks!

Emergent H7N9 Promiscuity
Leads to
Genetic Instability

Among the most recent human cases, at least three distinct strains of Emergent H7N9 have been detected in humans from the late Summer and throughout the Fall of 2013 (the second phase of Emergence).

HyperAssortment appears to be the norm with an emphasis at the segments of the Polymerase Complex. Beyond the increased ReAssortment activity, Single Nucleotide Polymorphisms (SNPs) are entering the H7N9 reservoir that have also occurred during Host-Switching (zoonosis / animals to people) in currently circulating human influenza such as Pandemic H1N1 2009 and Seasonal H3N2. The aggressive nature of this HyperMorphic behaviour suggests a viral reservoir that allocates resources to Host-Seeking mode.

On the segments that are considered Antigenic (included in Vaccine Designs), those SNP revisions, "Tried-and-True" in circulating human serotypes, continue to create Emergent H7N9 novelty. That Emergent H7N9 novelty, in turn, differentiates the currently transmitting disease from the genetics of the February / March 2013 early strains and the vaccine target.

During the emergence of Pandemic H1N1, that viral reservoir exhibited a similar series of distinguishment stages, at times with up to 7 distinct transmitting backgrounds and fatality on multiple contemporaneous backgrounds. While H7N9 is NOT in a pandemic phase, the reservoir does presently exhibit the characteristics of bi-directional promiscuity and genetic signals of active Host-Seeking behaviour.

The Open Access, Full Text studies at Emergent H7N9 Genetics and pH1N1 Genetics describe notable scenarios that underlie this synopsis of Emergent H7N9 promiscuity leading to genetic instability.

[NS1]

Re: China - H7N9 Human Isolates on Deposit at GISAID

Shaoxing, Zhejiang Fall 2013 Human H7N9 Displays Varied Genetics from Two Laboratories