Ebola incubation time previously questioned

[foxp3]

Hello I am a new member from Scotland and my background is in immunology. I am sorry if it seems cheeky to have just joined and starting a new topic, but I wondered if anyone would comment on the following pub med article on incubation time of Zaire. Also I have added a few questions about natural immunity to Ebola, I.e. asymptomatic cases as possible carriers. Any thoughts would be good. I did post on another forum but no takers. PS I have read this forum since 2009 when I was pregnant and worried about H1N1 and I was reading reports out of mexico, no one was listening and that is when I found flutrackers and like minded people. Thanks for that. Anyway on with post.

Incubation time article from 2011


Osong Public Health Res Perspect. 2011 Jun;2(1):3-7. doi: 10.1016/j.phrp.2011.04.001. Epub 2011 Apr 12.

Incubation period of ebola hemorrhagic virus subtype zaire.
Eichner M1, Dowell SF, Fires


OBJECTIVES:
Ebola hemorrhagic fever has killed over 1300 people, mostly in equatorial Africa. There is still uncertainty about the natural reservoir of the virus and about some of the factors involved in disease transmission. Until now, a maximum incubation period of 21 days has been assumed.

METHODS:
We analyzed data collected during the Ebola outbreak (subtype Zaire) in Kikwit, Democratic Republic of the Congo, in 1995 using maximum likelihood inference and assuming a log-normally distributed incubation period.

RESULTS:
The mean incubation period was estimated to be 12.7 days (standard deviation 4.31 days), indicating that about 4.1% of patients may have incubation periods longer than 21 days.

CONCLUSION:
If the risk of new cases is to be reduced to 1% then 25 days should be used when investigating the source of an outbreak, when determining the duration of surveillance for contacts, and when declaring the end of an outbreak.

So just wondered if anyone had read that article. I also have a few other points for my post.


I realise incubation time is just one factor and transmission patterns and Ro numbers are also heavily influenced by the population the virus is spreading in. Speed and distribution depends especially on how many susceptible hosts there are. Do we know if there are asymptotic cases, or what percentage of the West African people are naturally immune to its infection, and if this subset of people can be carriers passing on the disease. No virus has the ability to replicate in every individual. Natural immunity can come from previous exposure, I.e. living close to the natural vector (perhaps the fruit bat), or different genotypes, even coinfections with diseases such as malaria, and sickle cell which change blood biochemistry and influence the immune system response. Does anyone know if there is any data or research on this.

What happens in African population may be very different from infection patterns in a European, Asian or Hispanic population partly to do with genetic diversity. So I think there will be differences in how this outbreak plays out depending on whether or not there is any natural immunity in any of the main races. I am hoping it won't spread too well in cold climates but who knows.


Thank you for listening any comments on any point would be great.

fp

[Emily]

Re: Incubation time previously questioned.

Welcome, foxp3! That's interesting that the 21 day incubation period was questioned.

As for your question about asymptomatic cases, I think there were some in past outbreaks, but they were not believed to be spreaders.

As for transmissions patterns, I think the main determinant in ebola will be detection and the ability to quarantine, rather than population susceptibility.

[JimO]

Re: Incubation time previously questioned.

Welcome foxp3! I find it very interesting that so much faith has been put in the 21-day limit to the incubation period, so much so that people are released from observation or quarantene after 21 days. The article says up to 4.1% of cases might have an incubation period of more than 21 days, which could include dozens of contacts.

I doubt that records are accurate enough to document any cases with onset beyond 21 days except for possibly in Nigeria, so we might not have an answer any time soon.

[Sharky]

Re: Incubation time previously questioned.

Based on RNA sequencing, my understanding is that the current outbreak is not EB Zaire, but something new.

Field reports are still very murky, but from what I've read, it seems likely that the new variant has a longer incubation time than EBZ. If correct, that would increase the 4.1% number even more.

[Bam Bam]

Re: Incubation time previously questioned.

Re: Asymptomatic Carriers

http://www.ncbi.nlm.nih.gov/pubmed/10881895

We know these individuals tested positive for antigens but we don't know if their viral load was sufficient to transmit the virus.

[Laidback Al]

Re: Incubation time previously questioned.

Based on RNA sequencing, my understanding is that the current outbreak is not EB Zaire, but something new.

Field reports are still very murky, but from what I've read, it seems likely that the new variant has a longer incubation time than EBZ. If correct, that would increase the 4.1% number even more.

According to the NEJM article in April 2014 (link to full article), the sequencing indicated that the current outbreak is a separate clade of Zaire ebolavirus that probably emerged in December 2013 as a single introduction into the human population. With more than 2500 cases since then, the ebolavirus has had multiple opportunities to evolve and mutate with changes to pathenogencity, incubation period, transmission modes, etc.

[Vibrant62]

Re: Incubation time previously questioned.

My greatest concern is not so much related to incubation period, but the development of viral load during the course of infection.

Established thinking has it that infected people can only spread virus when showing quite acute symptoms of disease. I am wondering if this has changed, and that, as the virus is adpating to humans, it is increasing its replication efficiency such that viral load is higher earlier in infection i.e. it has become more transmissible earlier in infection via sweat, tears etc and prior to the diarrhoea and vomiting stage.

Something is behind the increasingly rapid spread, over and above the 'out of control' nature of the outbreaks. We have seen how infective people have been able to travel whilst ill (something that never used to happen) and I think we need to conclusively determine (within this outbreak) exactly when viral load builds to a point that transmission can occur.

Given the large number of human cases and those very likely to have contracted the disease, I hope that this is under active investigation by the WHO / CDC or other researchers.

Its a question where we need to be sure of the answer. If there is a period of transmissibility prior to clear onset of symptoms i.e in the early fever stage, it would suggest that contacts need to be quarantined, not monitored.

[Donners]

Re: Incubation time previously questioned.

We have seen how infective people have been able to travel whilst ill (something that never used to happen)

Not only has it happened, it happened as far back as the original 1976 outbreak with Mayinga as one prime example.

It's hardly remarkable; the early symptoms are not debilitating to the extent of preventing travel, especially in a region which is much more mobile that those which have been affected by Ebola in the past (excluding Kikwit, which was promptly shut off by Mobutu).

Of course it should and will be carefully studied by the various agencies to better inform the general understanding of the virus, but I wouldn't be at all surprised to find that the difference here is human behaviour.

[Vibrant62]

Re: Incubation time previously questioned.

Donners - thanks and accepted, and hopefully there might be viral load data etc published fairly quickly to answer the bigger question about precisely when people are infectious with this novel Zaire subclade. Hopefully you are right, and there is nothing intrinsic that has changed in the viruses behaviour.

My point though was that people who were sufficiently ill enough to be infectious were thought to be too ill/ unable to travel (at least this is what is often quoted in media communications and press) but we have been seeing this occur repeatedly during this outbreak, within the affected countries, most usually by bus or taxi. Previous data suggests that early symptoms e.g. mere fever alone is insufficient for the patient to be infectious.

Additionally, according to opinion pieces and interviews by some of the MSF, SIM etc medics working in the outbreak areas, who have also worked in previous ebola outbreaks, some infected people (but not all) have appeared astonishingly 'well' a long way into their disease including the diarrhoea and vomiting stage, before rapidly sickening further and dying within an additional 24 - 48 hours of looking fairly healthy.

I look forward to the data. Until then its all guesses and supposition anyway....

[foxp3]

Re: Incubation time previously questioned.

Thank you for your responses.

Bam Bam I read the article very interesting . So basically combination of 2 outbreaks in Gabon in 1996. 119 patients with clinical symptoms, and 24 cases of proven seroconversion but asymptomatic infection. These individuals did not have prior immunity to Ebola as they initially produced IgM then few weeks later IgG. So infection in non immune induviduals need not produce disease. Paper concluded early immunological events determine outcome, i.e. fatal vs recovery vs asymptomatic. Better outcomes were linked to early strong inflammatory responses including cytokines IL-1, IL-6 and TNFalpha. Also monocytes and macrophage attracting chemokines. They kept viral load low in initial stages.

This is just my thought but parasitic worms are endemic in these regions, and they are immunomodulators. They have to have mechanisms to skew and decrease the hosts immune response. They produce decoy agents and molecules to mop up cytokines, and can neutralise chemokines. There are numerous examples of parasites worsening viral infections. Bloodflukes rapidly worsen HCV Perhaps more people can't make that initial cytokine response required to fight ebola due to their parasitic load.....anyway just a thought.

I agree that the article does not really address if asymptomatic patients can pass the virus on, however the fact they could not detect virus in their serum, and only in WBC after 2 round of PCR gives the impression they must have had very low viral levels. Group should have tested semen...I would have for completeness....though don't know how popular I would have been.

LaidBack and Sharky. Thanks for the info about the sequencing. I guess mutations are expected under selective pressure. I don't know if it is a stable virus. I think RNA viruses don't have proof reading mechanism, so are more genetically unstable....I may be wrong. They NEJM article says there changes in several locations ( 6 I think). They don't say what parts of the virus they respond to. If it is in locations corresponding to attachment molecules, then transmission properties may have changed.

An interesting point from the NEJM article was that at the time of research the case number was still low enough to track outcomes. They found mortality to be 86%. Now WHO say around 53%, big difference, any thoughts anyone?

Transmission studies based on lab studies is often inaccurate. The thing that sits heavy with me is that they tend to infect monkeys with Ebola via the intramuscular route. However natural infection is likely to be via the mucosal route ( touching eyes mouth with infected fluids). However the mechanisms involved in the mucosal immune response is very very different from that of the systemic ( intramuscular or blood bourne route)immune system. Totally different cell phenotypes, cytokine profiles. Like comparing night to day. The gut, respiratory eg mucosal systems are predominantly immunosuppressive environments ( has to be due to the millions of non harmful foreign proteins theses routes daily are exposed to, I.e in the food we eat and air we breath). It is like eating an ice cream or injecting it into a muscle, very different outcomes. Therefore the real routes of transmission may not correlate to the lab data. I guess that is why epidemiological data from the outbreak is essential, but at the moment this essential information all seems quite disorganised. Shadow areas etc.

Lastly Vibrant as you say there may be high viral load early in infection and they are not seeing it. I totally agree with this. Doctors have reported with surprise how healthy some patients look and then 24 hrs later they die. Reports of patients scaling walls.

Vibrant from an immunology point of view, and this is just my random thoughts, I think what was found in the paper BamBam posted was significant. There was a correlation between early cytokines production and outcome, those with decreased early cytokines responses accumulated virus more rapidly.

Well it is the cytokines that make you feel terrible in the first few days of an infection, not the virus itself, i.e. the prodrome. One of the cytokines the paper mentioned was IL-6, which works on the hypothalamus to increase the temperature. If the patient is not making enough IL-6 in response to Ebola invasion then their temperature measurements won't necessarily increase linear with viral replication. Perhaps a subgroup of patients ( thoses ironically with poorer outcome are infectious before they appear ill ). You need cytokines to raise temperature.

Anyway sorry for rambling on, however so many good points were raised by those that replied. Thank you for the articles with the info.

Fp

[Lizw]

Re: Incubation time previously questioned.

There have been conflicting reoorts about whether Patrick Sawyer exhibited symptoms much in advance of collapsing. Some have said he appeared to be perfectly all right when he boarded the airplane; others that he was allowed to embark even though he had a high fever. In either case, he was steady enough on his feet to get himself to the airport and onto the plane. I too have wondered about the apparent sudden onset of symptoms way into the time period when the virus should have been already present in huge numbers.

[Rocah]

Re: Incubation time previously questioned.

Would the recent report (http://bigstory.ap.org/article/niger...ew-ebola-cases) of secondary contact infections in Nigeria give an indication of viral load at early onset of symptoms? Given that all the primary contacts with Mr Sawyer were under observation, so early symptoms should have prompted isolation quite quickly. However these two spouses still got infected.

[kondor]

Re: Incubation time previously questioned.

Here is another way of looking at the data.
In these West African countries health care providers are a rare commodity, registering below 1% of the nations population.

Yet we see about 8% of those infected are health care providers.

This indicates that, contrary to what we think might have happened due to the sheer numbers, in fact it still spreads mostly when someone has taken ill. Likewise, the rest of the number infected are usually close family.

What seems to be happening, is that whatever the current protection routine the health care providers are using it is not working under the conditions they are being asked to enforce it. Hence they catch Ebola and then take it home with them, spreading it amongst their family. Eventually one of the infected passes it on to another health care worker and the wheel keeps spinning.

Now there is, just happening now, a secondary effect to all this. As the strain on the health care system begins to grow more and more each passing day it follows that eventually, especially with limited numbers of staff, the health care system starts to break down. Bodies start being left on the streets, borders close, supplies of food dry up, and then looting and crime ensues.

So now we have a new situation, where we should expect to see the percentage who are health care workers getting it start to fall, and at the same time we should see a jump in the amount of people contracting the virus.

Obviously, with a broken health care system, the mortality should also jump. So more victims, and a higher mortality.

Of course, we hope the international bodies will increase their efforts, however it is looking more and more each day like that horse has bolted.

The initial problem was one of geographical spread, which should not have caught everyone out the way it did as we all knew it was bound to happen sooner or later. But the problem now is much deeper. The virus never needed to mutate. All it needed was the right location, where it could spread a large enough distance quick enough to catch us all with our pants down.

[foxp3]

Re: Incubation time previously questioned.

Hi Kondor,

The points you make are true and valid. How can people for example in West Point quarantine themselves for 21 days, when they have to work daily just to feed their families. They do not have the financial means to take a 21 day time out.

When I saw the photo with Dr Brantley high fiving his medical team, it dramatically highlighted the inequalities in global health care. This photo had him running down a corridor fiving his team of specialists. There must have been 2O medical individuals there from the infectious disease consultants, tropical medicine specialists, infection control teams, intensive care team, microbiologists and virologists, also his own nurses, lab staff and various others. All this for one man. Liberia has 3 doctors per 100,000 people, and that was before the collapse. I know the doctoring of Brantley was beneficial to doctor and patient, however it emphasised the polarity between his care and those poor cases we see left on hospital mattresses on school floors. Heartbreaking images , help seems so slow getting there.

http://www.dailymail.co.uk/news/article-2730694/Hospital-discuss-discharge-Ebola-patients.html

http://abcnews.go.com/Health/photos/tour-school-transformed-ebola-ward-25001627

I hope food aid arrives for them or they will be trapped in the sealed off zones starving. The riots would add to the already broken system.

However sad as it is I do not agree that your explanation covers all the questions surrounding the transmission.

Nigeria, 2 new cases were spouses of medics that died. Those medics were under quarantine conditions ( following WHO protocols, when they passed it on. They knew what to look for. Now a breakdown once perhaps, but not twice, bit of a coincidence. An incubation period ( period from infection to clinical symptoms), is often different than the latency period ( from infection to infectiousness) . Different diseases have different ratios. Only epidemiological data will give the answer, but that can take time.

So while I hear you on the healthcare problems, I also think that there is a possibility the latency period of this virus can in some individuals be shorter than the incubation period.

Fp

[kondor]

Re: Ebola incubation time previously questioned

I agree with you I am sure the latency period is less than the incubation period. Especially where close contact with a spouse is concerned, which often involves the exchange of fluids.