Emerging diseases and immunity

[mynah]

In 2007 a new strain of cold virus, an adenovirus named Ad14, infected an unknown number of people. At least 140 in the USA died of it, including young, previously healthy people, according to an article in the 6 September 2008 edition of NewScientist. By 2008, it had spread around the world – but by then the symptoms were no worse than those of any other cold.

 

In 2002 a coronavirus made a species jump from bats to human, resulting in SARS, causing prolonged respiratory symptoms in humans, who often died after weeks or months of suffering. By 2004 the disease had almost run its course, and those who did get infected generally suffered only mild illness.

 

Emerging diseases are often devastating when they first infect humans. A form of avian influenza, the Spanish flu of 1918, raged round the world, leaving millions dead in its wake before it finally subsided. Unlike most epidemic diseases, it was more likely to kill young, healthy adults in their prime than children and middle-aged sufferers.

 

The Spanish flu never really disappeared: Most of us have probably suffered infection, stayed in bed to recuperate for a day or two, and resumed our lives without getting too ill.

 

The explanation given for diminished virulence is usually that humans tend to build up antibodies and acquire at least partial immunity to new diseases, rendering infections relatively harmless. With global travel, infections spread round the world fast, but immunity is acquired at equal speed. In previous centuries, epidemics tended to be localized, but there were a few devastating exceptions: The Black Death was brought to Europe from Asia by merchant ships, Columbus and his successors decimated native Americans with European diseases (and took back syphilis as a souvenir that was much more lethal then than now), and the Spanish flu accompanied WWI soldiers to their native lands. In all cases the hapless recipients of the new germs were settlements of people who rarely traveled far from home, and whose immune systems experienced these viruses and bacteria as totally foreign.

 

It makes sense – but to me, it only does so to a point. I rarely get colds, and have not had one in the past two years. Does that mean that, when Ad14 rocks along, I’ll get really, really ill, or worse? If not, what confers immunity to those unaffected by the initial outbreak, and if I have been exposed, what prevented me from succumbing to severe illness the first time my body encountered the virus?

[Cedars]

It makes sense – but to me, it only does so to a point. I rarely get colds, and have not had one in the past two years. Does that mean that, when Ad14 rocks along, I’ll get really, really ill, or worse? If not, what confers immunity to those unaffected by the initial outbreak, and if I have been exposed, what prevented me from succumbing to severe illness the first time my body encountered the virus?

 

Some peoples immune systems are more likely to correctly detect an invader.

 

There is also the factor of exposure to something similar enough in the past (as your spanish flu comments relate) which may make you less suceptable to something related but not quite the same as the new variation/mutation.

[modest]

The Spanish flu never really disappeared: Most of us have probably suffered infection, stayed in bed to recuperate for a day or two, and resumed our lives without getting too ill.

 

Interesting. Where did you hear this?

 

it was more likely to kill young, healthy adults in their prime than children and middle-aged sufferers.

 

Monkeys recently infected with resurrected Spanish flu died with symptoms of Cytokine storm which explains why young, adult, healthy people suffered worse. It's an overreaction of the immune system - healthy immune systems doing the most damage.

 

~modest

[mynah]

Extract from an article I wrote for the South African Encyclopedia (available online, but unfortunately not without subscription) a few years ago:

 

Apart from the Black Death - the bubonic plague pandemic that ravaged Europe and Asia in the 1340s – no epidemic yet recorded spread so fast and affected such a number of people.

 

Although the pandemic reached Spain early and was given much publicity in that country, the devastating strain had its origins elsewhere. The movements of large numbers of soldiers who participated in World War One would no doubt have contributed greatly to the spread of the disease in an era before civil aviation.

 

In the spring of 1918 an army cook was the first person to get influenza at Fort Riley, a military base in the US state of Kansas. Within two days, 522 soldiers were affected. The base bred and slaughtered its own pigs and poultry, and it is possible that the cook was infected while working with meat of afflicted animals.

 

The initial cases were not unusually severe – but in August 1918 the virulent strain emerged almost simultaneously in France, the United States and Liberia. From the beginning it was clear that this no ordinary flu: Sufferers would often be too weak to walk within hours of becoming ill. Shortly afterwards the faces of many would take on a bluish tinge and, as they struggled for breath, bloody froth would bubble from their mouths. Millions of people died within a day of two after the first symptoms appeared. In the US the pandemic reached its peak in October 1918, and elsewhere the disease spread like wildfire. Almost 140 000 deaths were recorded in South Africa before the last cases occurred in 1919.

 

The Spanish flu pandemic was remarkable in a number of ways.

 

Mortality rates in influenza and most other infectious diseases typically form a U-shaped curve when plotted against age on a graph, indicating that elderly and very young patients are at greatest risk of dying from the disease. The Spanish flu, however, yielded a W-shaped curve, as young adults were more likely to die than those just younger or older. At the time the deaths were often noted to be due to “unusually severe pneumonia” – but it is now believed that sufferers mostly died as a result of cytokine storm. Healthy young adults were most at risk because of the efficiency of their immune systems.

 

Another characteristic of the pandemic was the rate at which it spread and the high percentage of people affected: The largest inhabited area unaffected by disease was an island in the estuary of the Amazon River. Mortality varied greatly from area to area: Although the average figure of around 2,5 percent in the industrialised countries was considerably higher than that usually reported for flu, the pandemic was not nearly as devastating there as in remote areas where the disease had never been recorded before: Among some Eskimo communities in Alaska a third or more of those who were infected died, and it is believed that entire villages in the Third World disappeared off the face of the earth.

 

The viral strain, which would later be named H1N1, showed the characteristics of a virus that had undergone species jumping. The high rate of contagion, prevalence of the disease and extraordinary virulence had the hallmark of a foreign virus that had found its way around the human immune system, and against which humans had little resistance. Variants of H1N1 are still circulating among humans – but because most people have developed a degree of resistance, as well as the fact that vaccines and antiviral drugs are now available, the virus is not in the least as threatening as in 1918.

 

It was long assumed that H1N1 originated in pigs, which are susceptible to a similar strain. In 2005, however, tests on the frozen body of a woman who died of the Spanish flu in Alaska proved that this disease was a form of avian influenza. It is, however, possible that the virus was first assembled in a pig that was infected by both avian and human flu viruses. On the other hand, the original mixing vessel may have been a human, and it could be that pigs were infected later by contact with humans.

 

[modest]

The viral strain, which would later be named H1N1, showed the characteristics of a virus that had undergone species jumping. The high rate of contagion, prevalence of the disease and extraordinary virulence had the hallmark of a foreign virus that had found its way around the human immune system, and against which humans had little resistance. Variants of H1N1 are still circulating among humans – but because most people have developed a degree of resistance, as well as the fact that vaccines and antiviral drugs are now available, the virus is not in the least as threatening as in 1918.

 

Spanish flu is a strain of H1N1, just like half of all flu viruses today are a strain of H1N1. N1N1 existed before spanish flu, and obviously still exists now. Nevertheless, Spanish flu is extinct in the wild - completely extinct.

 

People don't still get Spanish flu, yet have an immunity to it as you say 2 posts ago. A person infected today would presumably be just as affected as someone infected in 1918.

 

~modest

[mynah]

Perhaps - but it would be very hard to either prove or disprove that H1N1 circulated in humans before 1918. The virulence of the disease suggests a species jump - although the partial immunity of some populations may be due to exposure to not greatly dissimilar strains. As it were, H1N1 never caused a severe epidemic again: Even the Asian flu epidemic of 1957 that involved a double antigenic shift to H2N2 was not as serious, nor was the Hong Kong flu epidemic of 1968 (single antigenic shift to H3N2). The avian flu outbreak that started in Asia in 1997 was caused by a species jump. H5N1 had been identified in birds decades before, but had never been seen in humans until then. Unlike the Spanish flu it was marked by low infectivity but very high mortality in those affected - a typical situation in the early stages of a species jump.

[Cedars]

The avian flu outbreak that started in Asia in 1997 was caused by a species jump. H5N1 had been identified in birds decades before, but had never been seen in humans until then. Unlike the Spanish flu it was marked by low infectivity but very high mortality in those affected - a typical situation in the early stages of a species jump.

 

I dont know if I would call whats happened with H5N1 an authentic specie jump yet. Seems its poor handling of the poultry that is infecting people with a few cases of possible human to human transmission.

[modest]

Perhaps - but it would be very hard to either prove or disprove that H1N1 circulated in humans before 1918. The virulence of the disease suggests a species jump

 

Yeah, you've got a good point there. In fact, I went to school a stone's throw from Ft. Riley (Kansas State).

 

I personally think the severity of an epidemic or pandemic has as much to do with the mutations of the virus as the immunity of those infected. Why, for example, was the 1951 epidemic so much worse in Liverpool as the rest of England? Could the people of Liverpool lacked an immunity that the rest of the country had? I don't think so. The only reasonable explanation would seem to be with the virus - some subtle mutation as it spread.

 

Death rates in Liverpool were higher in '51 than from Spanish flu in '18 & '19. Had the '51 H1N1 strain kept it's virulent nature as it spread out of the heart of England it's easy to imagine a pandemic as bad as during World War 1.

 

Then again, there are examples like Russian flu of '77 which was clearly lessened in virulence with anyone who was exposed to a similar strain in '47 - '57. So, immunity is, of course, a factor.

 

I just hope we're not ruling out the possibility that H1N1 could make itself very deadly again. An unrelenting pandemic for which there is no natural immunity does not seem impossible. If Spanish flu got out of the lab...

 

I guess, at least we have vaccinations now -_-

 

~modest

[mynah]

I dont know if I would call whats happened with H5N1 an authentic specie jump yet. Seems its poor handling of the poultry that is infecting people with a few cases of possible human to human transmission.

It depends on how you define "species jump". Some would say a species jump had taken place once a disease had been transmitted from the host species to another species for the first time: In this article, for instance rabies due to Australian bat lyssavirus is listed among diseases that had undergone a species jump, even though only two human cases (both transmitted through bat bites) have been recorded. One should also keep in mind the stringent measures some countries took to limit the spread of avian flu: Vietnam, for instance, culled its entire farmed bird population and started anew with imported hatchlings.

 

The WHO defined three stages and six phases in the development of a flu pandemic: By their definition, avian flu had reached stage two (pandemic warning period) and was entering phase 4 ("Minor outbreaks of limited distribution from human to human occur, although such outbreaks are highly localised. This appears to indicate a viral strain that is not yet well equipped to infect humans.") when the tide was turned.

[mynah]

I personally think the severity of an epidemic or pandemic has as much to do with the mutations of the virus as the immunity of those infected. Why, for example, was the 1951 epidemic so much worse in Liverpool as the rest of England? Could the people of Liverpool lacked an immunity that the rest of the country had? I don't think so. The only reasonable explanation would seem to be with the virus - some subtle mutation as it spread.

Strange, indeed, especially as it did not carry the signature of a pandemic due to an entirely new strain (high mortality in young adults due to immune system overreaction and cytokine storm). The fact that the epidemic started in Liverpool may have something to do with it, but the rate at which the epidemic spread makes it unlikely that the virus lost potency through mutation in so many directions in such a short time. Perhaps there was some elusive co-factor at work, possibly in the same way that HIV infection now turns otherwise innocuous infections deadly?

[Cedars]

It depends on how you define "species jump". Some would say a species jump had taken place once a disease had been transmitted from the host species to another species for the first time: In this article, for instance rabies due to Australian bat lyssavirus is listed among diseases that had undergone a species jump, even though only two human cases (both transmitted through bat bites) have been recorded. One should also keep in mind the stringent measures some countries took to limit the spread of avian flu: Vietnam, for instance, culled its entire farmed bird population and started anew with imported hatchlings.

Fair enough. Some would say such things. I dont consider the avian flu a true jump yet, as it is not spreading as canine distemper did through the seal populations (and apparently the lion populations of Africa), nor is it like the parvo virus jump from cats to dogs in the late 70s or early 80s. A true jump (imo) requires the disease to be transmittable on a comparable level with the original host infection rate. The avian bird flu H5N1 tears through bird populations with a high percentage of them becoming ill and then dying. This also makes the efforts of Vietnam importing new populations of chickens pretty pointless, in that wild birds are the main carriers of H5N1. Unless of course they are importing birds who are carrying some type of immunity to this strain, as some wild asian mallards seem to have.

 

As far as rabies (and I am not sure its a good example), well theres all kinds of strains out there which have become specialized for one type of host (canine rabies) but is transmittable to a whole host of animals, man included. Is it really a new jump or an old genetic code that rears its head during mutations, hence the bat transmission being something that should be expected, rather than declared a new specie jump? Does anyone know where these particular bats obtained their original infection from? Would be kinda ironic if it was from some domestic animal, say a dog brought over on one of the prison transports to australia so many years ago.

The WHO defined three stages and six phases in the development of a flu pandemic: By their definition, avian flu had reached stage two (pandemic warning period) and was entering phase 4 ("Minor outbreaks of limited distribution from human to human occur, although such outbreaks are highly localised. This appears to indicate a viral strain that is not yet well equipped to infect humans.") when the tide was turned.

What tide was turned? Theres like 65,000 flu related deaths in the USA a year and not one of them related to H5N1. We have what? Less than 400 H5N1 (or is it 800?) deaths worldwide with the potential for a handful of them being person to person transmissions. Does the potential exist for H5N1 making a transition into something like the spanish flu? Sure. But it also has the potential of making that 'true jump' without being more than a typical flu season with all its new strains and variations of the same old, same old.

 

If I remember right, they have already seen mutation in the ebola virus which allows more of its hosts to survive. Its really not in a virus best interest to kill its host, well not kill them fast anyways. I suppose this is part of the evolutionary reason why viri and bacteria can mutate so fast. Whoops, I didnt mean to burn down the house Honest! :doh:

[mynah]

This also makes the efforts of Vietnam importing new populations of chickens pretty pointless, in that wild birds are the main carriers of H5N1. Unless of course they are importing birds who are carrying some type of immunity to this strain, as some wild asian mallards seem to have.

I'm not sure just what measures Vietnam took apart from the cull. (There were no chickens or ducks when I visited the country at the end of 2005, but according to Hanoi newspaper reports at the time, chicken would soon be available again.) The campaign did seem to have positive effects: After 61 cases were recorded in Vietnam in 2005, there were none at all in 2006. Since then, however, there have been a few cases. It would seem to me that Vietnam has a special problem in that many rural people, especially women, spend much of their working day in open water.

 

As far as rabies (and I am not sure its a good example), well theres all kinds of strains out there which have become specialized for one type of host (canine rabies) but is transmittable to a whole host of animals, man included. Is it really a new jump or an old genetic code that rears its head during mutations, hence the bat transmission being something that should be expected, rather than declared a new specie jump? Does anyone know where these particular bats obtained their original infection from? Would be kinda ironic if it was from some domestic animal, say a dog brought over on one of the prison transports to australia so many years ago.

I mentioned rabies specifically because it is one of the conditions that are problematic as far as the definition of a species jump is concerned. (Its unique and aggressive mode of transmission is responsible for its widespread presence in many mammals, rather than its transmissibility.) Australian bat lyssavirus (which is present in most states, but not outside Australia) is not a typical rabies virus, and appears to be quite different from the canine rabies virus - but that is a very interesting question! The original host of rabies viruses has never been found, but is most likely to be an African bat. There are several rabies strains that do not spread all that readily between species: If a rabid dog bites another dog and a human, for instance, the dog is far more likely than the human to get rabies.

 

What tide was turned? Theres like 65,000 flu related deaths in the USA a year and not one of them related to H5N1. We have what? Less than 400 H5N1 (or is it 800?) deaths worldwide with the potential for a handful of them being person to person transmissions. Does the potential exist for H5N1 making a transition into something like the spanish flu? Sure. But it also has the potential of making that 'true jump' without being more than a typical flu season with all its new strains and variations of the same old, same old.

I was referring to avian flu specifically, but perhaps it is too early to speak of the tide turning: Around 1975 the WHO thought it had malaria licked. There has been a decline in the number of cases of avian flu, but vigilance should be maintained. Worryingly, recent cases appear to have an increased mortality rate - although it could be that at the height of the outbreak more people with milder symptoms reported to doctors, or that doctors were more likely to have patients with flu symptoms tested.

 

If I remember right, they have already seen mutation in the ebola virus which allows more of its hosts to survive. Its really not in a virus best interest to kill its host, well not kill them fast anyways. I suppose this is part of the evolutionary reason why viri and bacteria can mutate so fast. Whoops, I didnt mean to burn down the house Honest!

Probably the most important reason why emerging diseases seem to decrease in virulence - and certainly a more plausible explanation than that people acquire immunity en masse to a particularly virulent strain.

[Cedars]

I mentioned rabies specifically because it is one of the conditions that are problematic as far as the definition of a species jump is concerned. (Its unique and aggressive mode of transmission is responsible for its widespread presence in many mammals, rather than its transmissibility.) Australian bat lyssavirus (which is present in most states, but not outside Australia) is not a typical rabies virus, and appears to be quite different from the canine rabies virus - but that is a very interesting question! The original host of rabies viruses has never been found, but is most likely to be an African bat. There are several rabies strains that do not spread all that readily between species: If a rabid dog bites another dog and a human, for instance, the dog is far more likely than the human to get rabies.

Australian bat lyssavirus - Wikipedia, the free encyclopedia

Thought a link to ABLV might be useful.

 

There are many variables regarding infection rates of rabies, I would like to see a link verifying a dog is more likely to get rabies than a human all things being equal. There are variables in how infected the source dog is, how deep the bite wound, how many bites, etc (such as related bleeding, viral access to central nervous system, etc) which do impact the rate of infection for all mammals as I understand it. There can be some very long incubation rates before rabies symptoms appear, but again, the body is not recognizing this virus as an invader, allowing it to continue to reproduce before it finally finds a way into the central nervous system.

 

I was referring to avian flu specifically, but perhaps it is too early to speak of the tide turning: Around 1975 the WHO thought it had malaria licked. There has been a decline in the number of cases of avian flu, but vigilance should be maintained. Worryingly, recent cases appear to have an increased mortality rate - although it could be that at the height of the outbreak more people with milder symptoms reported to doctors, or that doctors were more likely to have patients with flu symptoms tested.

Define vigilance. We had people mass consuming anti-virals to the point of causing shortages, price hikes and worse yet drug resistant flu strains all due to the increased awareness of a handful of cases of infections.

 

We diverted millions of dollars of research funding to investigate. How much time was lost on these other issues? How many other proven infection control programs lost funding (such as malaria) as funds were re-allocated to chase this particular OMG! the Experts Say We Gotta Do Something Now headline news bulletin flashed across the screen. We wont ever know.

 

And after all of this, we still dont have a mutated H5N1, and if I remember correctly, if it does mutate to a deadly epidemic/pandemic type infection, it will still take 6 months before the first vaccinations are available to the people on the short list (you know, politicians, their families, etc) and the medical people, emergency responders, etc.

 

6 of 1, half dozen of another. I really dont worry too much about what if a new disease pops up in the congo, in viet-nam, in china....

[mynah]

There are many variables regarding infection rates of rabies, I would like to see a link verifying a dog is more likely to get rabies than a human all things being equal. There are variables in how infected the source dog is, how deep the bite wound, how many bites, etc (such as related bleeding, viral access to central nervous system, etc) which do impact the rate of infection for all mammals as I understand it. There can be some very long incubation rates before rabies symptoms appear, but again, the body is not recognizing this virus as an invader, allowing it to continue to reproduce before it finally finds a way into the central nervous system.

 

You'll find most of what you want to know - well, perhaps more than you'd like to know - about rabies in this online book.

 

Two interesting facts about immunity to rabies:

 

Whereas early and appropriate treatment after exposure almost always always prevent rabies from developing in humans, such treatment is ineffective in dogs. (This is not to be confused with vaccination in animals, which is generally effective.)

 

It would seem that the human immune system does react to rabies exposure, and sometimes overcomes the virus. A fur trapper who had killed thousands of foxes in a rabies endemic area, for example, was found to have antibodies against the virus in his blood, even though he had never been vaccinated against rabies or received treatment after being bitten.

 

 

Define vigilance. We had people mass consuming anti-virals to the point of causing shortages, price hikes and worse yet drug resistant flu strains all due to the increased awareness of a handful of cases of infections.

If a severe strain of a virus that previously did not infect people it all begins to do so, one should take notice. If it begins to get spread directly from person to person, it is an indication that the outbreak may be progressing to phase 5 (Phase 5: More generalised outbreaks are seen, but transmission between humans is still limited. Indications are that the virus is still not readily transmissible between humans, but that it is becoming so. The risk of a pandemic is now significant.) Phase 6 is the pandemic itself. Though the incidence of H5N1 avian flu has decreased, it has not gone away - and the disease caused by it remains severe.

 

6 of 1, half dozen of another. I really dont worry too much about what if a new disease pops up in the congo, in viet-nam, in china....

As AIDS did? Remember, in these days of global travel, a new disease may just be a plane flight away... Here in South Africa, we are bearing the consequences of a government ignoring a new killer disease because acknowledging it happened to be politically inconvenient. As a consequence, average life expectancy is now down to 42 years.

[Cedars]

You'll find most of what you want to know - well, perhaps more than you'd like to know - about rabies in this online book.

 

Two interesting facts about immunity to rabies:

 

Whereas early and appropriate treatment after exposure almost always always prevent rabies from developing in humans, such treatment is ineffective in dogs. (This is not to be confused with vaccination in animals, which is generally effective.)

I will read the book later today if time permits.

 

I would like to say that because a treatment used on people does not work on dogs does not bear relation to whether or not a human is at equal risk for developing rabies without treatment. We develop treatments for canine diseases which do not work on similar humans diseases also. Lots of promising clinical trials on people have failed when they were successful on dogs (and other lab animals).

 

It would seem that the human immune system does react to rabies exposure, and sometimes overcomes the virus. A fur trapper who had killed thousands of foxes in a rabies endemic area, for example, was found to have antibodies against the virus in his blood, even though he had never been vaccinated against rabies or received treatment after being bitten.

Yes, and when spanish flu raged around the world not everyone exposed developed the disease. That is a immune system genetic difference that is apparent in most (if not all) diseases which rage through a population, whether human or animal.

If a severe strain of a virus that previously did not infect people it all begins to do so, one should take notice. If it begins to get spread directly from person to person, it is an indication that the outbreak may be progressing to phase 5 (Phase 5: More generalised outbreaks are seen, but transmission between humans is still limited. Indications are that the virus is still not readily transmissible between humans, but that it is becoming so. The risk of a pandemic is now significant.) Phase 6 is the pandemic itself. Though the incidence of H5N1 avian flu has decreased, it has not gone away - and the disease caused by it remains severe.

Except that H5N1 human exposures typically do not cause the disease in humans. As I have said, the risk of developing this particular disease is primarily due to the handling of infected animals, rather than simple exposure such as with a typical human flu. I have participated in the butcher of animals and the cleaning of their pens. It was very important that I not do certain things, such as being very careful while making cuts to not cut myself, exactly so I did not expose myself to a disease that animal may harbor which would not normally affect a human unless you did something to expose yourself.

As AIDS did? Remember, in these days of global travel, a new disease may just be a plane flight away... Here in South Africa, we are bearing the consequences of a government ignoring a new killer disease because acknowledging it happened to be politically inconvenient. As a consequence, average life expectancy is now down to 42 years.

 

AIDs discussion should probably have its own thread. As far as just a plane flight away, while true, we do have the example of SARs which never turned into the global pandemic, yet still exists out there in the real world. If I remember right, less than 9,000 deaths since its beginning.

 

Gotta go birding now.

[mynah]

I'd like to return to the subject of killer flu later (haven't had time for detailed postings recently!), but a classical situation concerning emerging diseases has arisen uncomfortably close to where I live.

 

On 12 September a woman aged 36 was airlifted, accompanied by a paramedic, from Zambia to a private hospital in Johannesburg, South Africa. She had fallen ill three days previously. In spite of treatment, she died two days later of symptoms suggesting viral haemorrhagic fever. However, tests for all known HFs came back negative.

 

On 27 September the paramedic (36) was admitted with similar symptoms. He died on 1 October. A nurse (34) who had treated the first patient sought medical treatment early in October and died in hospital 3 October. Another woman who had worked in the same ward has also died, but a link has not been confirmed.

 

The WHO is now investigating the outbreaK.

 

Since then, 121 people have been quarantined. Experts consider Crimean Congo fever the most likely culprit, although a number of findings are not consistent with such a conclusion, including:

 

* CCF, a tick-borne disease with a mortality of some 30 percent, is rarely transmitted from human to human, and secondary cases are rarely fatal.

* Most people who succumb to HFs only do so in the second week, whereas these patients died within five days or fewer.

Tests for CCF and all other known HFs have proven negative.

* The 100 percent mortality rate so far - in spite of good quality hospital care - is another obvious cause for concern.

[mynah]

Latest news in is that two more people have been admitted to hospital. No indication has been given of their condition.