Well, here we are already at Part IV of Measles Week.  Doesn’t time fly? Remember how young we all were, back at Part I, when I raised the question I’m trying to answer today? And those merry, innocent days of Part II (The origin of measles)? And then Part III (The probably-wrong explanations) — doesn’t it seem just like yesterday?

Today, Part IV is all about the explanations for the spectacular drop in measles case-fatality rates (between 40 and 150 times lower death rate per case of measles) in the first half of the 20th century (chart).  No one of these explanations alone seems to be completely adequate to explain the spectacular decline in measles deaths, but perhaps — probably — the combination of all of them put together, perhaps with contributions from some of the Part III explanations, account for the drop.

Explanations that (might be) right:

• Better treatment of measles, especially antibiotics. Measles is a viral disease and so not treatable by antibiotics, but it’s the secondary infections that kill; and those could be controlled by antibiotics.
• Reduction in crowding. There’s evidence that overcrowding, per se, can make severe measles disease more common. Improved living conditions might have helped with this.
• Demographic changes. This is a little vague, but I have a couple of specific aspects in mind.
• Nutrition. This is the most popular, and probably most important, explanation. But (to me, anyway) it doesn’t seem to be enough, all by itself.
• Vitamin A. As a subset of nutrition, and also as a treatment on its own.

Let’s leave nutrition to the last and quickly run through the other explanations first.

• First: Better medical treatment of measles patients. As I say, antibiotics probably put a big dent into the toll from secondary bacterial infections.  There were also advances in things like oxygen treatment during pneumonia and so on. Probably important factors, but the problem with this explanation is that by the time antibiotics became available, the trend to reduced measles mortality was already well under way.  You don’t see sudden drops in mortality associated with these things kicking in, just a continuation of the ongoing decline.

Antibiotics and 20th-century mortality rates 1

Compare to the chart of overall mortality rates in the 20th century¹ (to the left; this is the inset from the larger chart here). It shows two curves being fit to the data — one in the first 30-odd years of the 20th century, one in the second half of the 20th century.  From 1938 to 1953, between those smooth curves, there’s an especially dramatic drop in mortality rates.  That abrupt drop corresponds to the introduction of antibiotics. You don’t see that abrupt drop with measles death rates.

• Reduction in crowding.  This seems like a simple thing, but it’s been proposed (first, I believe, by Aaby and Coovadia,² in 1985) to be a major influence on measles mortality.

Their observations suggested that severe measles cases are most closely associated, not with malnutrition as you might expect, but with overcrowding. (Obviously, the two are both tightly linked to poverty in general, so pulling them apart is a little tricky.) They argue that you’re more likely to get a large dose of measles virus if you’re crowded together with a measles patient, and that getting more virus at the outset correlates with having more severe disease:

It was found that severe measles was not associated with PEM [protein-energy-malnutrition] but frequently accompanied overcrowding in Guinea-Bissau. Secondary cases fared worse than index patients. … The hypothesis which fits most of the observed facts postulates that the transmission of a large inoculum of virus particles to susceptible children is an important cause of severe disease. ²

(My emphasis) So, as overall wealth improved in the early 20th century and quality of life became better, children became less crowded, less likely to receive massive doses of virus, and were better able to control the lower doses they did get.

This makes sense, but I don’t think there’s enough of an effect to account for the drop in mortality — again, we need to explain a hundred-fold reduction in the case-fatality rate.  This is probably one significant factor, but not enough to account for everything.

• Reduction in crowding is a part of the next category, Demographic changes. This is much harder, for me anyway, to put together with hard data, but follow me here:

We  know that measles mortality rates are by far the highest in the youngest of its victims.  Children over, say, 5 years old or so are much less likely to die than are infants.³  So, any changes in society that would make measles more likely to infect older — even slightly older — children, would have a massive effect on mortality rates.  We see this even today, where small changes in age at infection lead to significant changes in survival. ⁴

Meanwhile, we see measles mortality rates beginning to drop just around the time of one of the biggest demographic changes in UK and US society — World War I.  What I don’t know, not being a historian, is just how WWI would affect measles epidemics. Were children mixed more, or less, as their fathers went off to war? Were children taken out of London and other cities, into rural areas, as they were in the second World War?  (We know that measles is an urban disease.)  And so on.  I don’t know enough about population movement and changes in this period to put the story together, but I’m personally convinced that this had a significant effect on measles mortality, and most likely because (somehow) it led to children being infected just a little bit later in their life.

(Edit: In the comments, Tsu Do Nimh [if that's his real name] points out that 1915 was the time family planning and birth control started.  That’s another potential cause of a significant demographic change toward smaller families, which in turn could lead to exposure to measles at a later age.)

I don’t think this is the whole story, but it does seem to be one of the explanations that (in principle) does have enough power to cause a hundred-fold drop in measles case-fatality rates.

• Moving on to the last two categories, which are closely related.  It’s well known, now, that vitamin A deficiency greatly increases the risk of death after measles infection.  And in England, at the least, in the first third of the 20th century, vitamin A deficiency was common,⁵ especially in the poor (who were almost entirely at risk of measles-related death; measles was never a big risk to the wealthy).

So vitamin A supplementation presumably must have had a big impact on measles mortality, once it became widespread.

But: First of all, vitamin A supplementation didn’t become part of measles treatment until the early 1930s.⁶ By that time, the case-fatality rate had already started to drop pretty dramatically, and, as always, we don’t see any sudden drop in the death rate that’s associated with any one factor.

Second, the effect doesn’t seem to be great enough — vitamin A supplementation reduces measles mortality about 2 to 3-fold,⁷ which is great, but nowhere near enough to account for the hundred-fold reduction in death rates we see.

So, yet again: Part of the story, but far from the whole story.

• Finally: Nutrition. It’s very clear that malnourished measles patients do much, much worse than those who are well nourished.  It can be a huge effect, certainly enough to account for the differences in 1910 and 1950 death rates.   Patients in the developing world, today, may suffer case-fatality rates that are much more like 1910 London (10-30% death rates) than 1950 and present-day London (0.025% death rates). ⁸

But my question — and again, I’m no historian — is, how badly malnourished were children in the 1920s?  The biggest loss in survival comes from the most malnourished children, from children who are severely malnourished. Just “ordinary” levels of malnourishment “only” cause about a 2- to 5-fold difference in survival.⁹ Yet again, not enough to account for the 100-fold change in survival by 1950.

Were children in England and the US, in 1920, really comparable to severely malnourished third-world children today? Of course it was almost entirely the poor who died; measles even in the 1910s were known to spare the rich and kill the poor. But even so — Am I naive, or were the ordinary working poor in those days really malnourished to the border of famine?

So there are the general explanations for the increased measles survival from 1915 to 1955.  Each of those factors I can easily see causing a 5- or even 10-fold improvement in mortality, but none of them seems, to me, to be enough for the effect we see.  There’s some room for synergistic effects, multiplying survival rates rather than additive (better-nourished patients who are less crowded and therefore receive lower doses of virus, getting better treatment after they do get sick) — but equally, there’s a lot of overlap (vitamin A deficiency isn’t completely separate from overall malnourishment).

(This is why I’d really, really like to see if modern measles virus and 1910 measles virus actually were similar at the genome level, or if there might be some change in the virus after all.)

As I said earlier, I’m not an expert on any aspect of this, and I welcome any corrections.  (But, again, comments that are your opinion aren’t going to be much help; data and references, please.)

1. Armstrong, G. (1999). Trends in Infectious Disease Mortality in the United States During the 20th Century JAMA: The Journal of the American Medical Association, 281 (1), 61-66 DOI: 10.1001/jama.281.1.61
2. Aaby, P. (1985). Severe measles: A reappraisal of the role of nutrition, overcrowding and virus dose Medical Hypotheses, 18 (2), 93-112 DOI: 10.1016/0306-9877(85)90042-8
3. Wolfson LJ, Grais RF, Luquero FJ, Birmingham ME, Strebel PM (2009) Estimates of measles case fatality ratios: a comprehensive review of community-based studies. Int J Epidemiol 38:192–205.
4. Marufu T, Siziya S (1998) Secular changes in rates of respiratory complications and diarrhoea among measles cases. J Trop Pediatr 44:347–350.
5. Semba RD (2003) On Joseph Bramhall Ellison’s discovery that vitamin A reduces measles mortality. Nutrition 19:390–394.
6. JB. E (1932) Intensive vitamin therapy in measles. BMJ 2:708.
   Semba RD (2003) On Joseph Bramhall Ellison’s discovery that vitamin A reduces measles mortality. Nutrition 19:390–394.
7. Madhulika Kabra SK, Talati A (1994) Vitamin A supplementation in post-measles complications. J Trop Pediatr 40:305–307.
   D’Souza RM, D’Souza R (2002) Vitamin A for the treatment of children with measles–a systematic review. J Trop Pediatr 48:323–327.
   Tielsch JM, Rahmathullah L, Thulasiraj RD, Katz J, Coles C, Sheeladevi S, John R, Prakash K (2007) Newborn vitamin A dosing reduces the case fatality but not incidence of common childhood morbidities in South India. J Nutr 137:2470–2474.
   Mishra A, Mishra S, Jain P, Bhadoriya RS, Mishra R, Lahariya C (2008) Measles related complications and the role of vitamin A supplementation. Indian J Pediatr 75:887–890.
8. Alwar AJ (1992) The effect of protein energy malnutrition on morbidity and mortality due to measles at Kenyatta National Hospital, Nairobi (Kenya). East Afr Med J 69:415–418.

   Latham MC (1975) Nutrition and infection in national development. Science 188:561–565.
   Morley D (1983) Severe measles: some unanswered questions. Rev Infect Dis 5:460–462.
   Kaler SG (2008) Diseases of poverty with high mortality in infants and children: malaria, measles, lower respiratory infections, and diarrheal illnesses. Ann N Y Acad Sci 1136:28–31.

9. Alwar AJ (1992) The effect of protein energy malnutrition on morbidity and mortality due to measles at Kenyatta National Hospital, Nairobi (Kenya). East Afr Med J 69:415–418.

Those inadequate explanations are:

• Poor surveillance. Did the medical establishment gradually, say, lose interest and stop recording measles deaths over the decades?
• Sanitation. There were huge advances in sanitation, especially in water treatment, in that period. Was that why measles deaths declined?
• Viral changes. Did the virus mutate and become less lethal in that period?
• Antiserum. In that time-frame, a new treatment for measles became available. Was antiserum treatment responsible for saving tens of thousands of patients’ lives?

(I’m going to repeat my disclaimer from the first post here: I’m not a historian, a medical doctor, or a measles researcher, and I’m more than happy to be corrected.  Anyone who has actual information on this, please let me know.  If you have an opinion, no offense, but I’m not interested unless you have data to back it up.)

All of these are actually fairly plausible answers, and probably some of them did play some role. But:

• Surveillance –identification of deaths due to measles, and notification of the authorities–probably didn’t change significantly. Certainly surveillance isn’t, and never has been, perfect, especially when comparing disease frequencies over time:

… because of changes in understandings of the disease and contemporaries’ presentation of the data, the size of that effect and its role in mortality decline more generally elude us. Our analysis of the past depends on numbers that reflect not only changing treatments but also changing understandings of disease at the end of the nineteenth century. ¹

And as I noted in Part I, in Britain measles did temporarily stop being a notifiable disease around 1919 — but when official surveillance kicked in again in 1939, measles was still there (chart), with the case-fatality rates right on the same trajectory as before.

In any case, changes in surveillance aren’t likely to account for a 100-fold reduction in death rates; you just don’t miss that much. And while you can probably miss a lot of deaths,² that’s something that’s more likely to be a factor early on, while the public health system is still getting established. In 1917, for example:

The deaths reported as due to measles give a very inadequate and incorrect idea of the real number due to this disease, for it is well known that most of the deaths are not due to the original disease, but to a complicating bronchopneumonia, and many phsyicians who have failed to report the original disease do not mention it on the death certificate. ³

So the later, lower death rates, which are the unexpected and surprising ones, are the most likely to be accurate.

• Sanitation. No one could argue that sanitation isn’t important. But it’s most important for water-borne diseases. Measles is a classic respiratory disease; it doesn’t need water to spread, and sanitation doesn’t stop it from spreading. Of course, we know that the frequency of measles cases didn’t drop, just measles deaths.

What about protection against secondary infections after measles infections? That’s more plausible, because by itself, measles doesn’t kill at high frequency; it’s the secondary infections that kick in afterward, in the immune-suppressed and weakened patient, that are fatal. Here, sanitation probably helped some; diarrheal diseases were occasional causes of death after measles infections. But they were far from the most common. Usually, measles patients died of pneumonia. And again, these respiratory infections are the kind that sanitation is less effective in preventing.

So sanitation undoubtedly had some effect; it’s probably heavily responsible for the overall reduction in childhood mortality (chart; note the scale compared to the measles charts) during that period.  But that background reduction in overall mortality is much less than the effect on measles deaths.  So sanitation alone probably isn’t nearly enough to account for the whole reduction in death rates.

• Did the virus mutate? Certainly that could happen — there’s precedent for viruses evolving that degree of change in virulence, in that kind of time-frame.

But modern measles virus can still kill children at the high rates of the 1910 epidemics, when the infections occur in the Third World. The virus hasn’t (apparently) lost its virulence; it’s the environment of the modern developed nation that lets us survive.

(That’s the conventional answer, anyway. I’m not completely convinced, and I would be really interested in seeing the sequence of some fossilized 1910 measles virus. Perhaps, like the 1918 influenza, there’s some frozen in the permafrost somewhere?)

• Antiserum treatment. (This story was new to me, and when I ran across the discussion of it I thought briefly I had found the explanation. But probably not.) In the early 1920s, doctors began to transfer serum from people who had recovered from measles, into measles patients.⁴ This transfers antibodies, which are protective, and it turns out to be a really good way of stopping an ongoing measles infection in its tracks. This  serum treatment was used pretty widely:

In the London County Council,over a period of more than 10 years up to 1943, 66 litres of convalescent measles serum and normal adult serum from over 3,000 donors were used to inoculate 36,000 contacts⁵

But even thousands per year in the London area is still not very much, in the context of hundreds of thousands of measles cases per year.  Serum treatment doesn’t seem to have been widely-enough used to make a big enough dent in country-wide measles deaths. A fascinating round-table discussion in 1945⁶ specifically considered and dismissed this as having enough effect:

DR. W. GUNN said that measles epidemics usually occurred every second year and reached their height in London about the middle of March, when the number of admissions to L.C.C. hospitals reached its highest level … and there did not seem to be any ready explanation why measles, a more contagious disease, was so slow in coming to a head. He did not think the use of sera had had any significant effect on reducing mortality, because so far few persons received injections. ⁶

(My emphasis) And that fits with the observation that there was not a sudden, abrupt drop in rates in the late 1920s, as antiserum started to be used, but rather a continuous gradual decrease from 1915 to 1955.

(Incidentally, in hindsight, I wonder how the serum was treated.  There’s no evidence that viral diseases like hepatits C or hepatitis B, or HIV, were spread via these treatments, but I don’t know if that was luck or design.)

So there are some possible explanations that, I think, don’t account for a large part of the drop in measles case-fatality rates. Tomorrow I’ll cover some of the answers that are more likely to have had bigger impacts.

1. Condran, G. (2008). The Elusive Role of Scientific Medicine in Mortality Decline: Diphtheria in Nineteenth- and Early Twentieth-Century Philadelphia Journal of the History of Medicine and Allied Sciences, 63 (4), 484-522 DOI: 10.1093/jhmas/jrn039
2. Especially since deaths due to measles-induced immune suppression may lag the actual measles infection by some time
3. Observations on Measles. Charles Herrman. Archives of Pediatrics 34:38-42 (1917
4. ZINGHER ABRAHAM (1926) Convalescent whole blood, plasma and serum in the prophylaxis of measles. JAMA 1180–1187.
5. COCKBURN WC, HARRINGTON JA, ZEITLIN RA, MORRIS D, CAMPS FE (1951) Homologous serum hepatitis and measles prophylaxis; a report to the Medical Research Council. Br Med J 2:6–12.
6. Butler W (1945) The Fatality Rate of Measles: A Study of its Trend in Time. Journal of the Royal Statistical Society 108:259–285.

This is part II of “Measles Week”; see Part I for an explanation of what this is about, and an outline of what’s to come.

Measles is a fairly young disease. Just how young is it?

One of the most characteristic features of measles is its epidemic nature. For example, look at the huge difference between the peaks and valleys here:

Weekly measles cases, England and Wales, 1950-1965 (click for a larger version)

There are usually a couple of years (one to five years is typical) in between each epidemic. There are a couple of things that drive this pattern:

1. Measles is incredibly contagious. R₀ for measles — the number of new cases that can arise from a single case, in the absence of immunity — is around 15, more than ten times higher than that of the swine-origin H1N1 we recently have been seeing.
2. Measles is very immunogenic and infection confers pretty much life-long immunity.  As a corollary to this: Measles infection is short-lived. The immune system eliminates the virus fairly quickly — there’s no carrier stage.

That means that when measles has enough susceptible hosts, it can explode and spread across a country almost overnight. But it leaves behind it a firebreak of people who are immune, who are no longer potential hosts. After the epidemic, just about everyone is immune; the virus smolders at some very low level, in the handful of people who are not yet immune. After a couple of years, there are enough new births that there’s a new population of susceptible hosts who can sustain a new epidemic, and so on.

If you think about it, those two factors mean that measles virus needs a pretty good-sized population to keep going. With no carrier stage, the virus has to meet up with a susceptible host in the brief period during which it sheds. In between epidemics, there aren’t many of those. If you’re talking about family groups or tribes or villages with a few hundred people, there aren’t enough newborns to keep the virus going in the epidemic valleys.

Given the observed facts on epidemic timing, spread, and so on, you can calculate out how many people you need to keep measles from going extinct: It’s somewhere around 250,000 to 500,000 people in contact with each other.¹

In other words, measles needs cities. It’s a disease of urbanization, and it couldn’t have existed in its present form before good-sized city-states were around.

Even in our highly connected modern world, measles is still an urban disease. Epidemiologically, measles epidemics look like standing waves emanating from cities:

In the pre-vaccination era, conspicuous hierarchical waves of infection moved regionally from large cities to small towns; the introduction of measles vaccination restricted but did not eliminate this hierarchical contagion. A mechanistic stochastic model suggests a dynamical explanation for the waves-spread via infective ’sparks’ from large ‘core’ cities to smaller ’satellite’ towns.²

Gozu Tenno, a Shinto god, punishes two gods of measles and offers advise on what to eat while suffering from measles. (1862)

Populations of that size arose around 2000-3000 BC, in the Middle Eastern river valleys; so measles really can’t be older than 4000-5000 years. It’s an emerging disease that emerged some time in recorded history. (Also, it probably arose from the closely-related cattle disease rinderpeste, or some common ancestor; so again, it has to post-date domestication of cattle.)

I personally don’t read Confucian-era Chinese or medieval Arabic, but there are people who do, who say that measles may be described in various old writings. But apparently these earliest descriptions aren’t very clear, and are most likely referring to some other disease. The earliest description that is clearly of measles is around the 9th century, by the great Persian physician Abu Becr Mohammed Ibn Zacariya Ar-Razi (Rhazes) (Wikipedia link).

Rhazes’ description may well have been of a brand-new disease, because it turns out to fit pretty well with a recent analysis, ³ tracking back measles mutation rates to see when it arose, that found a likely origin of measles from Rinderpeste somewhere around 1000 AD — somewhere in the range of 500 – 1600 AD. Also:

Linguistic evidence suggests that the disease was recognized before the Germanic migrations but after the fragmentation of the Roman Empire, i.e., between 5th and 7th centuries … Epidemics identified as measles were recorded in the 11th and 12th centuries³

So, based on genomic information, written documentation, and linguistic evidence, measles isn’t an ancient disease; it’s a disease that jumped into humans some time in the first millennium A.D.

Tomorrow in Measles week: Some explanations for the drastic drop in measles deaths that are plausible, but probably not correct.

1. Bartlet MS (1957) Measles periodicity and community size. Journal of the Royal Statistical Society 120:48–70.
2. Grenfell, B., Bjørnstad, O., & Kappey, J. (2001). Travelling waves and spatial hierarchies in measles epidemics Nature, 414 (6865), 716-723 DOI: 10.1038/414716a
3. Furuse, Y., Suzuki, A., & Oshitani, H. (2010). Origin of measles virus: divergence from rinderpest virus between the 11th and 12th centuries Virology Journal, 7 (1) DOI: 10.1186/1743-422X-7-52

I’ve talked before about measles incidence and the effect of vaccination.  Now I’m going to spend this whole week talking about measles deaths, because I ended up with more than I could cover in one or two posts.  So this is Part I of a five-parter.

A group of diseases which … even now are considered to be unavoidable are scarlet fever, measles, and whooping cough. … According to the statistics collected in the census of 1900, these three diseases were responsible for upward of thirty thousand deaths in the course of a year.”

–”The Conservation of the Child”, by Earl Mayo.  in The Outlook. A Weekly Newspaper. Volume XCVII.  January-April, 1911 (pp. 893-903)

That was the situation in 1911 and in the early 20th century generally, and for centuries before that.  Almost every child caught measles, and a lot of them died.  Measles wasn’t quite as lethal as smallpox, but it wasn’t too far behind:

Measles should no longer be considered a “minor” infection. It is a major illness causing a considerable mortality and a much greater morbidity among young children affected by it. ¹

(By the way, as well as citing my direct quotes in footnotes as usual, I’ve collected the 40-odd references I read while trying to figure this story out and put them up here.)

But, starting somewhere around 1915, that began to change.  Very gradually (so gradually that it almost escaped attention) measles stopped being a fatal disease.  In 1945, William Butler said:

In three-score years or so, during which the population of England and Wales has nearly doubled, the gross annual contribution of deaths from measles has fallen to about one-twelfth of the mean figure at which during several quinquennia it stood in the eighties and nineties of the last century.  Nor is there reason to believe–on the contrary–that measles is now less prevalent than it was. It is still true that nearly everyone at one time or another has measles. ²

And the trend didn’t stop there.  In 1945, about 163 out of every 100,000 measles cases died.  In 1955, just 25 of 100,000 died, and it’s hovered around there since.

In other words, a person who caught measles in 1900 was between 40 and 150 times more likely to die than someone who caught the virus in 1955.  You can play with the numbers in various ways, but no matter what you do there has been an absolutely, spectacularly, incredible drop in measles case-fatality rates.

Below are a couple of charts to illustrate this.  The UK (number of measles deaths in England and Wales) is on the left, the US (measles deaths per 100,000 population) on the right (click for larger versions).  The dashed blue lines are the actual numbers.  Because measles is a very, very epidemic disease, the numbers change hugely every year, so I’ve applied a crude smoothing to the raw numbers (the green solid lines) to make the trends easier to see.  My US numbers only go up to 1940, but here’s a chart through the 1960s, if you like – there’s no surprises in it, it’s pretty much like the UK.

Measles deaths in the UK, 1900 – 1965	Measles deaths in the US, 1900 – 1940

Important note: In England, measles was not a notifiable disease between 1919 and 1939 (and I believe the rules for notification changed for a few years before 1919³ as well), and the effect of this is easily seen — the abrupt drop in reported deaths just before 1920, and the flatter line for a few years afterward, is almost certainly not real (I’ve boxed that non-notifiable period off in red.)  But the overall trend is still easy to see even so.

This had nothing to do with the measles vaccine, because this survival increase happened entirely before the vaccine was available in 1963.  There was essentially no change in the number of measles cases over this period (adjusted for population, of course), it’s just that once you caught measles you weren’t as likely to die.  And case-fatality rates didn’t change significantly after the vaccine was introduced.  The death rate per case in 1955 (pre-vaccine) is pretty much what we see today in first-world measles outbreaks.

The vaccine did spectacularly reduce the number of cases, of course, and therefore did reduce the total number of deaths.  Also, equally obviously, vaccines aren’t only given to prevent deaths.  Even if measles doesn’t actually kill your child, she’ll still, quite possibly, be pretty sick; there’s a pretty good chance she’ll be hospitalized; and a significant number of survivors have some form of medium- or long-term complications.

Was measles unusual? Overall mortality, and especially childhood mortality due to disease, did drop over this period, and quite dramatically so:

The infant mortality rate has shown an exponential decline during the 20th century.  … For children older than 1 year of age, the overall decline in mortality during the 20th century has been spectacular. … Between 1900 and 1998, the percentage of child deaths attributable to infectious diseases declined from 61.6% to 2%.  ⁴

Here’s the famous chart of 20th-century mortality.⁵  (Note the brief, huge spike in 1918, due to the 1918 pandemic influenza!)

Mortality rates in the US through the 20th century

So yeah, in general mortality rates did improve greatly since 1900, flattening out in the 1950s, just the same pattern as with measles deaths.  But check the scale, and compare to the UK (especially) chart above: Measles outpaced this overall improvement, and by a huge amount.  Overall, during this period childhood mortality rates improved perhaps 8-10-fold — clearly a tremendous improvement, but still, at best a quarter of the improvement in measles survival. (And measles was a late starter, too — overall mortality had been dropping for at least 15 years before measles case-fatalities started to go down.)

So what happened between 1915 or so, when measles death rates began their decades-long drop, and 1955, when the drop stopped?  That’s the subject of this entire week’s worth of posts, but to give you a peek at the answer I came up with: It beats the hell out of me. There really isn’t a single, simple explanation for this, as far as I can find.

(I’m not a historian, a medical doctor, or a measles researcher, and I’m more than happy to be corrected.  Anyone who has actual information on this, please let me know.  If you have an opinion, no offense, but I’m not interested unless you have data to back it up.)

The problem is that the usual answers are either too vague to be useful (what exactly does “quality of living” mean, medically?) or inadequate (improved nutrition is certainly important, but as far as I can see probably only improves survival maybe 5-fold, not 100-fold).  Specific advances (antibiotics, etc) undoubtedly helped, but you don’t see abrupt short-term drops in mortality, as you’d expect if any single advance was a major factor; rather, you see a constant, gradual, improvement.

I’m left with the unsatisfying conclusion  that either a conglomeration of many factors may have acted together (the most likely situation, and that’s what the real world is often like — no simple answers), or that there’s some specific factor that I haven’t found out about.  I’ll talk about specific causes later this week.

Here’s my plan for Measles Week:

1. Monday: Explanation of the question, and evidence for it being a real question. Done!
2. Tuesday: History of measles virus
   • Origins and impact
3. Wednesday: Answers that are (probably) wrong
   • Changes in surveillance or notification
   • Sanitation
   • Change in the virus
   • Antiserum treatment
4. Thursday: Answers that (might be) right
   • Nutrition
   • Vitamin A
   • Less overcrowding
   • Antibiotics and other treatments
   • Demographic changes
5. Friday: What would measles be like today, without the vaccine?
   • Mortality and complication rates in modern 1st-world epidemics

Put on your party hats, blow up a balloon, pull up a chair, and stick around.

1. Prevention of Measles in a Children’s Hospital. W. E. Crosbie. Br Med J 1938;1:1003-1004
2. The Fatality Rate of Measles: A Study of its Trend in Time William Butler Journal of the Royal Statistical Society, Vol. 108, No. 3/4 (1945), pp. 259-285
3. Butler W (1945) The Fatality Rate of Measles: A Study of its Trend in Time. Journal of the Royal Statistical Society 108:259–285.
4. Guyer B, Freedman MA, Strobino DM, Sondik EJ (2000) Annual summary of vital statistics: trends in the health of Americans during the 20th century. Pediatrics 106:1307–1317.
5. Armstrong, G. (1999). Trends in Infectious Disease Mortality in the United States During the 20th Century JAMA: The Journal of the American Medical Association, 281 (1), 61-66 DOI: 10.1001/jama.281.1.61

Investigators face a daunting black box with emerging viruses: the challenge of developing a universal therapeutic agent to combat a genetically proficient virus that quite likely has many more options for emergence than we have yet considered.

–Graham, R., & Baric, R. (2009). Recombination, Reservoirs, and the Modular Spike: Mechanisms of Coronavirus Cross-Species Transmission. Journal of Virology, 84 (7), 3134-3146 DOI: 10.1128/JVI.01394-09

By analyzing hepatitis C virus genome sequences, you can trace the virus’s history through its spread by the slave trade, and linked 19th-century health models in different countries to viral spread and transmission. Similarly, by looking at leprosy DNA, you can track its spread along the Silk Road and along slave routes.

Yellow Fever was one of the most dreaded plagues of the 18th and 19th centuries, waning only after it was understood to be mosquito-borne, so that mosquito control pushed the virus back. It’s still prevalent in Africa and in some parts of South America, though. Yellow Fever virus, too, originated in Africa and was spread to the New World through the slave trade:

The most commonly cited hypothesis of the origin of YFV in the Americas is that the virus was introduced from Africa, along with A. aegypti,¹ in the bilges of sailing vessels during the slave trade. … We estimate that the currently circulating strains of YFV arose in Africa within the last 1,500 years and emerged in the Americas following the slave trade approximately 300–400 years ago. These viruses then spread westwards across the continent and persist there to this day in the jungles of South America.²

Mosquitoes aren’t merely passive carriers of the Yellow Fever virus. The virus actively infects the mosquitoes as well as their mammalian host, entering the insect gut, replicating and multiplying in various organs until it reaches the saliva, from which it can re-infect mammals³ when the mosquito bites and injects its anticoagulant saliva.

“Latest from the front — our friends the mosquitoes preparing and off for the summer campaign” (Harper’s Weekly, 1873)

Another pattern is possible: The virus could also be spread vertically, from the mosquito to its egg, infecting the newborn mosquito before it hatches. However, although this was shown to happen as long ago as 1905,⁴ just after mosquitoes were proven to be carriers, it hasn’t been very clear if this is a significant part of the natural viral cycle or if it’s more of a lab curiosity:

Although transovarial transmission of YFV has been demonstrated, the relative importance of this in maintaining the transmission cycle is unknown. ⁵

Now, genome sequence analysis suggests that in fact transovarial spread of Yellow Fever virus may well be common and important in the viral life cycle.⁶

This was based on comparisons of Yellow Fever virus genome sequences over time, with those of a close relative, Dengue virus. Dengue and YFV probably arose about the same time, in the same area, and were both spread along the slave trade. But Dengue seems to have diversified much more than YFV:

… it is intriguing that the overall age of YFV (emergence within the last 2,500 years) is broadly similar to the time of origin of the four DEN viruses. Hence, YFV and DENV seem to have radiated at approximately the same time. However, since this time, DENV has differentiated into four antigenically distinct viruses while YFV is still classified as a single serotype.⁶

(This is actually clinically very significant, because the most severe form of Dengue disease is caused by sequential infection with two different Dengue serotypes.) In fact, in general YFV shows a much slower rate of evolution over time than Dengue — about 5-fold slower per year. The authors consider a reject a number of explanations for this — it’s not that they have different mutation rates, because their raw mutation rates are probably quite similar; it’s not that they infect different hosts, because they have very similar insect and mammalian hosts; and so on — and finally suggest that the difference may be because YFV spends a significant part of each year lying more or less dormant in mosquito eggs:

In particular, it is possible that a mechanism of vertical transmission, such as transovarial transmission where the virus may remain quiescent in mosquito eggs for many months, plays a more important role in YFV than in DENV⁶

As a result of this quiescent period, YFV would simply have fewer replication cycles per year than does Dengue, and so it appears to evolve more slowly. For this to be detectable at this level, transovarian transmission would have to be a fairly common event, not just a once-in-a-while half-accidental option.

1. A. aegypti is the mosquito that is most involved in spreading the virus
2. Bryant, J., Holmes, E., & Barrett, A. (2007). Out of Africa: A Molecular Perspective on the Introduction of Yellow Fever Virus into the Americas PLoS Pathogens, 3 (5) DOI: 10.1371/journal.ppat.0030075
3. Mainly primates, for functional transmission
4. Marchous E, Simond PL. 1905. La transmission hereditaire du virus de la fievre jaune chez la Stegomyia fasciata. C. R. Soc. Biol. 59:259
5. Barrett, A., & Higgs, S. (2007). Yellow Fever: A Disease that Has Yet to be Conquered Annual Review of Entomology, 52 (1), 209-229 DOI: 10.1146/annurev.ento.52.110405.091454
6. Sall, A., Faye, O., Diallo, M., Firth, C., Kitchen, A., & Holmes, E. (2009). Yellow Fever Virus Exhibits Slower Evolutionary Dynamics than Dengue Virus Journal of Virology, 84 (2), 765-772 DOI: 10.1128/JVI.01738-09

Vaccinia virus is a widespread virus whose natural host remains unknown.  It turns out to be pretty good at jumping across species.

Vaccinia, of course, is the vaccine against smallpox.  Even though smallpox is eliminated in the wild,¹ vaccinia is still very widely used in research and even, to some extent, in the clinic, because the broad and deep experience with the virus gained from its importance in vaccination has carried over into other fields.

When Jenner developed his vaccine against smallpox, he used the cowpox virus.  But — in spite of a widespread misconception — vaccinia is not cowpox.  They’re quite distinct viruses, though they are related.  At some point along the centuries of vaccine use cowpox was replaced by vaccinia. (It’s also worth pointing out that the disease Jenner called cowpox, may not have been cowpox as we know it today. ²  It may have been a distinct strain of virus, or it may have been a different virus altogether.)

Remember that for a couple of hundred years, there was no tissue culture to grow the virus in, and it was basically propagated by continually re-infecting animals and collecting virus from their scabs.  At some point, presumably a cow that was being used as a vaccine incubator was infected with vaccinia instead of cowpox, and the vaccinia proved more effective, or perhaps safer or more convenient, as a vaccine, crowding out the vaccine cowpox.

“Cowpox inoculation sites” Douzhen dinglun (Definitive Treatise on Pox Diseases) by Zhu Chunxia, 1888

(By the way, it’s interesting to note that cowpox has an MHC class I immune evasion function,³ whereas vaccinia virus does not.  Obviously this immune evasion doesn’t prevent cowpox from acting as a strong immunogen, because it was an effective  vaccine for decades if not centuries, but perhaps it’s one reason vaccinia was a more popular vaccine.)

Where vaccinia virus came from — what animal it was infecting before it jumped into cattle  — no one knows.  Although vaccinia must have (or have had) a natural host at one point, the true host for the virus is now cultured cells in the lab incubator.

Does that mean vaccinia isn’t found in the wild? Not at all.  Vaccinia virus does infect a bunch of animals, in many parts of the world.  But what’s happened is that the virus has gone feral: It’s jumped from vaccinated humans into other species — usually cattle — and then spread among that population.  In Brazil, this feral vaccinia virus has become a significant emerging disease in cattle, from which it jumps back again into humans:

Starting in 1999 several VACV strains were shown to be responsible for zoonotic disease affecting more than 1100 dairy cattle and up to 80% of their handlers in rural tropical rainforest and woodland savanna areas in southeast Brazil ⁴

The origin of this Brazilian bovine vaccinia is unknown.  Almost certainly it’s derived from the vaccine — the alternative explanation, that it’s derived from the original, natural host of vaccinia, seems really unlikely, especially since the disease has only been detected in the past ten to twenty years. But genetically, it doesn’t look much like any of the known vaccine strains.⁵  (However, I remember reading a paper that I can’t turn up right now, that talked about vaccinia-based vaccines in the early 20th century. It made the point that there wasn’t particularly careful oversight or recording of precise strains or provenance of smallpox vaccines, and emphasized that there were several different strains of vaccinia used in South America, not all of which were well characterized.)   Grant McFaddden’s interpretation of the feral virus’s relationships is that there were probably recombinations between different strains of the virus, which makes it hard to reconstruct the genetic history of the virus; complicated by a long period of adaptation to its new host(s):

On the other hand, the Brazilian isolates appear to have escaped in a single event or in multiple events and probably adapted to a new host, until they re-emerged in man or cattle at least 25 years later. ²

Cowpox on a cow’s udder Trattato di vaccinazione con osservazioni sul giavardo e vajuolo pecorino by Luigi Sacco, 1809

There’s another puzzling aspect to the Brazilian vaccinia epidemics: How are they spreading? Although most of the epidemics can be traced back to infected humans, there are some exceptions:

… some VACV outbreaks are temporally and spatially distant from previously notified BV areas. … Rats, mice, opossums, foxes, wild dogs and small felids are frequently observed around farming properties. In theory, some of these species, especially rodents, could be VACV reservoirs. ⁶

Indeed, the virus was recently isolated from a wild mouse,⁶ suggesting that rodents might be spreading the virus between farms.

The implication is that over the past hundred years or so, vaccinia virus has sequentially jumped from its original, unknown host, into cattle, into humans, then back into cattle, into rodents, back into cattle, and then back into humans, not counting its long side-trip into the laboratory incubator.  It’s the Michael Jordan of jumping viruses.

1. Hopefully! But see this post for more
2. Moussatché N, Damaso CR, & McFadden G (2008). When good vaccines go wild: Feral Orthopoxvirus in developing countries and beyond. Journal of infection in developing countries, 2 (3), 156-73 PMID: 19738346
3. Alzhanova, D., Edwards, D., Hammarlund, E., Scholz, I., Horst, D., Wagner, M., Upton, C., Wiertz, E., Slifka, M., & Früh, K. (2009). Cowpox Virus Inhibits the Transporter Associated with Antigen Processing to Evade T Cell Recognition Cell Host & Microbe, 6 (5), 433-445 DOI: 10.1016/j.chom.2009.09.013
4. Essbauer, S., Pfeffer, M., & Meyer, H. (2010). Zoonotic poxviruses? Veterinary Microbiology, 140 (3-4), 229-236 DOI: 10.1016/j.vetmic.2009.08.026
5. DRUMOND, B., LEITE, J., DAFONSECA, F., BONJARDIM, C., FERREIRA, P., & KROON, E. (2008). Brazilian Vaccinia virus strains are genetically divergent and differ from the Lister vaccine strain Microbes and Infection, 10 (2), 185-197 DOI: 10.1016/j.micinf.2007.11.005
6. Abrahão, J., Guedes, M., Trindade, G., Fonseca, F., Campos, R., Mota, B., Lobato, Z., Silva-Fernandes, A., Rodrigues, G., Lima, L., Ferreira, P., Bonjardim, C., & Kroon, E. (2009). One More Piece in the VACV Ecological Puzzle: Could Peridomestic Rodents Be the Link between Wildlife and Bovine Vaccinia Outbreaks in Brazil? PLoS ONE, 4 (10) DOI: 10.1371/journal.pone.0007428

In principle, dying is fine,  because most cells can be easily replaced. ¹ Unexpected cell death isn’t fine, mind you — it means there’s something abnormal going on, and the immune system detects uncoordinated cell death as danger and responds with inflammation — but the usual form of cell death is highly coordinated, with the cell carefully tidying up before blowing out the candles.

This video² helps show just how organized programmed cell death is.  Here we’re seeing a cell whose mitochondria are double-stained.  Cytochrome c is green (it’s part of the mitochondrial energy-generating system); red is a dye that indicates functioning, respiring mitochondria. The cell is forced into programmed cell death.³ At the start the mitochondria are both green and red, making yellow.  Watch the dual waves sweep over the cell: First the cytochrome leaks out, leaving only the red behind, and then — this 15-second movie shows about 10 minutes of activity — the mitochondria wink out altogether as they stop breathing, leaving behind a peaceful corpse.

1. Obviously there are exceptions, like neurons, that aren’t as easily replaced.
2. This is one of the supplementary videos from
   Bhola, P., Mattheyses, A., & Simon, S. (2009). Spatial and Temporal Dynamics of Mitochondrial Membrane Permeability Waves during Apoptosis Biophysical Journal, 97 (8), 2222-2231 DOI: 10.1016/j.bpj.2009.07.056
3. By treatment with TRAIL

There’s a constant viral assault on us humans, as there is on just about all other species. We as a species have to contend not only with the vast pool of human pathogens, those viruses that constantly circulate among humanity; but also with the continual probes on our defenses from other viruses, viruses that normally infect other species.  All of us are exposed to these on a regular basis: Dog and cat viruses, mouse viruses, crow and pigeon viruses, bat viruses, not to mention the ocean of insect and fungus and amoeba and plant viruses.

Almost all of these assaults don’t even scratch our defenses.  The viruses can’t even enter our bodies, and if they do then they can’t enter our cells, and if they do they can’t replicate in our cells, and if they do then they can’t  …

Most viruses, in other words, can’t effectively jump species.  Even when they do, they’re usually not well adapted to the new species, and they can’t establish a productive chain of infections. Even if they cause a disease, they burn themselves out, infecting fewer and fewer individuals each round of infection, until they disappear.

But every so often, in a tiny minority of cases, the virus does get a foothold.  This is one of the ways that “emerging infections” get started.  It covers things like HIV, SARS, parvovirus of dogs, Ebola, and of course the new H1N1 swine-origin influenza virus (SOIV), among many others.

Why did these guys take off, when so many other viruses failed? Why did SOIV infect people last year, while decades of exposure to pigs and swine H1N1 influenza viruses didn’t lead to earlier pandemics?  Basically, we don’t know, and we’d really, really like to know, so we have a chance of predicting the next SOIV or HIV before it’s a pandemic.

OK, so that explains why I’ve written a fair number of posts here on species-jumping in viruses (here, here, here, here, and here), and partly explains why I want to mention a new paper from Bertram Jacobs‘ lab¹.  (The rest of the reason is, as always, that I just think it’s  cool.)  I’m not sure why Jacobs has done this particular project, because he’s more of an interferon guy, but he’s looked at the origins of ranaviruses and finds evidence for lots of species shifts in their history.

“The Smooth Terrapin (Emys terrapin)”, by James Dekay (Zoology of New York; or, The New York fauna, 1843)

Ranaviruses are probably best known as frog viruses, but they infect a bunch of cold-blooded animals — fish, frogs, salamanders, turtles, and so on — and several of them are causes of emerging infectious disease (as I discussed last time I talked about ranaviruses, here).  Jacobs’ group looked at about a dozen of them whose genomes are completely sequenced², and tried to put together their evolutionary history, which turns out to involve all kinds of cross-species jumps:

…we hypothesize that the most recent common ancestor of the ALRVs was an ancestral fish virus …  Both of these hypotheses suggest that for the majority of evolutionary time vertebrate iridoviruses were confined to fish, and much more recently, there appear to have been at least three species jumps, from fish to frogs, from fish to salamanders, and from frogs to reptiles, and perhaps as many as four species jumps, including a jump from tetrapod amphibians back to fish. It is tempting to speculate that activities associated with human harvesting of aquatic organisms during the past 40,000 years led to the more common recent jumping of ranaviruses among aquatic organisms.¹

(My emphasis) They don’t offer any specific reasons why the ranaviruses should be able to leap from species to species like the chamois of the Alps, but they do make the general point that these viruses tend to be rather promiscuous to start with.  Not only are closely-related viruses able to infect different hosts, but even the same viruses often are able to infect a wide range of species; the fish virus they sequenced in this paper, epizootic hematopoietic necrosis virus, can infect a half-dozen different species of fish.  They raise an interesting comparison:

In addition, the ability of this group of viruses to infect such a wide variety of host species suggests that more host shifts are likely. Therefore, it is important that we understand more of the evolutionary traits of this unique group of viruses, as there is no other closely related group of viruses that infect such a broad group of hosts, with the possible exception of the orthomyxoviruses.¹

Orthomyxoviruses, of course, include influenza viruses, which notoriously infect humans, pigs, ducks, chickens, wild waterfowl, horses, and dogs; and you’ll recall all the reports during the epidemic phase of SOIV of the virus infecting all kinds of other pets and domestic animals.  Influenza viruses are apparently evolving at an even faster pace than the ranaviruses, and experimenting with even more species; but there may be lessons for us (as influenza hosts) in the ranaviruses.

1. Jancovich, J., Bremont, M., Touchman, J., & Jacobs, B. (2009). Evidence for Multiple Recent Host Species Shifts among the Ranaviruses (Family Iridoviridae) Journal of Virology, 84 (6), 2636-2647 DOI: 10.1128/JVI.01991-09
2. Including epizootic hematopoietic necrosis virus, whose genome they sequenced themselves

But this indifference is new. Until the beginning of the 20th century, yellow fever ran rampant, and was one of the most dreaded of all diseases. Epidemics of yellow fever in New York, Philadelphia, Memphis, and New Orleans killed tens of thousands. There’s a WHO manuscript [pdf link] on yellow fever that lists these and many more outbreaks – page after page of fine-print dates and deaths.

Those who have not lived between Cancer and Capricorn can well fail to conceive readily the sensation of numb, chill dreariness which steals on all hearts, when the news spreads, from mouth to mouth, that Yellow Jack has once more come. … at last it is admitted on the housetops, as well as whispered in the closet, that the deadliest, most awe-inspiring of the plagues of the equatorial regions has obtained admittance within our borders.

–”Yellow Jack“, in Cornhill Magazine, 1892¹

As I noted earlier, Carlos Finlay made the original suggestion that yellow fever was a mosquito-borne disease in 1881;² in English, in 1886. ³ Walter Reed and his team confirmed this in 1900, and the discovery was seized on at once.

“Shows the Distribution of the Principal Mosquitoes of New Orleans”. Dark squares represent Stegomyia fasciata, the major carrier of yellow fever 4	Yellow fever cases in New Orleans, 1905. “The infected blocks are most numerous in the old, Italian, quarter of the city.”

(This post was mainly an excuse to post those maps.⁵  Click for larger versions.)

New outbreaks were checked with enthusiastic mosquito control.

In a few days with very little opposition, sixty to seventy thousand cisterns had been screened in order to prevent the breeding of the Stegomyia fasciata. Mosquito nets became more than ever the rule …

–Yellow Fever Prophylaxis in New Orleans, 1905⁵

The virus itself was was isolated in 1927 and the vaccine, made in 1937 by Max Theiler, turned out to be extremely effective; but even before that,  the understanding that mosquitoes were the carriers allowed great strides in reducing the disease.  Not just in the USA, but throughout the Americas:

Havana and Cuba freed from fever by Gorgas, who organized anti-mosquito measures, 1901-1902; example followed in Rio de Janeiro and Vera Cruz, 1903-1909; Panama Canal Zone successfully protected by same methods, 1904-1906 …  intensive campaign, 1918-1919, under Connor eliminated disease from Guayaquil, the chief endemic centre …

–”Yellow Fever in Retreat“, 1922⁶

1. Cornhill Magazine
   New Series, Vol. XIX, July to December 1892
   Smith, Elder, & Co.
   15 Waterloo Place, London
2. C. Finlay (1881). El mosquito hipoteticamente considerado como agente de trasmislon de la flebre amarllla An. de la Real Academia de ciencias med. de la Habana, 18, 147-169
3. C. Finlay (1886). Yellow Fever, its transmission by means of the Culex mosquito Am. Journ. Med. Sci., 92, 395-409
4. If I follow this right — I’m neither an entymologist nor an entomologist — Stegomyia fasciata was subsequently renamed Stegomyia aegypti, then Aedes agyptyi, and now (since 2005) is properly is officially called Stegomyia aegypti once again but usually, if not always, with “Aedes” in brackets to clarify. There was also, maybe, a point at which it was Stegomyia calopus, unless that was something else.
5. Yellow Fever Prophylaxis in New Orleans, 1905
   Rubert Boyce
   April, 1906
   Published for the Committee of the Liverpool School of Tropical Medicine
   by Williams & Norgate
   14 Henrietta Street, Covent Garden, London
6. Current History
   A Monthly Magazine of the New York Times
   Volume XVI, April-September, 1922