Deadly GAS
Hugh Pennington
Streptococcus pyogenes is also known as Lancefield Group A. In the 1920s and 1930s, at the Rockefeller Institute in New York, Rebecca Lancefield discovered that streptococci could be grouped at species level by a surface polysaccharide, A, and that A strains could be subdivided by another surface antigen, the M protein.
Ronald Hare, a bacteriologist at Queen Charlotte’s Hospital in London, worked on Group A Streptococci in the 1930s, a time when they regularly killed women who had just given birth and developed puerperal fever. He collaborated with Lancefield to prove that GAS was the killer. On 16 January 1936 he pricked himself with a sliver of glass contaminated with a GAS. After a day or two his survival was in doubt.
His boss, Leonard Colebrook, had started to evaluate Prontosil, a red dye made by I.G. Farben that prevented the death of mice infected with GAS. He gave it to Hare by IV infusion and by mouth. It turned him bright pink. He was visited in hospital by Alexander Fleming, a former colleague. Fleming said to Hare’s wife: ‘Hae ye said your prayers?’ But Hare made a full recovery.
Prontosil also saved women with puerperal fever. The effective component of the molecule wasn’t the dye, but another part of its structure, a sulphonamide. It made Hare redundant. The disease that he had been hired to study, funded by an annual grant from the Medical Research Council, was now on the way out. He moved to Canada where he pioneered influenza vaccines and set up a penicillin factory that produced its first vials on 20 May 1944.
He returned to London after the war and in the early 1960s gave me a job at St Thomas’s Hospital Medical School. I wasn’t allowed to work on GAS. There wasn’t much left to discover about it in the lab using the techniques of the day, and penicillin was curative.
John Smith, a bacteriologist in Aberdeen, had shown in 1931 why women developed puerperal fever. Some carried streptococci before they fell ill, but they caught the GAS that caused the fever and sometimes killed them from the obstetrician, GP or midwife who attended them at delivery. Assiduous hand-washing and mask-wearing have since made maternity wards very unlikely places to catch a hospital acquired infection.
Nearly a hundred years earlier, Richard Bright at Guy’s Hospital had made the connection between scarlet fever and the development of acute glomerulonephritis, a kidney complication caused not by bacteria infecting the kidneys but by the host response to mischief caused by them elsewhere in the body.
Even more serious are the cardiac manifestations of another delayed complication of GAS infection, acute rheumatic fever: antibodies made against GAS M antigens react with heart muscle proteins, damaging them and the heart valves. This has held up vaccine development. So has M diversity; 250 variants have been identified.
All attempts to produce an effective, safe anti-GAS vaccine have been unsuccessful. They started 130 years ago. The 1930s Anti-Catarrh (Public Schools) Vaccine was said to contain Streptococcus regius, a GAS isolated from a serious infection suffered by King George V. This may have helped it commercially but as a protective vaccine it was useless.
Diphtheria, whooping cough and measles used to be big paediatric killers. Their lethality for children in the Global North has been virtually abolished by vaccines. So when healthy children die from an infection caught from their friends, classmates or parents, something seems to have gone wrong: it is unsurprising that there has been such public concern and media interest in response to the deaths of children associated with GAS infections this autumn and winter in England, Wales and Northern Ireland.
This interest is different from the 1994 media outbreak stimulated by two non-fatal cases of necrotising fasciitis in Stroud in early February, with four later cases elsewhere in Gloucestershire. Necrotising fasciitis is a rapidly moving, destructive GAS infection of soft tissues. It was first described by an American surgeon in Beijing in 1924. It has always been rare. It still is.
I had been awarded a research grant in 1992 to fingerprint GAS strains, and was a port of call for journalists chasing the necrotising fasciitis story. A local radio report in May about the Gloucestershire cases started the media outbreak. A tabloid paper picked it up. I was interviewed. ‘Killer virus scoffs three’ was one of its headlines. Things went quiet. Then, after twelve days, there was a surge of calls from ten newspapers. An even bigger surge of inquiries came from fifteen radio and TV stations two days later. The development of the story followed the mass-action principle, just as in an outbreak of infection, when the rate of spread is proportional to the product of the density of susceptibles multiplied by the density of sources of infection. The media outbreak even had an incubation period.
The hypothesis that underpinned the work of my research group on the increase of serious GAS infections was that they were caused by a nasty new clone with particular virulence toxins. We found a clone that had previously caused serious infections in the United States, but other serious infections in Scotland were caused by several different clones. There was a cluster of serious and fatal infections in 1986 in Nairn, caused by three different clones. Why they had got commoner we couldn’t explain.
The coming and going of severe GAS infections is not new. Thomas Sydenham described scarlet fever as a mild disease in 1676. It got nastier in the late 18th century, then milder, then developed high mortality with a peak in the early 1860s, then got milder again. There was a surge in the 1980s and 1990s. It would be hard to say that evolution hasn’t been at work. The current increase in severe paediatric GAS infections in the UK is said to be part of a rebound of infections caused by a relaxation of Covid-19 social distancing measures. In spite of the novelty of Sars-CoV-2, our understanding of its evolution during the pandemic is vastly greater than for GAS, whose incessantly changing genome is more than sixty times bigger than the virus’s. Making sense of it is an enormously complex task.
Comments
-
14 December 2022
at
8:37pm
noel thomas
says:
"Diphtheria, whooping cough and measles used to be big paediatric killers. Their lethality for children in the Global North has been virtually abolished by vaccines. "
-
14 December 2022
at
9:24pm
Alex Bowles
says:
@
noel thomas
Nonsense. McKeown showed that other factors than medicine were important in improving life expectancy in the 19th century, but absolutely doesn't demonstrate your claim, and there is no such "97%" number.
-
14 December 2022
at
11:45pm
DrVanini
says:
@
Alex Bowles
Mortality isn't the only measure of catastrophic consequences. Measles encephalitis can turn healthy children into something close to a persistent vegetative state in a week or two.
-
15 December 2022
at
1:15am
John Ehrenreich
says:
@
Alex Bowles
You are both right, at least partially. Measles deaths did decline by 99% before there was a vaccine. The vaccine was the main cause of the decline in pertussis and diphtheria. TB deaths dropped very sharply well before antibiotics. As for scarlet fever, the death rate declined well before the introduction of sulfanimide. This was written about well before McKeown, by F.MBurnett and Rene Dubos.
-
15 December 2022
at
3:09am
Darren Kitchen
says:
I am always delighted to see a new post from the unfailingly interesting Hugh Pennington, but I hope I may be forgiven for having reached the end of this entry while being none the wiser as to what GAS might stand for.
-
15 December 2022
at
8:47am
N Gault
says:
@
Darren Kitchen
I was in a similar position so resorted to an online trawl. I think Group A Streptococci the most likely source of the acronym. There are many other choices some of which hold up for the first few lines of the blog.
-
15 December 2022
at
10:01am
Arthur Blue
says:
@
Darren Kitchen
As a long-retired spanner wielder I can’t follow all the medical technicalities, but I do get the bit about density of source multiplied by density of susceptibility, and its parallels in public perception.
-
15 December 2022
at
12:09pm
Thomas Jones (blog editor)
says:
@
Darren Kitchen
I thought it was fairly obvious what GAS stood for but clearly not. Apologies. It's now spelled out.
Read moreTom McKeown demonstrated half a century ago that the mortality of those diseases had fallen by about 97% before antibiotics and vaccines were introduced. Mc Keown's findings were reproduced by other researchers in due course. The idea that antibiotics and vaccines were essential is obviously part of the pharma agenda, but we should be aware of what actually happened.
Darren
Also that these diseases continually evolve, and we had better keep on our toes with regard to them.