by David Isaacs
From the 1880s, invasive lung surgery was used to treat TB, but it was never subjected to trials to see if it worked. It almost certainly did no good. Often doctors would deliberately collapse one lung. One technique was to pump oxygen or nitrogen into the chest cavity under pressure. Another operation was thoracoplasty, which involved removing part of the rib-cage so the chest wall collapsed. Mycobacteria need oxygen to survive, so the aim was to deprive them of oxygen, but the surgery was deforming and sometimes fatal; the ‘cure’ may well have been worse than the disease. Over the next 25 years, 100,000 patients had a lung collapsed, until the practice fell out of favour.
In the 1930s and 1940s, a treatment known as phrenic paralysis came into fashion. This involved crushing the phrenic nerve, which runs beside the lung and causes the diaphragm to work, so that diaphragm would be paralysed and the lung on that side would not inflate or deflate until the nerve healed. The apparent rationale was that if the lung did not inflate, the TB organisms would be deprived of oxygen. The trouble was, the poor patient was also deprived of oxygen.
Improved sanitation and cleaner water, then the development of BCG vaccine, saw a slow decline in TB, but it would take the advent of effective antibiotics in the 1940s for TB to all but disappear from Western countries within a few years.
As scientists worked to develop an antibiotic cure, tuberculosis was the focus of the first ever large-scale double-blind randomised controlled trials. ‘Double blind’ means that neither the participants nor the researchers know which treatment the patient has received until the trial is completed. ‘Randomised’ means the patients are randomly assigned to one or the other treatment, for example by being given a vial with a coded number, with the code only broken at the end of the trial. The trial is ‘controlled’ because the patient is given either the new treatment or an alternative, and the patients receiving the alternative act as a ‘control’ for the active vaccine; the vaccine recipients can then be compared with the controls.
Scientists had long known it was wise to include a control group in trials: if the control group got better just as quickly as treated patients, the treatment had done nothing, except perhaps cause side effects. One of the first controlled clinical trials was carried out by James Lind, a medical apprentice from Edinburgh. He joined the Royal Navy as a surgeon’s mate in the late 1730s. In 1747, on board HMS Salisbury, he divided 12 men suffering from similar symptoms of scurvy into six pairs and treated each pair with a different popular remedy: a quart of cider; elixir of vitriol; half a pint of sea-water; a paste made of garlic, mustard seed, horseradish, balsam of Peru (a mix of cinnamon and vanilla) and gum myrrh; vinegar; and finally citrus fruits (specifically two oranges and one lemon). By the end of the week, the two men who received citrus fruits had recovered sufficiently to nurse the others.
While Lind’s was a successful controlled trial, trials such as this, where it is known which treatment the patient is getting, are susceptible to bias. Well-meaning researchers can inadvertently affect the results, for example by making sure the sickest patients receive the treatment they think is most likely to work. This tendency to bias is only human.
In the United Kingdom in the 1940s, a new antibiotic, streptomycin, was found to be active against tuberculosis in the laboratory. It was in short supply. The British Medical Research Council elicited the help of a statistician, Bradford Hill, who pointed out that the scarcity of streptomycin ethically justified trials in which only half the patients received the drug.
Hill felt that doctors could not be trusted to avoid bias, conscious or unconscious, and to guard against this he proposed randomly determining which patients would receive streptomycin and which would not. For the latter group, he suggested using a disguised placebo instead of no treatment. This meant that both patients and doctors were ‘blinded’ as to which treatment had been given.
The trial clearly showed that patients given streptomycin fared better. Streptomycin caused deafness and was later superseded by less toxic drugs, but Bradford Hill’s scientific method has survived. He was deservedly knighted for his contribution to science.
Tuberculosis today
Almost every industrialised country used to give routine BCG immunisation to children. But tuberculosis is rare in industrialised countries nowadays, not because of antibiotics or BCG vaccine but because of improved living standards. As TB disappeared from the Western world, BCG immunisation programs were stopped, and now countries like Australia only recommend BCG vaccine for people who are in contact with a person with infectious TB, or people planning to live in countries with a high incidence of TB. BCG vaccine is no longer given orally but intradermally – as an injection into the skin that is slowly absorbed.
In developing countries, however, BCG vaccine is still given routinely to newborns and still saves lives. Since 1974, BCG has been part of the WHO’s Expanded Programme on Immunization in all countries with a high incidence of TB disease.
Tuberculosis remains a major problem in these countries. In 1990, I was invited to teach in Kota Bharu in Northern Malaysia. When I visited the colourful local market, I was shocked to see two hunchbacked children of perhaps seven or eight, begging among the stalls. Their spines were permanently deformed by tuberculosis.
TB is still the number-one killer among infectious diseases (though almost exclusively in developing countries). Yet not everyone exposed to TB becomes infected, and not everyone infected becomes ill with disease. Mycobacterium tuberculosis is a very slow-growing organism that can remain hidden (latent) in the body for years. If a child becomes ill with tuberculosis in an industrialised country nowadays, they have usually been infected by a parent who was born in a poor overseas country or the child has spent a prolonged time overseas. An adult in an industrialised country who develops TB was usually born in a poor country and infected with TB as a child, and the TB has come back many years later. We have effective antibiotics against TB, but have to use three or four at once to stop resistance to the drugs developing. Worldwide there is an increasing problem with strains of TB becoming resistant to a number of antibiotics (multi-resistant TB), necessitating the use of more experimental and more toxic antibiotics.
A third of the current world population has been infected with TB. Less than 10% of them will develop the disease at some time in their lives. The WHO reported that in 2016 more than 10 million people globally became ill from TB and 1.3 million died. More than 95% of them lived in low- and middle-income countries and over half of them in just five countries: China, India, Indonesia, Pakistan and the Philippines.
Tuberculosis is no longer the great killer that it was in the 19th century, and it is a tribute to the human immune system that more than 90% of people infected with tuberculosis will manage to keep the disease forever at bay. Nevertheless, tuberculosis remains a festering human health problem, and the development of more effective vaccines against tuberculosis is one of science’s top priorities.
CHAPTER 6
Diphtheria, the scourge of childhood
Memories are short. People nowadays worry more about whether vaccines are safe than about what infections their child might catch if unimmunised. Yet even within living memory, before almost any vaccines existed, the story was so different.
A close friend and colleague used to visit Deniliquin in country New South Wales as a child. He was an inquisitive boy and asked why there were six white posts clustered together in a distant field. They marked the spot where the three children of the neighbouring farmer had been buried, at a safe distance from any human habitation, after they all died from diphtheria. In the decade from 1926 to 1935, more than 4000 children died from diphtheria in Australia.
Samuel Clemens had been a printer’s apprentice, a steamboat pilot on the Mississippi River, a prospector who found no gold, and a Confederate soldier who never fought in a battle, but in 1861 he headed west in search of adventure. There he wrote about his experiences and also met Olivia (Livy) Langdon, the love of his life. He courted he
r for 17 months, and finally they married. Clemens’s first book, The Innocents Abroad, was a great success. He published it under the nom de plume of Mark Twain (Twain means two; ‘Mark twain’ would have been shouted out on the steamboat when the plumb-line showed a depth of 2 fathoms).
Yet tragedy soon struck Sam and Livy. In 1872, their first son, 17-month-old Langdon, contracted diphtheria, which choked him to death. He died in his mother’s arms. Clemens always blamed himself for Langdon’s death, saying Langdon caught a chill in his carriage when Clemens let slip the blanket covering him.
We now know that catching a chill is not the cause of diphtheria. Clemens was innocent of all blame. Had Langdon been born less than a century later, in the golden age of immunisation, he would never have caught diphtheria and might even have become a great writer like his father.
All about diphtheria
Diphtheria is a dreaded disease that hits communities in epidemic waves and used to be called ‘the scourge of childhood’. The 16th century Belgian physician Joost van Lom (also known as Jodocus Lommius) wrote of the disease:
The patient is racked with pain, labours under a violent fever and dreads suffocation. The mouth is open wide, gasps for cool air and discharges a frothy saliva. The tongue hangs out and is frequently agitated like that of over-ridden horses. The liquor drunk returns through the nostrils, the lips become livid, and the neck is rendered rigid . . . on account of the violence of the suffocation, the patient neither knows what he hears or says or does, till at last being seized with syncope [fainting] he dies.
British bacteriologist Frederick Andrewes wrote in 1923, ‘The manner of death is described as most piteous, for the breath had a putrefactive odour so that the patients could not endure the smell of themselves.’ Sometimes a terrified child’s neck will swell up with inflammation to give a ‘bull neck’ appearance.
Diphtheria was described clinically by the great Greek physician Hippocrates, and its name comes from the Greek word for a leather hide, because of the thick membrane that forms and sticks to the throat, choking the victim to death. A 17th century Spanish physician, Juan de Villareal, described the membrane as having the consistency of wet leather or wet parchment. In Spain, 1613 is still known as El año de los garrotillos, the year of strangulations, because of a devastating outbreak of diphtheria that killed thousands of children and young adults. (The Spanish used to execute prisoners by garrotting, so they were experts on the symptoms.) Diphtheria spread from Spain, where it was known as ‘the strangler’, to Italy, where it was called ‘the gullet disease’.
To perform a tracheostomy, making a hole in the windpipe while the patient is still awake, was the only hope of survival for many children and young adults suffocating to death from diphtheria. The first person to perform a tracheostomy for diphtheria was the same man who gave diphtheria its name, the famous French physician Pierre Fidèle Bretonneau of Tours. That Bretonneau had made two unsuccessful attempts at tracheostomy for diphtheria before succeeding is less well remembered. He performed the first successful tracheostomy in 1825, on four-year-old Elisabeth de Puységur. She survived and became the Comtesse de Billy, which success did as much for his reputation as the 540-page treatise he wrote on diphtheria.
Finding a vaccine
In 1884, German microbiologists Edwin Klebs and Friedrich Löffler described the organism Corynebacterium diphtheriae (sometimes called the Klebs-Löffler bacillus), which was the cause of the diphtheria that killed Langdon Clemens and millions of other children.
In 1888, Louis Pasteur’s long-suffering colleague Emile Roux and Swiss microbiologist Alexandre Yersin showed that the organisms causing diphtheria produce a toxin (poisonous substance) that could cause disease at a distant site. Many patients died from diphtheria as the toxin spread in the bloodstream, poisoning the heart, which failed, and their nerves, which paralysed them.
A toxoid is a toxin that has been weakened with heat or chemicals. The diphtheria vaccine we have used for almost a century is made by modifying diphtheria toxin using the chemical formaldehyde. Thus, the discovery of diphtheria toxin was a critical piece of research.
The first diphtheria toxoid vaccine suitable for widespread use in humans was developed in 1923. Before that time the most effective treatment for people with diphtheria was to use an antitoxin. The principle of an antitoxin is that if you can make an animal immune by injecting it with the toxin from the organism, then you can use the animal’s serum (blood plasma) as an antitoxin.
We now know that this is possible because the animal produces antibodies to protect itself, and injecting those antibodies provides the human with passive protection – passive immunisation as it’s known. This is a different process from most modern immunisations, which use a vaccine to stimulate a lasting immune response for future protection (active immunisation).
The first diphtheria antitoxin was developed in 1890 in Berlin by Kitasato Shibasaburō, a baron of the Empire of Japan, and Emil von Behring, later a professor of hygienics. They showed that if they heated diphtheria toxin and injected it into guinea-pigs, the guinea-pigs were protected against diphtheria infection and against further injections of diphtheria toxin. Moreover, they could cure a guinea-pig suffering from diphtheria by injecting serum from a guinea-pig immunised with heated toxin (toxoid).
They had in fact discovered the principle of making a toxoid vaccine and, had they decided to take that route, could have developed a diphtheria toxoid vaccine before 1923. However, that is easy to say with hindsight. At the time, they followed a different route, which was to mass-produce antitoxin for passive immunisation.
A guinea-pig doesn’t contain much serum, so they thought bigger. They had problems immunising cows and sheep, but horses proved a success. When given repeated doses of the toxin they developed antibodies, and could be bled to yield a potent antitoxin. Horse antiserum could cause severe allergic reactions and even anaphylaxis, but it saved many thousands of children and adults from dying of diphtheria.
Emil von Behring became a national hero, and was called ‘the saviour of children’, ennobled into the Prussian nobility, and awarded the first ever Nobel Prize in Physiology or Medicine. Kitasato Shibasaburō was nominated for the Nobel Prize but got nothing. Either he was just not pushy enough or he was plumb unlucky.
On a sour note, von Behring never acknowledged the contribution of a major collaborator, Paul Ehrlich, a German scientist. Ehrlich always felt von Behring cheated him out of the considerable rewards that resulted from developing diphtheria antiserum.
Although diphtheria antitoxin produced in horses reduced mortality, a sceptic could say it was shutting the stable door after the horse had bolted. It only worked once a child had diphtheria, and did nothing to prevent children from catching the disease or spreading it to other children. We know prevention is better than cure. The situation came to a head in the United States in 1921, when there were an unprecedented 206,000 cases of diphtheria, causing 15,520 deaths.
William H Park was a bacteriologist who headed the laboratory at the New York City Board of Health. Park was an innovator who, although best known for his pioneering work on diphtheria, published research on many other childhood infections.
Park had long been an advocate of diphtheria antitoxin, and initiated an ambitious diphtheria antitoxin program in New York schools from 1918. In the space of 15 years, the City of New York administered 500,000 doses. The number of deaths each year from diphtheria fell from 800 in 1920, to 416 in 1929, and 198 in 1930.
Meanwhile, in 1923, AT Glenny and Barbara Hopkins from the Wellcome Research Laboratories in Beckenham, Kent, published a seminal paper, ‘Diphtheria Toxoid as an Immunising Agent’. They not only showed that diphtheria toxoid induced a much stronger immune response than antitoxin, but also that a small amount of alum (aluminium salts) could be added to act as an adjuvant (a substance that improves the immune response – from the Latin for ‘help’).
Park was impressed, and started to use a diphtheria toxoid
vaccine made in the United States that was based on Glenny and Hopkins’s vaccine. Park performed studies comparing children’s antibody responses to three different vaccines. He found that antibodies were produced by 90% of children given diphtheria antitoxin, 93.7% given diphtheria toxoid without alum and 98.2% given diphtheria toxoid with alum. Park’s work was an important step in proving that diphtheria toxoid with an alum adjuvant was the most protective vaccine. He also showed it was extremely safe.
The particular strain of Corynebacterium diphtheriae most often used to make contemporary diphtheria toxoid vaccines was discovered by Dr Anna Williams, who worked in Dr Park’s laboratory. A biography written about Park is called The Man Who Lived for Tomorrow. Park’s tomorrow is our today. The diphtheria toxoid his laboratory produced is the basis for all modern diphtheria vaccines.
Australia introduced school-based diphtheria vaccination programs in 1932 and routine infant immunisation in 1940, which led to a rapid and sustained reduction in diphtheria. A similar pattern was seen throughout the United States, Canada and Western Europe. In the United States from 2004 until the end of 2017, there were only two cases of diphtheria throughout the entire country.
Diphtheria today
We may reassure ourselves and say: ‘Diphtheria has gone. It won’t ever come back to a safe country like ours.’ However, the organism that causes diphtheria, Corynebacterium diphtheriae, has not gone away. It still circulates in the throats of healthy children and adults. Being immunised protects us against developing the disease, even if the organism infects us. But if we stop immunising, even in rich countries where children are healthy and well fed, diphtheria will return.