About two miles down our dirt road that leads toward the south end of the lake, there is a section of woods that people refer to as “the Dark Forest,” an appropriate name as the trees seem larger, closer together, and more overgrown than in surrounding areas. Less light penetrates the foliage and the shadows between the trees sometimes allow one to see things that probably aren’t there. Old stone walls section the forest giving evidence that the land must once have been cleared. Our neighbor Trudell, who owns much of that area, came over for lunch a few weeks back and told us a story that has lingered in my mind.

Those stone walls mark the fields of a once prosperous farm. The foundation of the original farmhouse is just off the road. According to Trudell, the man who farmed this land, along with his wife and some unknown number of children, all succumbed to diphtheria. The farmer’s brother, in order to halt spread of whatever contagion led to their deaths, burnt their house to the ground. The farm was long abandoned. Trudell used a phonetic pronunciation of this disease’s name, calling it ‘difftheria’ so it took me a moment to realize what she meant. She tells us this all happened in 1750. She is close, and possibly correct, with the date, but it is hard to believe that an old shoe she claims to have found in the ruins did belong to the original inhabitants.

The epidemic of what was called throat distemper or putrid throat swept through New England, including this part of Maine, in waves starting in 1735. Trudell’s story could have occurred in 1750 or even earlier. Until vaccines were developed two hundred years later, diphtheria was a leading cause of death in our country, especially among children. The epidemic struck first in New Hampshire (NH) in May 1735, killing about 1% of that state’s population. It spread south through the Massachusetts Bay Colony into Connecticut and northeast into Maine. As the epidemic ran its course, more than 5000 people died, over 75% of them were children. The Rev. Roland Sawyer wrote in his history of the epidemic that, by 1738 in Kensington, NH, so many children had succumbed to diphtheria “there were few children left to die.”

Estimates of the magnitude of the epidemic vary. Most accounts are local, tallying mortality in a single township. In Kensington’s cemetery, there are graves of 250 children who died of diphtheria between 1744 and 1779.

Accounts of diphtheria date back to Hippocrates. Cotton Mather recorded cases of the disease in Massachusetts in December 1659. Yet, the 1735 outbreak was more virulent than any prior outbreak. One theory suggests that a mutation in the causative bacteria had occurred and the variant was more transmissible and deadly than earlier strains, a concept we are now currently sadly familiar with. The 1735 outbreak started in Kingston, New Hampshire, and from there spread to Hampton Falls, then to Exeter, Durham, Dover, Chester, and then to Portsmouth. From that crossroad, it spread outward from New Hampshire to Maine, Massachusetts, and Connecticut.

“Diphtheria caused over 1,000 deaths amongst the colonists between 1735-1736 alone. In New Hampshire, 90% of those deaths occurred in children under the age of 10.”¹ Across New England some 5,000 people died of diphtheria between 1735 and 1740. More than 75 percent were children. Overall, it killed 22 of every 1,000 people. In New Hampshire, where it struck first and worst, 75 out of every 1,000 people died of it. The case-fatality ratio was almost 40% though few of the young survived. Afflicted children often died within three days. Roads were few and travel patterns in New England were simple enough that epidemiologists have tracked the spread in detail. Physicians had trouble agreeing on a diagnosis for the disease, calling it cynanche, angina, canker, bladders, rattles, or throat distemper.²

These numbers seem small in contrast to the hundreds of thousands of deaths in the waves of our modern epidemic, but we should remember how few the inhabitants were back then. In 1730 the recorded population of New Hampshire was less than 11,000.

Dr. Josiah Bartlett, who practiced in Kingston, NH, is of some interest to us. He initially adhered to the general treatment guidelines of depletion and antiphlogistic treatment. The medical standard of care back then was to treat this disease by bleeding the patient from a vein behind the tongue. Bartlett saw no benefit from this intervention during the early years of the epidemic. During subsequent waves, Bartlett instead of bleeding dosed his patients with Peruvian bark, that is, Cinchona officinalis. He reported in 1754 that Cinchona might relieve the disease’s symptom long enough for patients to recover. Of course, this was the era when Cinchona was highly valued as a treatment for malaria. Whether or not Cinchona proved efficacious for these patients is unclear. It may have simply reduced the doctor’s obligation to bleed resulting in less iatrogenic harm. Or, perhaps it did slow disease progression as Bartlett suggested. This is no longer a question that needs an answer. Effective antidotes are now available to treat diphtheria. Bartlett is far more famous as a signatory of the Declaration of Independence and for his roles in state and national politics than for promoting Cinchona.

Credit is given to the French physician Pierre Bretonneau for naming the disease in 1826, calling it diphtérite from the Greek word for “leather” to describe the pseudomembrane that coats the throat as a result of the disease. Bretonneau is on record for performing the first successful tracheotomy in a case of diphtheria, though his first attempts were sadly unsuccessful. This procedure involves cutting an opening in the trachea and inserting a tube to allow passage of air and removal of secretions. Another French physician, Armand Trousseau, with practice, managed to achieve a survival rate of about 25% using tracheotomies.

Diphtheria is referred to as “the paradigm of toxigenic infectious disease.” In 1883 Edwin Klebs, a Swiss-German pathologist, identified and described the bacterium responsible as having a club-shaped appearance. The shape led Klebs to name the bacteria, using the Greek word for club (κορυνε/ koruna): Corynebacterium diphtheriae.  In 1884, Friedrich Loeffler became the first to cultivate these Corynebacterium diphtheriae. The bacteria could only be grown from the nasopharyngeal cavity. Loeffler postulated that the damage to internal organs resulted from a soluble toxin.

In 1888, Roux and Yersin injected animals with sterile filtrates of C. diphtheriae and showed that the animals developed similar organ pathology to what was seen in humans with diphtheria, proving the existence of Loeffler’ toxic protein that underlay the disease’s virulence. This was the first bacterial exotoxin recognized by science. As C. diphtheriae colonize the upper respiratory tract, it is this toxin that injures and then destroys cells. Waste products and proteins from the dying cells form the thick gray substance over the pharynx. This pseudomembrane sticks to tissues and obstructs breathing. The toxin may also damage the heart, muscle, kidneys, liver, and other areas.

Guinea pigs and rabbits are highly susceptible to diphtheria toxin (DT) while mice and rats are resistant. This may be what gave rise to our continuing reluctance to volunteer as “guinea pigs” for laboratory experiments. The lethal dose of DT for humans is small, ∼0.1 µg/kg of body weight.

In 1890, von Behring and Kitasato showed that susceptible animals could be immunized by injection with graded doses of diphtheria bacilli, and that blood serum taken from these animals protected other susceptible animals from the effects of DT. This serum became known as antitoxin. A year later, in 1891, such antitoxin was used successfully to treat diphtheria in a child. The time period from the identification of the disease-causing bacteria to the introduction of antitoxin therapy for treating diphtheria was remarkably short. Perhaps even shorter was the interval to when von Behring received his Nobel Prize in 1901.

In 1909, Theobald Smith came up with the strategy of using a mixture of DT and diphtheria antitoxin together to immunize humans against diphtheria. A large-scale trial of this toxin-antitoxin vaccine was conducted in 1922 in New York City by W. H. Park and proved successful. In 1923, Ramon discovered that treating DT with formalin eliminated its toxicity while retaining its required immunogenicity. Formalin-treated DT, now called diphtheria toxoid, became the preferred vaccine against diphtheria. This diphtheria toxoid (used in combination with other vaccines) is still used for active immunization against diphtheria. The PW8 strain of C. diphtheriae, isolated by Park and Williams in 1896 continues to be used throughout the world to make DT for production of diphtheria toxoid for vaccine.

Given the widespread use of intubation during the current Covid pandemic, it is appropriate to mention that the technique was first introduced in 1885 by Joseph O’Dwyer as a method for rescuing young diphtheria victims from pseudomembranous suffocation. O’Dwyer died in 1898 from complications of diphtheria acquired while intubating a patient.

Widespread use of the vaccine has sharply reduced diphtheria incidence in the US and globally.

The Centers for Disease Control (CDC) recorded only 57 cases in the United States between 1980 and 1994, while the World Health Organization (WHO) reported 3,978 cases worldwide in 2006. The last major outbreak in the United States was in Seattle in 1971.

Few of us have had the misfortune of ever diagnosing diphtheria in our patients. This is a good thing, a very good thing. One can barely imagine the kind of horror described in these historical accounts. One can easily forget the depth of tragedy earlier generations lived with, except when it happened just down the road.

References