From the Throat to the Heart: Charting the Long History of Rheumatic Fever
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It took more than 100 years and the work of dozens of dedicated clinicians and researchers to grasp the true nature of rheumatic fever, according to Adam J. Brown, MD, associate staff physician in the department of rheumatic and immunologic diseases at Cleveland Clinic, and host of the Healio Rheuminations podcast.
“How the disease was classified, and how the cardiac manifestations were eventually recognized, and how treatment was pursued, and how our understanding of the genetics and pathophysiology arose, is a long history,” Brown said in the podcast. “We take for granted that streptococcal pharyngitis can lead to joint pain and sometimes heart problems. But I, for one, did not realize how long it took to put those puzzle pieces together. It is really quite impressive.”
Going back to the early 1700s, physicians did not have a complete understanding of various types of atraumatic joint inflammation, according to Brown. “There were not a whole lot of things a patient like this could be diagnosed with,” he said. “There was gout, and there was this throw bag called rheumatism.”
Later in the century, however, individuals who developed cardiac manifestations of this phenomenon they called rheumatism began to separate themselves from other patient populations, prompting Gerhard van Swieten to write, “Sometimes when the pain in the limb ceases, there arises an anxiety in the breast, a palpitation of the heart, an intermitting pulse,” Brown said. “This was likely rheumatic fever.”
The invention of the stethoscope in 1816 was a “big leap forward,” according to Brown, because it allowed physicians to begin to understand the regular and irregular sounds of the heart, and then connect those sounds to what they observed with their eyes post-mortem. Through the 1830s and 1840s, physicians began to notice that a certain subset of children and adolescents with rheumatism also had irregular heart sounds. The dots were further connected when many of these patients showed enlarged hearts on autopsy.
But mystery continued to shroud this disease. A critical issue was that some patients presented with mild symptoms that lasted just days, while others were riddled with chronic pain and myriad comorbidities lasting months or years until early and untimely death. “There was not any true categorization of these diseases,” Brown said. “So, obviously, it was really hard to start compiling these patients to study them and better understand what each and every disease was.”
In the 1880s, a physician named Walter Butler Cheadle arrived at the conclusion that all of these patients were suffering from the same disease. “He recognized that rheumatic fever could be fever plus arthritis plus something else,” Brown said. “That ‘something else’ could be either carditis, chorea, erythematous rash, subcutaneous nodules, tonsillitis, pleurisy or hyperpyrexia, as he called it.”
Brown described this breakthrough as “massive.” Once it had been recognized, toward the last half of the 19th century, rheumatic fever spent a significant amount of time as the leading cause of death in children aged 5 to 20 years, and was second only to tuberculosis in fatalities for those aged 20 to 30 years, according to Brown. “It was a dominating force of morbidity and mortality,” he said.
This continued through the early 20th century, when, in 1944, T. Duckett Jones “put math behind” the description by Cheadle with a paper in the Journal of the American Medical Association. “He devoted his career to these patients that eventually led to his paper, “The Diagnosis of Rheumatic Fever,”” Brown said.
Brown then detoured the podcast through the history of streptococcus and its association with rheumatic fever. It is now known that group A strep is the strain seen in these patients, but when physicians first began trying to make sense of the link, they faced a challenge that they likely were not even aware they were facing. “Imagine trying to figure this out without even knowing that there are different kinds of strep,” Brown said.
What eventually clarified the situation was what Brown called the “heroic” antistreptolysin O titer. “The ASO titer showed that the vast majority of patients with rheumatic fever had previous exposure to streptococcus,” he said.
Most experts might assume that if there is a final turn in the story of rheumatic fever, it is the advent of penicillin. But Brown suggested that the fever was, in fact, on the decline well before penicillin was discovered. “Of course, penicillin played a big part in the decline of rheumatic fever, but other factors may include changing serotypes of group A streptococcus and overall improvements in sanitation that led to less likelihood of transmitting it from one person to another,” he said.
Regarding genetic implications that may predispose an individual to rheumatic fever, Brown highlighted that HLA-DQ single nucleotide polymorphisms may be implicated and that other studies show increased incidence of the fever in twins. “We also have data on molecular mimicry in the heart tissue,” he said.
In closing, Brown said that he failed to appreciate the seriousness of rheumatic fever, historically speaking. “This was a devastating disease,” he said. “It took many people dedicating their lives to it for us to fully understand it.” – by Rob Volansky
Reference:
Healio Rheuminations podcast:
https://www.healio.com/rheumatology/podcasts/rheuminations/episode-twenty-three
For more information:
Adam J. Brown, MD, can be reached at 9500 Euclid Avenue, Cleveland, OH 44195; email: browna22@ccf.org.
Disclosures: Brown reports no relevant financial disclosures.
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