DDP Newsletter – Vol. XXXVI, No. 2
The “silver bullet” of antibiotics seemed to herald the conquest of infectious diseases, and the Centers for Disease Control and Prevention (CDC) shifted its focus to noninfectious “epidemics” such as cancer and heart diseases. But with the rise of multiply resistant bacteria as well as the ever-present threat of viral diseases, we might soon be living in the post-antibiotic era. We need to review methods from the pre-antibiotic era, which rapidly lost favor after the discovery of penicillin.
In 1892, William Osler wrote that lobar pneumonia “is a self-limited disease and runs its course uninfluenced in any way by medicine. It can be neither aborted, nor cut short by any known means at our disposal.” By 1913, leaders at the Rockefeller Institute initiated equine serum therapy for the treatment of pneumonia. Two decades later, mortality from lobar pneumonia was 25%–40% in patients not receiving serum, but 10%–20% in those who received this therapy. While the treatment was a major advance, it was expensive, time-consuming, needed to be matched to the serotype of the bacteria, and limited by allergic reactions to horse or other serum. Serum therapy was soon eliminated after the introduction of sulfonamides in 1939.
X-irradiation began to emerge as an alternative to the therapeutic monopoly of serum treatments in the 1930s. Edward Calabrese and Gaurav Dhawan (Yale J Biol Med 2013;86:555-570, tinyurl.com/s7ua856) trace its history, beginning with the first report in 1905. Radiotherapy (RT) was broadly accepted early in the 20th century, with notable successes in the treatment of many inflammatory and infectious diseases such as gas gangrene, carbuncles, sinusitis, arthritis, and inner ear infections.
A total of 863 cases of pneumonia of various types treated with RT were reported in the literature, with 717 reported cures, a mortality comparable to that with serum or sulfonamides. An attempt at a controlled trial, using serum or RT in alternate patients, was stopped for ethical reasons: Patients receiving RT were relieved of their respiratory and circulatory distress within a few hours.
While the mechanism by which RT reduced symptoms of pneumonia and enhanced its resolution has not been explicitly evaluated by contemporary methods, there is substantial evidence that it profoundly reduces the inflammatory response.
RT never achieved broad administrative support or widespread scientific standing. Now there is widespread radiophobia-even though estimates of cancer risk using a linear dose response methodology is approximately 20/million, a value about four orders of magnitude below the background malignant tumor incidence. Calabrese asks how we could reactivate a well-established, yet 65-year-old hypothesis, with contemporary research methods. He notes that the use of RT has continued for the treatment of arthritis in Germany, with 50,000 people treated annually.
RT is being used on a small scale in COVID-19 pneumonia. In Peru, Del Castillo et al. reviewed the literature and presented a detailed report on a 64-year-old man with rapidly progressing pneumonia, who was successfully treated with a single exposure of 1 Gy to the whole-lung volume (https://tinyurl.com/y6l5afrk).
A preliminary report from an Emory University study of nursing-home residents hospitalized with COVID-19, mean age 78 years, showed that in the first ten patients who received 1.5 Gy, there was a three-fold risk reduction in time to clinical improvement compared with a control cohort (https://tinyurl.com/y3x7t4ch).
A trial was also started in Israel, when some older radiotherapists remembered the use of RT for pneumonia 70 years ago (https://tinyurl.com/y63q2jj5). The treatment needs to be given “at the start of acute symptoms and before COVID-19 has caused overwhelming organ damage,” said Prof. Zvi Symon of the Radiation Oncology Dept. of Sheba Medical Center in Tel Hashomer.
Archival results and possible mechanisms of immunomodulation are reviewed by Yannic Hanekamp and colleagues of the University of Groningen in the Netherlands (https://tinyurl.com/y6fognb9), who note that in a 1942 study of 176 patients, “X-Ray therapy has been found strikingly free from any toxic side-effects.” As of June 25, 2020, ten trials of RT in COVID-19 had been registered at ClinicalTrials.gov.
One potential advantage of RT over antiviral medications is that the latter would likely exert intense selective pressure on the virus (https://tinyurl.com/y6q8t2na).
An anti-inflammatory effect of radiation has been reported in a broad range of biological models, suggesting that it may be broadly generalizable. RT was used to treat pertussis from 1923–1936, reducing mortality by more than 90% (tinyurl.com/y6eummnj).
Hundreds of clinical studies involving 37,000 patients were conducted in a variety of inflammatory conditions. Calabrese et al. compiled results (https://tinyurl.com/y5qst3qj). Until the 1950s, RT was used in thousands of patients with severe bronchial asthma; about half had complete symptom relief lasting months to years (https://tinyurl.com/y39q486g). In necrotizing fasciitis caused by “flesh-eating bacteria,” use of RT at the first suspicion of the diagnosis could save both life and limb (https://tinyurl.com/y5bujlnr).
PATIENTS’ LIVES VS. THE LNT
Antibiotics, vaccines, steroids, and other asthma therapies decreased the perceived need for RT, and the coup de grâce was the linear no-threshold theory (LNT). This proclaims that “no dose is safe”—first of ionizing radiation, then of demon “chemicals.”
The history of the LNT is one of “mistakes, ideological biases, and scientific misconduct by key scientists,” writes Edward Calabrese, in a comprehensive assessment of its foundations (https://tinyurl.com/y4xtreff). After LNT has harmed everything it has touched, it’s time to write its obituary (https://tinyurl.com/y44w4asm).
LNT died on Jan 10, 2017, “due to a poor theoretical basis, an incapacity for validation and a rejection by hundreds of studies, along with a striking ineptness for accurate predictions in the low dose zone.” The discovery of dose rate effects and DNA repair presented serious problems. “Its nearly century-long life…could end on a positive note if it were to symbolize how science becomes eroded when an ideologically-driven hypothesis is blindly followed, never proven and incuriously followed as central dogma.”
Evidence from Hiroshima survivors, long supposed to support LNT, underestimated dosages, neglected other cancer causalities, and improperly used not-in-city subjects as controls. Longevity data clearly shows the J-shaped dose-response curve characteristic of hormesis—the protective adaptive response at low doses. Without the LNT, tremendous human and economic losses after the Fukushima accident would have been averted (https://tinyurl.com/y2x59ncz, https://tinyurl.com/yywbysr4).
Regulators remain recalcitrant. Emerging diseases as well as increasing antibiotic resistance make the defeat of this destructive anti-scientific ideology ever-more urgent.