Focal infection theory

Focal infection theory (FIT) explains that a localized infection, often asymptomatic, can disseminate microorganisms or their toxins to distant sites within the body, and thereby initiate disease. The resulting diseases are often systemic and chronic, but usually not thought infectious, such as arthritis, atherosclerosis, cancer, or mental illness.^[1][2][3][4] (Distant injury is focal infection's key principle, whereas in ordinary infectious disease, the infection itself is systemic, as in measles, or the initially infected site is readily identifiable and invasion progresses contiguously, as in gangrene.)^[5][6] This ancient concept took modern form around 1900, and was widely accepted in Anglosphere medicine by the 1920s.^[4][6][7][8]

In the theory, the focus of infection is often unrecognized, while secondary infections might occur at sites particularly susceptible to such microbial species or toxin.^[6] Several locations were commonly claimed as foci—appendix, urinary bladder, gall bladder, kidney, liver, prostate, and nasal sinus—but most commonly oral tissues. Not only chronically infected tonsils and dental decay, but also sites of dental restoration and root canal therapy were indicted as the foci.^[4][6] The putative oral sepsis was countered by tonsillectomies and tooth extractions, including of endodontically treated teeth and even of apparently healthy teeth, newly popular approaches—sometimes leaving individuals toothless—to treat or prevent diverse chronic diseases.^[4]

Drawing severe criticism in the 1930s, focal infection theory, whose popularity zealously exceeded consensus evidence, was generally discarded in the 1940s amid overwhelming consensus of its general falsity, whereupon dental restorations and root canal therapy became again favored.^[4][6] Untreated endodontic disease retained recognition as fostering systemic disease,^[4][6] but only alternative medicine and later biological dentistry continued highlighting sites of dental treatment—root canal therapy, dental implant, and, as newly claimed, tooth extraction, too—as foci of infection promoting systemic diseases.^[9] The primary recognition of focal infection is endocarditis if oral bacteria enter blood and infect the heart, perhaps its valves.^[5]

Entering the 21st century, scientific evidence supporting general relevance of focal infection theory remained slim, yet evolved understandings of disease mechanisms had established a third possible mechanism—altogether, metastasis of infection, metastatic toxic injury, and, as recently revealed, metastatic immunologic injury—that might occur simultaneously and even interact.^[5][10] Meanwhile, focal infection theory has gained renewed attention, as dental infections apparently are widespread and significant contributors to systemic diseases, although mainstream attention is on ordinary periodontal disease, not hypotheses of stealth infections via dental treatment.^[11][12][13] Despite some doubts renewed in the 1990s by critics of conventional dentistry, dentistry scholars maintain that endodontic therapy can be performed without creating focal infections.^[4][6]

Rise and popularity (1890s–1930s)

Roots and dawn

In ancient Greece, Hippocrates reported cure of an arthritis case by tooth extraction.^[6] Yet modern focal infection theory awaited Robert Koch's establishment of medical bacteriology in the late 1870s to early 1880s.^[3][14] In 1890, Willoughby D Miller attributed a set of oral diseases to infections, and a set of general diseases—as of lung, stomach, brain abscesses, and other conditions—to those.^{[3][15][16][17]} In 1894, Miller became the first to reveal existence of bacteria in samples of dental pulp.^[18][19] Miller advised root canal therapy.^[3][6] Yet focal infection theory met a cultural climate where ancient and folk ideas, long entrenched via Galenic humoral medicine, found new outlets through bacteriology—a pillar of the new "scientific medicine".^[20]

Emigrating from Russia in 1886, international scientific celebrity Elie Metchnikoff—discoverer of phagocytes, mediating innate immunity—was embraced in Paris by Louis Pasteur, who granted him an entire floor for research once the Pasteur Institute, the globe's first biomedical institute, opened in 1888.^[21] Later the Institute's director and 1908 Nobelist, Metchnikoff believed, as did his rival Paul Ehrlich—theorist on antibody, mediating acquired immunity—and as did Pasteur, that nutrition influenced immunity.^[21][22] Sharing Pasteur's view of science as a means to suppress the problems plaguing humankind, Metchnikoff brought into France its first cultures of yogurt for probiotic microorganisms to foster health and longevity by suppressing the colon's putrefactive microorganisms alleged to foster the colon's toxic seepage, autointoxication.^[20][21][23]

As the 20th century opened, British surgeons were still knife-happy, and called for "surgical bacteriology".^[20] Surgical pioneer Sir Arbuthnot Lane, famed for an emergency appendectomy performed on England's royalty, drew from Metchnikoff and clinical observation to issue dire warnings about "chronic intestinal stasis"—that is, constipation—its "flooding of the circulation with filthy material" and causing autointoxication,^[20] which Lane then treated with colon bypass and colectomy.^[23][24] In America, alleged bowel sepsis wreaking degeneration and disease had been targeted since 1875 by John Harvey Kellogg in Michigan at his huge Battle Creek Sanitarium—he coined the term sanitarium—yearly receiving several thousand patients, including US Presidents and celebrities, and advertising itself as the "University of Health".^[20] When embracing focal infection theory, however, American medical doctors sided against alleged "health faddists" like Kellogg as well as Sylvester Graham, and endorsed the academic tradition of German "scientific medicine".^[20]

Medical popularity

In 1900, British surgeon William Hunter blamed many disease cases on oral sepsis.^[3][25][26] In 1910, lecturing in Montreal at McGill University, he claimed, "The worst cases of anemia, gastritis, colitis, obscure fevers, nervous disturbances of all kinds from mental depression to actual lesions of the cord, chronic rheumatic infections, kidney diseases are those which owe their origin to or are gravely complicated by the oral sepsis produced by these gold traps of sepsis."^[3] He apparently indicted dental restorations.^[15] Incriminating the execution, rather, his American critics lobbied for stricter dental licensing requirements.^[3] Still, Hunter's lecture—as later recalled—"ignited the fires of focal infection".^[27] Ten years later, he proudly accepted that credit.^[7] And yet, read carefully, his lecture asserts a sole cause of the sepsis: dentists who instruct patients to never remove partial dentures.^[27][28]

Focal infection theory's modern era really began with physician Frank Billings, based in Chicago, and his case reports of tonsillectomies and tooth extractions claimed to have cured infections of distant organs.^[27] Replacing Hunter's term oral sepsis with focal infection,^[4] Billings in November 1911 lectured at the Chicago Medical Society, and published it in 1912 as an article for the American medical community.^[29] In 1916, Billings lectured in California at Stanford University Medical School, this time printed in book format.^[30] Billings thus popularized intervention by tonsillectomy and tooth extraction.^[3] A pupil of Billings, Edward Rosenow held that extraction alone was often insufficient, and urged teamwork by dentistry and medicine.^[15] Rosenow developed the principle elective localization, whereby microorganisms have affinities for particular organs, and also espoused extreme pleomorphism.^[27][31][32]

Since 1889, in American state Minnesota, brothers William Mayo and Charles Mayo had built an international reputation for surgical skill at their Mayo Clinic, by 1906 performing some 5,000 surgeries a year, over 50% intra-abdominal, a tremendous number at the time, with unusually low mortality and morbidity.^[20][33] Though originally distancing themselves from routine medicine and skeptical of laboratory data, they later recruited Rosenow from Chicago to help improve Mayo Clinic's diagnosis and care and to enter basic research via experimental bacteriology.^[20][33] Rosenow influenced Charles Mayo,^[20] who by 1914 published to support focal infection theory alongside Billings and Rosenow.^[34][35][36]

At Johns Hopkins University's medical school, launched in 1894 as America's first to teach "scientific medicine", the eminent Sir William Osler was succeeded as professor of medicine by Llewellys Barker,^[37] who became a prominent proponent of focal infection theory.^[20] Although many of Hopkins' medical faculty remained skeptics, Barker's colleague William Thayer^[38] cast support.^[20] As Hopkins' chief physician, Barker was a pivotal convert propelling the theory to the center of American routine medical practice.^[20] Russell Cecil,^[39] famed author of Cecil's Essentials of Medicine, too, lent support.^[27] In 1921, British surgeon Hunter announced that oral sepsis was "coming of age".^[7]

Although physicians had already interpreted pus within a bodily compartment as a systemic threat, pus from infected tooth roots often drained into the mouth and thereby was viewed as systemically inconsequential.^[40] Amid focal infection theory, it was concluded that that was often the case—while immune response prevented dissemination from the focus—but that immunity could fail to contain the infection, that dissemination from the focus could ensue, and that systemic disease, often neurological, could result.^[40] By 1930, excision of focal infections was considered a "rational form of therapy" undoubtedly resolving many cases of chronic diseases.^[2] Its inconsistent effectiveness was attributed to unrecognized foci—perhaps inside internal organs—that the clinicians had missed.^[2]

Reception by dentistry

In 1923, upon some 25 years of researches, dentist Weston Andrew Price of Cleveland, Ohio, published a landmark book,^[6][41] then a related article in the Journal of the American Medical Association in 1925.^[42] Price concluded that after root canal therapy, teeth routinely host bacteria producing potent toxins.^[6] Transplanting the teeth into healthy rabbits, Price and his researchers duplicated heart and arthritic diseases.^[6] Although Price noted often seeing patients "suffering more from the inconvenience and difficulties of mastication and nourishment than they did from the lesions from which their physician or dentist had sought to give them relief."^[43] his 1925 debate with John P Buckley was decided in favor of Price's position: "practically all infected pulpless teeth should be extracted".^[44] As chairman of American Dental Association's research section, Price was recognized even in Britain as the individual who, perhaps beyond any other, shaped opinion in the dentistry profession.^[45] His 1923 treatise was relied on by textbook authors into the late 1930s.^[46]

Unsuspected periapical disease was first revealed by dental X-ray in 1911, the year that Frank Billings lectured on focal infection to the Chicago Medical Society.^[27] Introduced by C Edmund Kells,^[47] the technology became used to feed the "mania of extracting devitalized teeth".^[48] Even Price was cited as an authoritative source espousing conservative intervention at focal infections.^[49] Kells, too, advocated conservative dentistry.^[47] Many dentists were "100 percenters", extracting every tooth exhibiting either necrotic pulp or endodontic treatment, and extracted apparently healthy teeth, too, as suspected foci, leaving many persons toothless.^[4][6] A 1926 report published by several authors in Dental Cosmos—a dentistry journal where Willoughby Miller had published in the 1890s—advocated extraction of known healthy teeth to prevent focal infection.^[50] Endodontics nearly vanished from American dental education.^[4][6] Some dentists held that root canal therapy should be criminalized and penalized with six months of hard labor.^[4]

Psychiatric promulgation

Besides heredity, focal infection and autointoxication was psychiatry's predominant explanation of schizophrenia near the turn of the 20th century.^[51] In American state New Jersey, the director of the psychiatric asylum at Trenton State Hospital since 1907 was Henry Cotton.^[52] Drawing influence from the medical popularity of focal infection theory,^[20] Cotton identified focal infections as the main causes of dementia praecox (now schizophrenia) and manic depression (now bipolar disorder).^[52] Cotton routinely prescribed surgery to clean the nasal sinuses and to extract the tonsils and dentition.^[52] Yet, seeking to clean the entire body of focal infections, Cotton frequently prescribed surgical removal of the appendix, gall bladder, spleen, stomach, colon, cervix, ovaries, testicles, and thereby claimed up to 85% cure rate.^[52]

Despite the death rate of some 30%, Cotton's fame rapidly spread through America and Europe, and the asylum drew influx of paying patients.^[52] The New York Times praised his accomplishments and heralded "high hope".^[52] Cotton made a European lecture tour,^[52] and Princeton University Press and Oxford University Press simultaneously published his book in 1922.^[53] Despite skepticism within his profession, psychiatrists were under pressure to match Cotton's treatments, as patients would ask why they were being denied successful intervention.^[52] Other patients, ostensibly for their own good, were pressured or compelled into treatment without their own consent.^[54] Cotton had his two sons' teeth extracted as preventive healthcare—although each later committed suicide.^[52] By the 1930s, however, focal infection fell from psychiatry as an explanation.^[51]

Criticism and decline (1930s–1950s)

Early skepticism

Addressing the Eastern Medical Society in December 1918, New York City physician Robert Morris had explained that focal infection theory had drawn much interest but that understanding was incomplete, while the theory was earning disrepute through overzealousness of some advocates.^[55] Morris called for facts and explanation from scientists before physicians continued investing so steeply in it, already triggering vigorous disputes and embittering division among clinicians as well as uncertainty among patients.^[55]

In 1919, in New Orleans, at the annual meeting of the National Dental Association (forerunner of the American Dental Association), dental X-ray originator and pioneer C Edmund Kells^[47] delivered a lecture, published in 1920 in the Association's journal,^[56] largely discussing focal infection theory, which Kells condemned as a "crime".^[48] Kells stressed that X-ray technology is to improve dentistry, not to enhance the "mania of extracting devitalized teeth".^[48] Kells urged dentists to reject physicians' prescriptions of tooth extractions.^[57]

Focal infection theory's elegance suggested simple application, but the applications brought meager "cure" rate, occasional disease worsening, and inconsistent experimental results,^[3] although the lack of controlled clinical trials, among present criticism,^[3] was standard at the time—except in New York City.^[52] Around 1920, at Henry Cotton's claims of up to 85% success treating schizophrenia and manic depression, Cotton's major critic was George Kirby, director of the New York State Psychiatric Institute on Ward's Island.^[58] Two researchers, bacteriologist Nicolas Kopeloff and psychiatrist Clarence Cheney, ventured from the New York State Psychiatric Institute to Trenton, New Jersey, to investigate Cotton's practice.^[52]

Research attacks

In two controlled clinical trials with alternate allocation of patients, Kopeloff, Cheney, and Kirby found no effectiveness of Cotton's psychiatric surgeries, as patients who improved already had that prognosis and others did so without surgeries.^[52][59] They presented their findings at the American Psychiatric Association's 1922 and 1923 annual meetings, and published two papers.^[52][60] Most of Cotton's data were questioned at Johns Hopkins University by Phyllis Greenacre, who later helped steer American psychiatry into psychoanalysis.^[52] Colectomy for psychosis vanished except in Trenton until Cotton—who used publicity and word of mouth, kept the 30% death rate unpublicized, and passed a 1925 investigation by New Jersey Senate—died by heart attack in 1933.^[52]

As early as 1927, Weston Price's researches were criticized for "faulty bacterial technique".^[61] In the 1930s and 1940s, researchers and editors dismissed the studies of Edward Rosenow and of Price as flawed by insufficient controls, massive doses of bacteria, and contamination of endontically treated teeth during extraction.^[6] In 1938, Cecil and Angevine reported 200 cases of rheumatoid arthritis, but no consistent cures by tonsillectomies or tooth extractions.^[6][62] They noted that, "Focal infection is a splendid example of a plausible medical theory which is in danger of being converted by its enthusiastic supporters into the status of an accepted fact."^[3] Newly a critic, Cecil alleged that foci were "anything readily accessible to surgery".^[27]

In 1939, E W Fish implanted bacteria into guinea pigs' jaws and reported^[63] that four zones develop.^[6] The first zone was the zone of infection, whereas the other three zones—surrounding the zone of infection—revealed immune cells or other host cells but no bacteria.^[6] Fish theorized that by removing the infectious nidus, dentists would permit recovery from the infection, and Fish's reasoning and conclusion became the basis for successful root canal treatment.^[6] Still, endodontic therapy of the era indeed posed substantial risk of failure, and fear of focal infection crucially motivated endontologists to develop new and improved technology and techniques.^[4]

End of the focal era

The review and "critical appraisal" by Hobart A Reimann and W Paul Havens, published in January 1940,^[28] was perhaps the most influential criticism of focal infection theory.^[3] Recasting Hunter's views of 30 years earlier as widely misinterpreted, they summarized that "the removal of infectious dental focal infections in the hope of influencing remote or general symptoms of disease must still be regarded as an experimental procedure not devoid of hazard".^[50] By 1940, Louis I Grossman's textbook Root Canal Therapy flatly rejected the methods and conclusions made earlier by Price and especially by Rosenow.^[64] Amid improvements in endodontics and medicine, including release of sulfa drugs and antibiotics, a backlash to the "orgy" of tooth extractions and tonsillectomies ensued.^[3]

Easlick's 1951 review in the Journal of the American Dental Association notes, "Many authorities who formerly felt that focal infection was an important etiologic factor in systemic disease have become skeptical and now recommend less radical procedures in the treatment of such disorders".^[65] A 1952 editorial in Journal of the American Medical Association tolled the era's end by stating that "many patients with diseases presumably caused by foci of infection have not been relieved of their symptoms by removal of the foci, many patients with these same systemic diseases have no evidence focus of infection, foci of infection are as common in apparently healthy persons as in those with disease".^[66][67] Some support extended into the late 1950s,^[68][69] yet focal infection vanished as the primary explanation of chronic, systemic diseases,^[12] and was generally abandoned in the 1950s.^[70]

Revival and evolution (1990s–2010s)

The principle of focal infection remained embedded in scientific understanding of the complications of tuberculosis, gonorrhea, syphilis, pneumonia, typhoid fever, and mumps.^[71] It formally remained with idiopathic scrotal gangrene^[72] and angioneurotic edema.^[73] Meanwhile, by way of continuing case reports claiming cures of chronic diseases like arthritis after extraction of infected or root-filled teeth, and despite lack of scientific evidence, "dental focal infection theory never died".^[4] Actually, severe endodontic disease resembles classic focal infection theory.^[4][67] In 1986, it was noted that, "in spite of a decline in recognition of the focal-infection theory, the association of decayed teeth with systemic disease is taken very seriously".^[74]

Reported during the 1960s and 1970s were cryptic, pleomorphic bacteria—bacterial L forms as well as bacterial genus Mycoplasma—in fluid samples from both healthy and rheumatoid arthritic humans, but far more numerous in the latter, and difficult to culture.^[75] By the 1980s, microbiologists accepted that over 99% of microorganisms in most natural environments elude culturing.^[76][77] By 2010, the Human Microbiome Project found that human bodies routinely host unculturable microorganisms and pleomorphic bacteria, long studied but controversial,^[78][79] that associate with diverse diseases.^[76] Meanwhile, focal infection theory drew reconsideration.^[70] Apparently, dental infections, including by uncultured or cryptic microorganisms, contribute to systemic diseases.^{[77][80][81][82][83][84]} Conversely, attribution of endocarditis to dentistry has entered doubt via case-control study, as the species usually involved is present throughout the human body.^[85]

Periodontal medicine

With the 1990s' emergence of epidemiological associations between dental infections and systemic diseases, American dentistry scholars have been cautious,^[70] some seeking successful intervention to confirm causality.^[6][86] Some American sources emphasized epidemiology's inability to determine causality, categorized the phenomena as progressive invasion of local tissues, and distinguished that from focal infection theory—which they assert was evaluated and disproved by the 1940s.^[6] Others have found focal infection theory's scientific evidence still slim, but have conceded that evolving science might establish it.^[5]

European sources find it more certain that dental infections drive systemic diseases, at least by driving systemic inflammation, and probably, among other immunologic mechanisms, by molecular mimicry resulting in antigenic crossreaction with host biomolecules,^[13][87][88] while some seemingly find progressive invasion of local tissues compatible with focal infection theory.^[88] Acknowledging that beyond epidemiological associations, successful intervention is needed to establish causality, they emphasize that biological explanation is needed atop both, and the biological aspect is thoroughly established already, such that general healthcare, as for cardiovascular disease, must address prevalent periodontal disease,^[87][89] a stance matched in Indian literature.^[90] Thus, there has emerged the concept periodontal medicine.^[13][70]

Amid continuing research interest,^[10] Indian textbooks find focal infection theory established, if in more modest form than originally.^[12][91] Akshata et al have attacked the stigma and posed focal infection theory as a correct theory earlier misapplied and thereby discredited yet later refined as knowledge grew over time.^[82] In a paper winning an Indian prize, they clarify "that the oral cavity can act as the site of origin for dissemination of pathogenic organisms to distant body sites, especially in immunocompromised hosts", especially those "suffering from malignancies, diabetes, rheumatoid arthritis", or "undergoing other immunosuppressive treatment", and that "uncontrolled advanced periodontitis" "presents a substantial infectious burden for the entire body by releasing bacteria, bacterial toxins, and other inflammatory mediators into the bloodstream that then affect the other parts of the body", this altogether "a paradigm shift in thinking about the directionality of oral and systemic associations".^[82]

Dental controversies

During the 1980s, controversial dentist Hal Huggins spawned biological dentistry, as it were, which claims that conventional tooth extraction routinely leaves within the tooth socket the periodontal ligament that often becomes gangrenous, then, forming a jawbone cavitation seeping infectious and toxic material.^[9] Sometimes forming elsewhere in bones after injury or ischemia,^[92] cavitations are recognized as dental foci of infection also in osteopathy^[92] and in alternative medicine,^[93] but conventional dentists generally conclude are nonexistent.^[92] Huggins and many biological dentists also espouse Weston Price's findings on endodontically treated teeth routinely being foci of infection,^[9] although these dentists have been accused of quackery.^[94] Conventional belief is that microorganisms within inaccessible regions of a tooth's roots are rendered harmless once entrapped by the filling material, although little evidence supports this.^[95]

A H Rogers in 1976^[96] and E H Ehrmann in 1977^[97] had dismissed any relation between endodontics and focal infection.^[50] Dentist George Meinig's 1994 book Root Canal Cover-Up Exposed, discussing researches of Rosenow and of Price, provoked some dentistry scholars' fears that patients would lend new credence to these works deemed already evaluated and disproved by the 1940s.^[98][99] Suggesting that even Price would have disapproved of Meinig's presentation of Price's work, Hasselgren asserted existence of debate, not coverup.^[100] Still, Hasselgren noted that many endodontists seem enraptured by endodontic technology but neglect biological principles underlying their work, as "one-visit treatment of necrotic, infected teeth is being advocated and practiced even if no long-term study has been performed to investigate this kind of treatment. The work of Dr Weston Price is therefore still to a great extent valid and important and the role of infection cannot be underestimated".^[101]

A European source places Meinig among three authors who, in the early 1990s, independently renewed concern about endodontic therapy promoting disease systemically.^[50] Boyd Haley and Curt Pendergrass found especially high levels of bacterial toxins in root-filled teeth.^[102] Yet there remained a lack of carefully controlled studies definitely establishing adverse systemic effects.^[50] The possibility appears especially likely amid compromised immunity, as in individuals cirrhotic, asplenic, elderly, rheumatoid arthritic, or using steroid drugs.^[50] Conversely, some if few studies have investigated effects of systemic disease on root canal therapy's outcomes, which apparently tend to worsen with poor glycemic control, perhaps via impaired immune response, a factor largely ignored until recently but now being recognized as important.^[50] Still, even by 2010, "the potential association between systemic health and root canal therapy has been strongly disputed by dental governing bodies and there remains little evidence to substantiate the claims".^[50]

Although researchers have noted L forms or Mycoplasma present but routinely overlooked in normally healthy humans' blood,^{[75][84][103]} molecular methods have, even nearing 2010, brought no generally accepted reports of bacteremia traced to asymptomatic endodontic infection.^[4] Although endodontic therapy can fail and eventually often does,^[95][104] dentistry scholars maintain that it can be performed without fostering systemic disease.^[6] Whereas Meinig's warnings regarded the conventional root-filling material, named gutta-percha,^[105] a new filling material, Biocalex, drew initial optimism, but was later reported by Haley to likewise fail.^[106] Some dentists have advocated laser use to sterilize the tooth interior.^[106][107] In any event, the predominant view is that shunning endodonthic therapy or routinely extracting endodontically treated teeth to treat or prevent systemic diseases remains unscientific and misguided.^[6][99][108]

Stealth pathogens

Chronic infections contribute to cancers via chronic inflammation, although other mechanisms, including biochemical, are tenable.^{[109][110][111][112][113][114]} Yet microorganisms recovered from tumor samples might often have arrived after tumor development,^[115] as varying species have affinities for particular tissues, and can promote a tumor's either growth or regression.^[116] Apparently, the microbiome's diversity of microorganisms associating with diverse diseases and conditions, even obesity, often exist normally in symbiosis with human hosts.^{[117][118][119][120]} Like head and neck malignant tumors found to harbor bacteria deep within, human internal organs previously presumed sterile might not be sterile.^[120] Thus, in such recent findings as saliva's bacterial profile associating with chronic pancreatitis and with pancreatic cancer, the direction of possible causality is unclear.^[120] Infectious but "unculturable" factors of chronic prostatitis, for instance, seem frequent but overall ambiguous.^[121]

Stealthy dissemination of bacteria from foci, including internal organs like spleen, is evidenced for bacterial L forms, which can adhere to and travel via red blood cells,^{[78][83][122]} especially from oral tissues and the intestines during dysbiosis.^[84] Perhaps some of Weston Price's identified "toxins" in endodontically treated teeth were L forms,^[83] thought nonexistent by bacteriologists of his time and widely overlooked into the 21st century.^{[103][123][124]} Despite mention of L forms in medical education,^[125] some activists for conventional medicine incidentally deny the existence of such pleomorphic variants of bacteria.^[126] Since the 1920s, basic research has amassed evidence that pleomorphic bacteria, including L forms and Mycoplasma, can have intimate yet stealthy causal roles in cancerous tumors,^[127][128] although translation to clinical application for corroboration by intervention trials in humans has been stymied by rival interests via ideological, cultural, and socioeconomic factors.^[129] Evidence is strong for their causal roles in diverse diseases of cryptic etiology and especially autoimmune diseases^[75][76][78] where recent results of clinical application for intervention have been encouraging.^{[76][130][131]}

Footnotes