Focal infection theory: Difference between revisions

Focal infection theory (FIT) describes a localized site of infection that disseminates microorganisms or their toxins to distal locations, which thereupon host secondary infections that initiate, sustain, or worsen systemic diseases, usually chronic, such as atherosclerosis or arthritis or cancer.^[1][2][3][4] (The criterion of spread to distant sites distinguishes focal infection from infectious spread by progressively expanding invasion of local tissues.)^[5][6] Such an idea is ancient, yet 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 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, of which popularity far outstripped medical evidence of the era, was generally discarded in the 1940s, 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 implants, 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 20th century, scientific evidence supporting the general relevance of focal infection theory remained slim, yet evolved understanding of disease to grant the theory a third possible mechanism—altogether, metastasis of infection, metastatic toxic injury, and, recently revealed, metastatic immunologic injury—that might occur simultaneously, or even through interacting.^[5][10] Meanwhile, focal infection theory has resurged, as dental infections apparently are widespread and significant contributors to systemic diseases, but mainstream attention is on ordinary periodontal disease, not hypotheses of stealth infections at sites of dental treatment.^[11][12][13] Despite some doubts renewed from conventional dentistry's critics since the 1990s, dentistry scholars maintain that endodontic therapy can be performed without creating focal infections.^[4][6]

In ancient Greece, Hippocrates reported cure of an arthritis case by tooth extraction.^[6] Modern focal infection theory awaited Robert Koch's establishment of medical bacteriology in the late 1870s to early 1880s.^[3][14] In 1890, Willoughby 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.^[6][3] Focal infection theory met a cultural climate where ancient and folk ideas, long entrenched via Galenic humoral medicine, found new outlet through Bacteriology—a pillar of the new "scientific medicine".^[20]

At 1886, emigrating from Russia, 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 after 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 relieve the problems plaguing humankind, Metchnikoff brought into France its first cultures of yogurt for probiotic microorganisms to promote health and longevity by suppressing the colon's putrefactive microorganisms alleged to foster the colon's toxic seepage, autointoxication.^[20][21][23]

At the opening the 20th century, British surgeons called for "surgical bacteriology".^[20] Sir Arbuthnot Lane, famed for his appendectomy that saved the life of England's monarch, issued dire warnings about "chronic intestinal stasis"—that is, constipation, "flooding of the circulation with filthy material" and causing autointoxication,^[20] treated by colon bypass and colectomy.^[23][24] In America, the idea of degeneration and disease via bowel sepsis had been espoused and the condition treated 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 U.S. Presidents and celebrities, and advertising itself as the "University of Health".^[20] Admonishing alleged "health faddists" like Kellogg and Sylvester Graham, American physicians who nonetheless embraced the focal infection theory, cast themselves in the academic tradition of German "scientific medicine".^[20]

In 1900, British surgeon William Hunter identified oral sepsis as a cause of systemic diseases.^[3][25][26] Lecturing in 1910 at McGill University's medical school in Canada at Montreal, 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] Hunter apparently indicted dental restorations.^[15] Even his American critics incriminated the execution of dental restorations, a view lobbied to impose stricter dental licensing requirements.^[3] Still, Hunter's lecture—as later recalled—"ignited the fires of focal infection".^[27] Ten years later, Hunter proudly accepted such credit.^[7] And yet, read carefully, his lecture lists only one cause of dental sepsis: dentists who instruct patients to never, under any circumstance, remove partial dentures from their mouths.^[27][28]

The modern era of the focal theory of infection 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 the 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 in support of 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 his 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 the existence of pus within a bodily compartment to be a systemic threat, pus from infected tooth roots was often allowed to drain into the mouth and was thought to be systemically inconsequential.^[40] Even amid adherents of focal infection theory, it was concluded to be often true, because supposedly immune response could prevent dissemination from the focus—but that immunity could fail to contain the infection, and could thus permit dissemination from the focus, and result in systemic disease, often neurological.^[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 had been missed by clinicians.^[2]

In 1923, after some 25 years of research, dentist Weston Price of Cleveland, Ohio, published a landmark book,^[6][41] and 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", his 1925 debate with John P. Buckley was decided in favor of Price's position: "Practically all infected pulpless teeth should be extracted".^[43] 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.^[44] His 1923 treatise was relied upon by textbook authors into the late 1930s.^[45]

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,^[46] the technology became used to feed the "mania of extracting devitalized teeth".^[47] Even Price was cited as an authoritative source espousing conservative intervention at focal infections.^[48] Kells, too, advocated conservative dentistry.^[46] 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.^[49] 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]

Besides heredity, focal infection and autointoxication was psychiatry's predominant explanation of schizophrenia near the turn of the 20th century.^[50] In the American state New Jersey at the psychiatric asylum Trenton State Hospital was directed since 1907 by Henry Cotton.^[51] Drawing influence from the medical popularity of focal infection theory,^[20] Cotton identified focal infections as the main cause of dementia praecox (now schizophrenia) and manic depression (now bipolar disorder).^[51] Cotton routinely prescribed surgery to clean the nasal sinuses and to extract the tonsils and dentition.^[51] 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 an 85% cure rate.^[51]

Despite a death rate of some 30%, however, Cotton's fame rapidly spread through America and Europe, and the asylum drew an influx of paying patients.^[51] The New York Times praised his accomplishments and heralded "high hope".^[51] Cotton made a European lecture tour,^[51] and Princeton University Press and Oxford University Press simultaneously published his book in 1922.^[52] 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.^[51] Other patients, ostensibly for their own good, were pressured or compelled into treatment without their consent.^[53] Cotton had his two sons' teeth extracted as a prophylactic measure—although each later committed suicide.^[51] Not surprisingly, by the 1930s, focal infection fell from psychiatry as an explanation.^[50]

Addressing the Eastern (U.S.) Medical Society in December 1918, New York City physician Robert Morris explained that focal infection theory had drawn much interest but that understanding was incomplete, while the theory was earning disrepute through the overzealousness of some advocates.^[54] Morris called for facts and explanation from scientists before physicians continued investing so steeply in it, already triggering vigorous criticism by and division among clinicians, and uncertainty among patients.^[54]

In New Orleans at the 1919 annual meeting of the National Dental Association, the forerunner of American Dental Association, dental X-ray originator and pioneer C Edmund Kells^[46] delivered a lecture, published in 1920 in the Association's journal,^[55] largely discussing focal infection theory, which Kells condemned as a "crime".^[47] Kells stressed that X-ray technology is to improve dentistry, not to enhance the "mania of extracting devitalized teeth".^[47] Kells urged dentists to reject physicians' tooth extraction prescriptions.^[56]

Focal infection theory's elegance suggested simple application, but this meant a low "cure" rate, occasional disease worsening, and inconsistent experimental results,^[3] although the lack of controlled clinical trials, a commonly heard criticism currently,^[3] was standard at the time—except in New York City.^[51] Around 1920, replying to Henry Cotton's claims of up to 85% success treating schizophrenia and manic depression, was Cotton's major critic, George Kirby, director of the New York State Psychiatric Institute on Ward's Island,^[57] which prompted bacteriologist Nicolas Kopeloff and psychiatrist Clarence Cheney to venture to New Jersey to investigate Cotton's practice.^[51]

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 an improved prognosis, and others improved without surgeries.^[51][58] They presented their findings at the American Psychiatric Association's 1922 and 1923 annual meetings, and published two papers.^[51][59] Most of Cotton's data was questioned by Phyllis Greenacre of Johns Hopkins University, who led New York's psychoanalytic ascendance.^[51] Colectomy for psychosis vanished except at the Trenton asylum until Cotton—who used false publicity and word-of-mouth, kept the 30% death rate unpublicized, and managed to pass a 1925 New Jersey State Senate investigation—died by heart attack in 1933.^[51]

As early as 1927, Weston Price's research were criticized for "faulty bacterial technique".^[60] In the 1930s and 1940s, researchers and editors dismissed the studies of 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 that in 200 cases of rheumatoid arthritis, there were no consistent cures by tonsillectomies or tooth extractions.^[6][61] 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] Cecil became a harsher critic, alleging that foci were "anything readily accessible to surgery".^[27]

In 1939, E. W. Fish implanted bacteria into guinea pigs' jaws and reported^[62] that four "zones" developed .^[6] The first was the zone of infection; the other three zones, surrounding the zone of infection, revealed immune cells or other host cells but no bacteria.^[6] Fish theorized that removing the reservoir of infection, the nidus, would permit recovery from infection—and this 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, improved technology and techniques.^[4]

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".^[49] By 1940, Louis I, Grossman's textbook Root Canal Therapy flatly rejected the methods and conclusions made earlier by Price and especially by Rosenow.^[63] 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".^[64] A 1952 editorial in the 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".^[65][66] Some support extended into the late 1950s,^[67][68] but waning as the primary explanation of chronic, systemic diseases,^[12] it was generally abandoned in the 1950s.^[69]

Through 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] Even so, it is embedded in the scientific understanding of tuberculosis, gonorrhea, syphilis, pneumonia, typhoid fever, and mumps complications.^[70] It formally remained with idiopathic scrotal gangrene^[71] and angioneurotic edema.^[72] Severe endodontic disease resembles classic focal infection theory.^[4][66] 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".^[73]

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 in any event difficult to culture.^[74] By the 1980s, microbiologists accepted that over 99% of microorganisms in most natural environments elude culturing.^[75][76] By 2010, the Human Microbiome Project helped provide crucial, mounting evidence that within human bodies, unculturable microroganisms and pleomorphic bacteria, long studied but controversial, contribute to diverse diseases.^[75][77][78] Researchers sought to reevaluate focal infection theory.^[69] Currently it is held that infection of dental structures, including with uncultured or cryptic microorganisms, can contribute to systemic diseases.^{[76][79][80][81][82]} Conversely, attribution of endocarditis to dentistry has entered doubt via case-control study and realization that the species usually involved is present throughout the human body.^[83]

With the 1990s' emergence of epidemiological associations between dental infections and systemic diseases, American dentistry scholars have been cautious,^[69] some seeking successful intervention to confirm causality.^[6][84] Some American sources have emphasized epidemiology's inability to determine causality, categorized phenomena as progressive invasion of local tissues, and make distinctions away 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 concede 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][85][86] while some seemingly find progressive invasion of local tissues compatible with focal infection theory.^[86] 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,^[85][87] a stance matched in Indian literature.^[88] Thus, there has emerged the concept of Periodontal Medicine.^[13][69]

Amid continuing research interest,^[10] Indian textbooks find focal infection theory established, if in more modest form than originally.^[12][89] 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.^[81] 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"; altogether, "a paradigm shift in thinking about the directionality of oral and systemic associations".^[81]

During the 1980s, dentist Hal Huggins spawned biological dentistry, which claims that conventional tooth extraction, which is routinely performed on wisdom teeth of young adults in the U.S., usually leaves remaining within the tooth socket the [[periodontal ligament]] that often becomes gangrenous; then, forming a jawbone cavitation, seeps infectious and toxic material.^[9] Sometimes forming elsewhere in bones after injury or ischemia,^[90] cavitations are recognized as dental foci of infection also in Osteopathic Medicine^[90] and in alternative medicine,^[91] but are generally found nonexistent by conventional dentistry.^[90] 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.^[92] Conventional belief is that microorganisms within inaccessible regions of a tooth's roots are rendered harmless once entombed by the endodontist's filling material, although little evidence supports this.^[93]

Rogers in 1976 and Ehermann in 1977 had dismissed any relation between endodontics and focal infection.^[49] Dentist George Meinig's 1994 book Root Canal Cover-Up Exposed, discussing research 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.^[94][95] Suggesting that even Price would have disapproved of Meinig's presentation of Price's work, Hasselgren asserted existence of debate, not coverup.^[96] 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".^[97]

A European source places Meinig among three authors who, in the early 1990s, independently renewed concern about endodontic therapy promoting disease systemically.^[49] Boyd Haley and Curt Pendergrass found especially high levels of bacterial toxins in root-filled teeth.^[98] Yet there remained a lack of carefully controlled studies definitely establishing adverse systemic effects.^[49] The possibility appears especially likely amid compromised immunity, as in cirrhotic, asplenic, elderly, rheumatoid arthritic individuals, or those using steroid drugs.^[49] 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.^[49] 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".^[49]

Although researchers have noted L forms or Mycoplasma present but routinely overlooked in normally healthy humans' blood,^[74][99] 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,^[93][100] 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,^[101] a new filling material, Biocalex, drew initial optimism, but was later reported by Haley to likewise fail.^[102] Some dentists have advocated laser use to sterilize the tooth interior.^[102] 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][95][103]

Chronic infections are established to contribute to cancers by driving chronic inflammation, although there are other possible mechanisms, including biochemical.^{[104][105][106][107][108][109]} But microorganisms recovered from tumor samples might often have arrived after tumor development,^[110] as varying species have affinities for particular tissues, and can promote a either tumor's growth or its regression.^[111] Apparently, the microbiome's diversity of microorganisms associating with diverse diseases and conditions, even obesity, often exist normally in symbiosis with human hosts.^{[112][113][114][115]} Like head and neck malignant tumors found to harbor bacteria deep within, human internal organs previously presumed sterile might not be sterile.^[115] 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.^[115] Infectious but "unculturable" factors of chronic prostatitis, for instance, seem frequent but overall ambiguous.^[116]

Stealth or cryptic dissemination of bacteria from foci, including internal organs like the spleen as well as dental structures, is evidenced for bacterial L forms, which can adhere to and travel via red blood cells.^{[77][82][117]} Perhaps some of Weston Andrew Price's identified "toxins" in endodontically treated teeth were L forms,^[82] thought nonexistent by bacteriologists of his time and widely overlooked into the 21st century.^{[99][118][119]} Despite mention of L forms in medical education,^[120] some conventional medicine proponents incidentally deride the existence L forms, pleomorphic, and cell-wall deficient organisms.^[121] 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,^[122][123] although progress to clinical application for corroboration by intervention trials in humans has been stymied by rival interests per ideological, cultural, and socioeconomic factors.^[124] Evidence is strong for their causal roles in diverse diseases of cryptic etiology and especially autoimmune diseases^[74][75][77] where recent results of clinical application for intervention have been encouraging.^{[75][125][126]}