Tuberculosis II: the failure of the BCG vaccine

Medical Hypotheses (1999) 53(1), 32–39 © 1999 Harcourt Publishers Ltd Article No. mehy.1997.0706

Tuberculosis II: the failure of the BCG vaccine R. F. Maes Department of Research, Anda Biologicals, Strasbourg, France

Summary BCG (bacille Calmette-Guérin) is an attenuated pathogen characterized by its capacity to induce cellular and humoral immune responses primarily against a nonpeptidic antigen, lipoarabinomannan. Immune responses against this substance contribute to the immunoprotection of the patient if the production of IL-2 and INF-γ is not impaired. The most adequate production of INF-γ and IL-2 is obtained by immunoreactivity against proteinic antigens. The formation of IgG-type antibodies and of cellular immunity against mycobacterial peptidic and proteinic antigens is an additional immunological response essential for a good protection. This is achieved by the BCG vaccine in only a small proportion of the vaccinees. A vaccine adjuvant that also finds application as an immunotherapeutic agent is composed of proteinic antigens such as sonicates of Mycobacterium vaccae and antigen 60 of Mycobacterium bovis. These enhance the beneficial Th1-pole of the immune response. In addition, A60 induces the formation of antibodies against species-specific proteinic antigens. Despite the questioning of its innocuousness and efficacy, the BCG vaccine was imposed worldwide in 1950 by medical and political organizations that showed no concern for these questions. The contemporary structures of research administration in this area make it unlikely that the efficacious means recently developed to complement the action of the vaccine and of chemotherapies to face the surge of tuberculosis (TB) will be readily adopted. INTRODUCTION The problem that TB poses today can be clarified by a knowledge of how the situation evolved in the past (1). The surge of TB that took place in developed countries since about 1990 cannot be traced solely to the rise of the human immunodeficiency virus (HIV) epidemic. Other factors, among which a substantial degradation in the standard of living of socially fragile populations, are incriminated. With a vaccination programme by BCG that was initiated about 45 years ago and a contemporary world coverage of 85%, the epidemiological proof of the inefficacy of the vaccine is patent. Additional means for facing the resurgence of the disease are urgently needed. The purpose of this communication is to define the factors that allowed the introduction and the use of an inefficacious and potentially harmful vaccine, to précis the reasons why it was never improved, and to evaluate the possibility that the situation is unlikely to change for the better in the near future. Received 31 October 1997 Accepted 23 December 1997 Correspondence to: R. F. Maes Dr Sc, Anda Biologicals, 37, rue de la course, 67000 Strasbourg, France. Phone: +33 3 8832 81 22; Fax: +33 3 8832 19 80

THE PAST EPIDEMIOLOGIC AND THERAPEUTIC TRIUMPHS An incurable disease In the eighteenth century, the importance of tuberculosis was comparable to that of lung cancer today, with a death rate of about 10%. The rapid progress of the tuberculous endemy in the 1860s corresponds to the period of industrialization, urbanization and pauperism existing in Europe at that time. Initially, the two professions principally at risk were the lacemakers and the laundresses. The progressive attenuation of the social and economic forms of exploitation of women inverted the tendency in 1900. In 1900, TB was specifically a scourge for children and adolescents, with a maximum of specific mortality from birth to 1 year. In adults, the major risk became silicose and anthrasilicose. The regression of the endemy, of about 4% per year, coincided with the improvement of the nutritional state of the working class. The male overmortality is now very pronounced (factor 4) but the mortality, as late as 1989, was exceedingly low (1). No therapy existed before 1947. The treatment of pulmonary TB until World War II, was more an art than a science. Since Philip of Valois (✞ 1350) who touched the scrofulae of 1500 subjects in a single session, progress 32

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remained at a standstill. The disease, recognized as chronic, led almost invariably to death. If the disease was linked to poverty and destitution, the fact that it struck also physicians and pharmacists, cossetted ladies of leisure, babies and adolescents, complicated the understanding of this pathology. Sanatorium treatment Treatment was accompanied by prolonged stays in a sanatorium, separation from the family, revalidation cures and surgery, which made the treatment trying at the human level and ruinous for the community. The management of this costly and complex system was entrusted in different countries to ‘vertical’ structures whose mission it was to cover the whole of the fight against TB: detection and eradication of bovine TB, vaccination, immunologic, bacteriologic and radiologic detection, treatment, isolation (in the past) and education. The advantages of the vertical structure are: liberty of action versus the economic mechanism of private medicine, integrated system of information, technical qualification (inoculation and lecture of the intradermo-reaction), and interest for the prophylaxy. A risk fostered by a monopoly of action is factionalism, with a strong tendency to exclude any external contributions. This policy of exclusion is incompatible with one of the essential foreseen activities: coordinate private or State initiatives with the progress of science, sustain the projects through the granting of subventions (1). Soluble extracts of M. tuberculosis Koch describes the bacillus in 1882 and succeeds in propagating it in vitro. This success allows a concentration of soluble sterile mycobacterial products of degradation, i.e. old tuberculin. Koch verifies the inocuity of tuberculin in the guinea-pig, observes that tuberculin interferes with the propagation of the tuberculous infection, controls the innocuousness of the tuberculin in healthy humans and presents the tuberculin as an immunotherapeutic product against TB in 1890. The vaccinal treatment with old tuberculin ended with the death of 55 of the first 1769 patients treated (2). Live M. chelonae A second candidate was M. chelonae, live bacillus of Friedmann. This German Jew had discovered in 1904 the natural weak pathogenicity of this bacillus for mammals. Human newborns were inoculated in 1912. The raise of antisemitism and of nationalism resulted in a lawsuit against Friedmann in 1937, the suppression of manufacture of the product in Italy at the demand of Hitler, © 1999 Harcourt Publishers Ltd

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the burning of the Friedman Institute in Leipzig and a French legal interdiction to use this vaccine, in favor of live attenuated M. bovis. Live M. bovis Children having developed a tuberculous cervical lymphadenitis after drinking milk contaminated with M. bovis appeared protected against more serious forms of pulmonary TB. Calmette proceeded to attenuate the bovine bacillus by repeated subculture in vitro for 13 years. This live vaccine provoked in the guinea-pig a general lymphatic disease that was claimed to heal spontaneously within 3 weeks (3). On the basis of this observation, the vaccine was administered per os to human newborns, despite the fact that the BCG itself was shown to multiply during months in various organs of the guinea pig (4). BCG The First International Congress of BCG, held in June 1948 at the Pasteur Institute, certified (only points 1, 2, 5 & 9 are relevant and reported): 1. that the study of more than ten million vaccinations made throughout the world confirms the absolute innocuousness of BCG for the human species; 2. that vaccination by BCG is the most efficacious means of prevention against tuberculosis; 3. that the Congress recognizes as good any vaccination method with BCG that induces a neat and durable allergy in a short time; 4. that the Congress considers as of urgent interest, the largest possible diffusion of vaccination by BCG. On the basis of these recommendations, France forbade the use of the vaccine of Friedmann and imposed the vaccination of all children under French jurisdiction, i.e. throughout the Empire, with the vaccine of Calmette. M. microti The vole bacillus was shown apathogenic for humans. A vaccine based on it was developed and assayed, principally in England. Its use was abandoned after the endorsement of the BCG vaccine by the World Health Organization (WHO) and the claim that the vole vaccine presented no decisive advantage over BCG. Chemotherapy In 1944, streptomycin was found to be bacteriostatic against M. tuberculosis. In 1946, the anti-tuberculosis virtues of para-aminosalicylic acid were established. In 1952, isoniazid appeared. A simple and efficacious Medical Hypotheses (1999) 53(1), 32–39

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treatment, applicable at home and available since 1947, a vaccination at birth, available since 1950, and a spontaneous decrease of 4% per year of the annual risk of an active tuberculosis since 1860, were therapeutic and epidemiological triumphs which appeared to indicate that the TB problem was settled for ever. THE CONTEMPORARY THERAPEUTIC AND EPIDEMIOLOGICAL FAILURES Dogmatism and factionalism In the guinea-pig, the live bacillus was found by Calmette to limit the dissemination of inhaled TB bacilli towards the liver as well as their secondary dissemination toward the lungs. He refused to evaluate the consequences of the observation that the BCG itself infected various organs for several months (4). To monkeys at risk, the vaccine lent no protection at all but Calmette refused to examine either the monkeys or the results (4). In children, the protective efficacy of the vaccine was wildly exaggerated (5): the occasional occurrence of meningitis cases in vaccinees was explained by contaminations with M. tuberculosis, which indeed occurred once (6) and served as an explanation for all the cases. Vaccinated children were purposely isolated in a ‘healthy’ environment and unvaccinated children were purposely kept living in a ‘contaminated’ environment. The flaws in the experimental designs set up to prove the efficacy of the BCG, and the misuse of the statistics exploiting the results (4), came to full light when a country discontinued the universal coverage of its population and analysed the effects of this measure (7): the adverse effects were tenfold superior to those commonly reported (8). The study of TB cases among vaccinees (8) and the benefits of the vaccination (9) appear to have been dominated by the concern to find BCG innocent. The absolute innocuonsness and superior efficacy of BCG were questioned as early as 1927, with the recommendation to apply the vaccine only to exposed groups. Calmette answered the objection by challenging the medical competence of the investigator, a veterinarian (4). It was rapidly realized that physicians inoculating with BCG were not proceeding to a vaccination but to a primo-infection with a bacille whose pathogenicity for humans and cattle was not eliminated. Nevertheless, the conclusions of the Congress were adopted by the French Academy of Medicine, by the French Ministry of Health and by the chairman of UNICEF’s Subcommittee on Medical Projects. The chairman was the brother of an influencial French politician who needed reconstruction money, pacific heroes and heroic achievements for a country that had emerged in discomfiture from World War II (10). The Pasteur Institute, BCG and Calmette fulfilled his expectations, inasmuch as their achievement Medical Hypotheses (1999) 53(1), 32–39

was community-oriented. UNICEF in turn offered $3 million to the WHO to endorse the vaccine (10). The WHO accepted the bribe and popularized the vaccine. The warranty of this moral authority spelled triumph for BCG. The constant concern of the organizations in charge of the TB problem has been to severely restrict the production of the BCG vaccine to a few laboratories, which enjoy a de facto monopoly (11). The mode of production of the vaccine is legally defined and immutable and its protective efficacy unquestioned, although there are no sure means to verify it (11). The undisputable epidemiological evidence of vaccine inefficacy shown by a regression of the endemy in non-covered countries at a rate similar to that observed in vaccinated populations was met with procrastination. No heed was given to the disastrous South-India trial (12). The consequences of these multiple interrogations have been a monopoly of diffusion of information reserved to the members of the vertical structures and hostile action manifested by censorship, insults, sarcasms, the perverse use of ill-applied statistics (13,14), the destruction of careers, bankruptcy and the closing of the laboratories of those investigators who insist on pursuing unwanted alternative lines of research on improved vaccines and improved therapeutic regimens (4,15). A challenge of the paradigms currently governing this area of research could get published only in a journal operating outside the sphere of control of the censors (16,17). The heritage of Calmette and Guérin Their legacy, transformed into a dogma on June 28, 1948, turned out to be an iron collar for the restriction of fruitful applied research. The claim that the BCG was totally innocuous paralysed the faculty of analysis concerning the BCGitis cases observed after vaccination. The discordance observed in the low frequency of 28% tuberculinopositives in vaccinated children isolated from contaminations versus 60% tuberculinopositives among unvaccinated controls kept in a ‘contaminated’ environment, the reverse of claim 5 of the Congress, remained unexplained and, therewith, the real meaning of the observed tuberculinopositivity. The assertion that only a live organism is immunoprotective, despite the results obtained by Koch with tuberculin, oriented research toward vaccines meeting very precise criteria, which one may of course not prejudge but which increase the difficulty of accomplishment of the project (18). The heritage of Koch Most mycobacteriologists strictly adhere to Koch’s postulates of disease causation (19). These postulates are © 1999 Harcourt Publishers Ltd

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still applied today with a disarming mathematical zeal. The experts know their job backwards, impermeable to the notion that the power of Koch’s postulates comes not from their rigid application but from the spirit of scientific rigor that they foster. The incapacity to accept what cannot be framed within a rigid law of causation true under all circumstances, i.e. the ignorance of the scientific process, leads to insecurity that makes cling to the status quo. Dubos, in 1954, and Middlebrook, in 1962, underlined the formidable capacity of resistance to change of their colleagues. It has not improved since then: the immunological advances of the last 20 years have been ignored (20). Serodiagnosis, seroprognosis and immunotherapy are absent from orthodox exposures of the tuberculosis problem (21). A positive contribution of immunological studies to the understanding of the pathogenicity of the disease is negated, whose immunological component is claimed to be without incidence on the evolution of the infections under chemotherapy (22). The consequence of this self-inflicted blind spot is that we know more about the intimate cellular and hormonal machinery governing the immune response to TB and BCG in mice than we do about the immune answer mounted by BCG-vaccinees and TB patients. TB PATHOGENICITY In most humans, mycobacterial infections are quietly evacuated without symptoms. The enigma is that some infected subjects come down with disease. The factors of aggravation are the immune status of the infected individual and the immunosuppressive capacities of the pathogen. The BCG is unable to meet this recent challenge.

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immune weakness: internalization of immunosuppressors (nicotine, recreational drugs), use of immunosuppressive treatments that are the necessary complement of modern therapies, consistent with exposure to stressful events in the environment (noise, work-related stress, overcrowding and commuting) (25). Undernutrition is another calamity that recently extended to the developed world: in 1997, 11 million US citizens were chronically undernourished, of whom at least 800 000 were children. In elderly people, undernutrition is common. It carries an appreciable morbidity but is often unrecognized or ignored, difficult to treat, with few rapid effects, leading clinicians to handle it with benign neglect (26). Immunodepressions The increase in life-expectancy is an additional aggravating factor: in the elderly, the production of IL-2 and INF-γ is naturally reduced (27,28). Also, N-acetyl-cysteine enhances antibody-dependent cellular cytotoxicity in neutrophils and macrophages while glutathione depletion inhibits proliferation of T-lymphocytes (29) and impairs nitrite production by macrophages (30). Natural antibodies against these anti-oxidants have been detected in healthy people and HIV-seropositive patients (31). A glutathione deficit is noticed in the elderly and among smokers (32). A depletion in glutathione inhibits Th1associated cytokine production (33). Finally, a protein which induces T-cell unresponsiveness through interaction with glutathione and cysteine has been isolated in Trypanosoma cruzi (34) and such an immunosuppressive protein could also be produced by mycobacteria. Mycobacterial colonizations

Nutritional imbalances Vitamins, hormones, fatty acids, UV light and trace elements such as zinc, copper, chromium, manganese, selenium, etc. are essential for normal growth and development (23,24). An unbalanced diet is traditionally due to ignorance and/or to a lack of the financial means to provide the necessary nutrients or the avoidance of poisons: in former times, flakes containing lead used in paints were frequently adsorbed by toddlers living in dilapidated housing. This may explain in part the high mortality of toddlers in former times. Nowadays, the imbalance is traced to the ease of acquisition and of preparation of second-grade nutrients (fast foods) and to the increased consumption of foods rich in energy but nutritionally sterile (lemonade, soft drinks, cookies, sweets, french fries, popcorns, crisps, etc.). These nutritional unbalances may be aggravated during adulthood by the adoption of habits that reinforce the © 1999 Harcourt Publishers Ltd

An additional factor is increased exposure to atypical mycobacteria. The dominance of M. avium opportunistic infections among HIV-seropositives living in developed countries is an enigma (17) that may find an explanation in an heavy consumption of cigarettes (35). This adds to a degraded environment, such as acid rains, that favor the multiplication of mycobacteria and their colonization of the human gut, where they are likely to overload the immune system. Colonization can be further favored by proctological lesions linked to homosexual practices (36). The postWWII wave of homosexual behavior in the West is probably iatrogenic, linked to the massive consumption of steroid hormones, used either as birth control in humans or else as weight-gain inducers in cattle and fowl (T. Nawrocki, personal communication, 1997). Recently, the introduction of organic farming practice in the UK was found to drastically increase the numbers Medical Hypotheses (1999) 53(1), 32–39

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of nitrate-reducing growers (37). Such an alteration of the profile of environmental mycobacteria may have important implications for the immunological priming, sometimes to the advantage of BCG vaccination (38). The BCG may indeed be beneficial to some groups living in some environments but the overall record, even in newborns (39), indicates severe shortcomings of the vaccine. The immune response against BCG All BCG strains hitherto analysed are poor producers of phosphorylated nonpeptidic antigens (40). BCG does not mobilize neutrophils and is not responsive to G-CSF: neither depletion of neutrophils nor administration of G-CSF affects the DTH reaction elicited with BCG in mice (41,42). Also, BCG increases LPS-induced lung injury independently of neutrophils (43). Hence it will probably rarely provoke a Shwartzmann reactivity. Thalidomide reduces significantly the size of the liver granulomas formed by BCG in mice (43), indicating that the LAM of BCG is active. BCG powerfully stimulates dendritic cells, which are the most potent antigenpresenting cells capable of initiating primary immune responses. The induction results in the secretion of TNF-α 50-fold above basal level (44). BCG activates antigen-specific CD4+ cytotoxic cells that kill antigenpulsed presenting cells, resulting in suppression of IL-2 production (45). In some cases, a weak IgM output against protein antigens is detected but IgG antibodies against protein antigens are rarely produced (46). Finally, IL-6 is specifically produced during BCG infections (47). Approximately 10 000-fold more IL-6 is produced by M. avium – infected macrophages, compared with uninfected controls. This cytokine suppresses T-cell responses. One would thus be inclined to think that BCG elicits a response essentially to its surface antigens, lipoarabinomannan and glycolipids. In some vaccinees, a substantial immunosuppression is likely to be the result of the infection, which explains the increase in frequency of parasitic mycobacterial infections among vaccinated infants (48). BCG vaccination Billions of doses of the M. bovis vaccine, strain bacille Calmette-Guérin (BCG), have been administered during the last 45 years. The vaccine world coverage is about 85%, yet one-fifth to one-third of humanity is infected with a mycobacterial entity, the annual death rate due to tuberculosis being about 3 million. The incidence of TB, 7.5 million cases per year in 1995, is expected to increase to 11.9 million in 2005. The case-fatality rate is estimated at 55% in untreated people and 15% in the chemoMedical Hypotheses (1999) 53(1), 32–39

therapeutically treated patients. However, this view is optimistic as the treatment success rate of drug-resistant infections in HIV-negative patients is only 56% today. BCG-vaccinated children may be predisposed to disease instead of protection and BCG-vaccinated children occasionally go down with BCG-meningitis (39) despite the claim that BCG protects most efficaciously against meningitis (9). The administration of BCG is not a vaccination but a primo-infection, best evidenced by the possibility of the induction of BCG-meningitis upon revaccination (39). Under some conditions, a global regression of TB cases may be observed after BCG administration, that still incorporates some unwarranted cases due to inoculation. The question, since 1927, centers around the claim of absolute innocuousness. The issue is not, and never was, the number of cases averted by BCG. The issue is how many cases have been provoked by BCG that would have been averted if the ‘vaccine’ had not been given. The cardinal rule of a therapeutic intervention is ‘primum non nocere’ and, with the BCG, this exigency that the therapeutic intervention inflicts no undue harm has been deliberately ignored (10). The possibility that BCG may favor subsequent mycobacterial infections (17) is intrinsically a repulsive idea. Yet, the early observation that vaccinated monkeys all contracted TB upon exposure is the first indication that this idea is not absurd. The Lübeck disaster may also be discussed in this light: we know that TB is only weakly pathogenic, since about 25% of humanity is or was infected, with only a fraction showing symptoms. In the Lübeck case, children were inoculated with a mixture of BCG and TB (4). To what extent was the inclusion of BCG not a stimulant of the pathogenicity of TB? The excess of TB cases observed during the first five years following BCG vaccination of children in the Southern India trial corroborates this view. In Southern India, the interference of environmental mycobacterial entities was suspected (12). Worth mentioning is the result of the study of the specificity of the antibodies produced by TB patients against antigen 60 of M. bovis (49,50). It was conducted by analysing sera before and after their adsorption with M. vaccae antigens. These are supposed to adsorb antibodies non-specific for M. tuberculosis and M. bovis. The surprising result was that, in some countries, such as Portugal, a significant number of patients produced large amounts of non-specific antibodies whereas others had mainly specific antibodies. This result may signify that TB disease may be associated with MOTT infections much more frequently than usually suspected (17). Lind et al. showed that sensitin reactors (M. avium, M. scrofulaceum) were in a large excess seven to ten years after BCG vaccination (48). As claimed by the London © 1999 Harcourt Publishers Ltd

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investigators (37), these atypical infections, sometimes favored by the BCG, may either improve or else endanger the immune status of the infected people. IMMUNOSTIMULATION The claim that case-finding of bacilliferous cases detected by bacilloscopy, and of contacts detected by DTH, followed by their isolation and chemotherapy under directly observed therapy (DOT), are sufficient to stop disease propagation (21) is sophomoric. This policy could have worked in times of economic growth and steady improvement of the living conditions but these times are now gone. Contrary to the opinion that entire generations of populations in industrialized countries are free of tuberculous infections (21), the inapparent infections detected by serology amount to about 4% of the population (51). In exposed groups, this percentage may increase to 50% (52,53). An immunological weakness may, in some cases, easily flare up into an infection accompanied by symptoms. One way to improve the BCG vaccine and to assist chemotherapy would be to incorporate, within the vaccine or at the initiation of the chemotherapy, an immunostimulant that drives a Th1 response. Friedmann’s vaccine was apparently able to promote such a response. Friedmann had recognized the non-specific value of his vaccine and advocated its use as a general immunostimulant. Another precursor in this line of development was Spahlinger, who started work with mycobacterial heat-shock proteins 50 years before anyone else (54). M. vaccae sonicates have also proven useful to this end, with the intriguing possibility to cure HIV-seropositive TB patients (55). A60 from BCG is also a good candidate for this goal. There is no doubt that a deficiency in INF-γ and/or its receptor are responsible for at least half the cases of BCG disease (56). The effect of A60 is to promote the synthesis of INF-γ and IL-2 (57). Antigen 60 from M. bovis, strain BCG, is used as an immunotherapeutic agent in complement of chemotherapy for the treatment of tuberculous cases under chemotherapy and of chemotherapeutically treated cancers in remission. Its superiority is that it is reproducibly and easily made and physico-chemically well characterized, that it induces a DTH in humans and is a protective vaccine against a live tuberculous challenge in mice and that it contains species-specific protein antigens and thus possesses an intrinsic superiority over antigens originating from other species, when applied to tuberculous cases. CONCLUSION As long as the administration of medical sciences is in © 1999 Harcourt Publishers Ltd

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the hands of scientists, physicians and politicians brought up in a tradition of culture, this field of human activity will fare well. In cases of fraud, wrongdoing, mismanagement and misconduct, no faith can be put in the courage and determination of the scientific community, the reliability and fairness of committees of scientific peers, the freedom and aggressivity of the press (15,58). Corrective measures can be implemented only by a leadership focusing on integrity. A felonious direction allows factionalism. In the absence of a humanist culture of fairness, decency and integrity (4), the vast majority of experts will be more anxious to participate in the advantages of a country’s or organization’s hierarchy of power than to exercise a creative and autonomous scientific and medical activity (4,15,58,59). Their activity is characterized by routine thought processes, coteries and cabals, which are not particularly well recognized as good sources of original ideas or novel approaches for dealing with diseases. The management of the tuberculosis problem by specialised organizations has consistently produced poor results. The sanatorium treatment healed only 2% of the treated patients. The Friedmann vaccine based on a weak human pathogen was discarded due to Friedmann’s nationality and ethnic origin. The BCG, based on a virulent species was imposed as the sole possible vaccine despite its known residual pathogenicity. The apathogenic M. microti was abandoned without any valid reason. For nearly 50 years, the side-effects and infectiousness of the BCG vaccine were vastly underrated, with a monopolization of the information and unabashed censorship. Smith, tracing the path of acceptance of the vaccine, mentions inertia and ineptitude, to which he added territoriality (5). These characteristics have not changed and be added to then scientific illiteracy and medical obtuseness must unfortunately. The recent advice to treat TB patients with at least two drugs for at least 6 months (60) ignores the extrapulmonary cases, the importance of the immune status of the patient, the impact of cytocidal drugs on the patient’s immune resources, the emergence of multiple-drug resistant strains and the economic and social situation of the patients, who will stop treatment as soon as they feel better, even in industrialized countries. Directly observed therapy (DOT) is a sensible policy applicable in financially secure countries determined to control the spread of the disease among exposed groups. Its cost and practical conditions of application make it prohibitive for countries where the disease is endemic. Grange literally begs the community of TB workers, the clinical and political leaders, to come down to earth, be realistic, face the truth and begin to adapt their strategies of treatment to the reality of the situation (15). The management of the TB problem has produced the Medical Hypotheses (1999) 53(1), 32–39

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greatest fraud in the history of medicine. This heritage is difficult to cast off. Grange’s public complaint of a denial of public subventions for his research, with the need to sustain it with private funds, is naïve: the subventions go to the improvement of the BCG. The channelling of the subventions toward this hopeless end is achieved by direct attribution, by the rejection of grant applications for other projects as immunotherapy and also by the presentation to the granting agencies of biased and false information concerning this research line (61). The future of productive TB research appears bleak.

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ACKNOWLEDGMENTS I thank Dr Maurice Gittos for his help in the editing of these manuscripts.

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