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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 1  |  Issue : 4  |  Page : 234-239

Prevention is a neglected aspect in the eradication policies against tuberculosis


Department of Research, Parabolic Biologicals, Beauvechain, Belgium

Date of Submission11-Aug-2022
Date of Decision09-Nov-2022
Date of Acceptance17-Nov-2022
Date of Web Publication5-Dec-2022

Correspondence Address:
Roland Maes
Parabolic Biologicals, Rue de l' Ecluse, 2, 1320 Beauvechain
Belgium
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpdtsm.jpdtsm_93_22

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  Abstract 


Tuberculosis remains unapparent in about 80% of the infected cases. It turns symptomatic in cases of stress, undernourishment, i.e., weakening of the immune defenses, hygiene deficits, or massive exposure of fragile and/or stressed populations, including overworked health agents, to the pathogen. It is, thus, mostly a disease of the stressed, the poor, and the indigents. Prevention demands a detection of unapparent infections at risk of turning symptomatic. Diagnostic tests based on the detection of the antigen in sputum and occasionally in other organs have their use but need to be completed with the detection of asymptomatic cases. It is possible by the monitoring of immunoglobulin G (IgG) antibodies during the early process of infection, before the bacillus has reached a mass able to vigorously suppress the immune capacities of the patient. Some drugs are immune depressive and impair the recovery of successfully treated patients. At consultation, the patient is often already fully immune depressed; a monitoring of his IgG-specific antibodies shows that the level of antibodies is very low and will rise if the treatment is successful. The monitoring of the immune status of the patients and the application of immunostimulating products to those patients who show a need therefore will complete the chemotherapy. Nothing of this is currently applied and the serodiagnostic, so useful in rural areas, has been banned, to be replaced by an expensive and inaccurate antigen-test. In addition, the continuing use of an iatrogenic vaccine defeats the purpose.

Keywords: Diagnostic, drugs, ethics, immune stimulants, prevention, prognostic, serodiagnostic, tuberculosis


How to cite this article:
Maes R. Prevention is a neglected aspect in the eradication policies against tuberculosis. J Prev Diagn Treat Strategies Med 2022;1:234-9

How to cite this URL:
Maes R. Prevention is a neglected aspect in the eradication policies against tuberculosis. J Prev Diagn Treat Strategies Med [serial online] 2022 [cited 2023 Jan 29];1:234-9. Available from: http://www.jpdtsm.com/text.asp?2022/1/4/234/362830




  Introduction Top


Today, in 2022, about 1 person dies of hunger every 4s. Tuberculosis (TB) is expected to expand on this fertile ground.

The Indian Ministry of Health enforced in 2012 an ambitious Revised National Tuberculosis Control Programme (RNTCP) whose aim was to revolutionize TB management in the country and stamp it out. To this end, the RNTCP banned TB serology, introduced the GeneXpert® MTB/RIF and two other diagnostic tests, and provided patients with a chemical treatment based on the four drugs recommended by the World Health Organization (WHO). It failed to curb the burden of the disease. In addition, the RNTCP had no focus on prevention, a key requirement for reducing the disease burden. What would ideally bring down the incidence, which was the stated focus of the RNTCP, are preventive measures, best assessed by a blood test able to detect early and latent infections, before the bacilli suppress the immune responses.

I will show that the means currently applied to combat TB, i.e., the Bacillus Calmette–Guérin (BCG) vaccine, the drugs and a diagnosis based solely on detection of the antigen and genome in sputum and other organs are not adequate to successfully fight TB because the vaccine sometimes promotes TB multiplication instead of eradication, some drugs are immunosuppressive and may, under some conditions, favor relapse, the diagnosis limited to the detection of the pathogen, essentially in sputum,-neglects other organs and ignores the immune condition of the patients under treatment.


  Background Top


Charles D. Wells warned the mycobacterial community in 2007 that the combined impact of The human immunodeficiency viruses (HIV) and Multi drug-resisting-TB (MDR-TB) will render the problem these pose, nearly intractable.[1] The Indian Ministry of Health resolved to confront the problem with the RNTCP under the guidance of the WHO. The WHO Expert Group and the WHO Strategic and Advisory Group for TB recommended in an unprecedented move a ban on all existing sero-diagnostic tests (i.e. blood tests), and recommended the use of the Xpert/RIF diagnostic test as the initial diagnostic test in individuals suspected of MDR-TB or HIV-associated TB.[2] The RNTCP followed this advice and forbade the use of all TB-sero-diagnosis tests to the whole of the Health Care Community on June 7, 2012, and initiated the use of the GeneXpert® MTB/RIF test by the public sector along with traditional sputum tests.[3] The consistent care of patients with first-line and second-line drugs completed the policy. On February 11, 2013, the British Medical Journal announced: “TB looks set to defy concerted efforts to treat it successfully with powerful drugs, turning the clock back to the 1930s.” On February 20, 2013, The Wall Street Journal said: “Global TB fight hits a wall. India's new strategy actually makes disease more drug resistant, doctors say.

Despite the rise in TB cases observed after the implementation of the RNTCP, the Indian Journal of Medical Ethics urged on June 2013 the Indian Ministry to phase-in the nationwide deployment of Xpert/RIF test or a quality lower-cost molecular diagnostic alternative, at all points of care of the country as soon as reasonably possible,[4] basing this obligation on the WHO's Guidance on ethics of TB prevention, care and control, published in November 2010. It justifies this ethical obligation by the absolute inaccuracy of TB-sero-diagnosis and the excellence of the Xpert/RIF test. Prof. G. Babu replied that ethical considerations in no way demanded this extension and wrote on January 2014: “It is completely unethical to term prevalence cases as incidence cases, a practice which… allows for the false declaration that the burden of new disease has fallen.[5]

On January 9, 2014, a post on the LinkedIn group “Healthcare India” complained: ”There is a huge possibility of medication or diagnostics being advised disproportionate to the need, and people at large feel that is what is happening.” This complaint has taken more weight by the introduction of the interferon and lipoarabinomannan (LAM) diagnostic tests. While no one doubts the desire of WHO and the Indian Ministry to handle the TB problem in an ethically responsible way that will result in a substantial improvement of the current situation, this protest emanating from professional groups snubbed by the WHO and RNTCP deserves attention. This response vigorously challenges paradigms that are currently in force, and comfort the demand for ethics currently widely expressed by Indian Health Care providers active in the field. Decades of TB-mismanagement are at the source of the present discomfiture.


  Discussion Top


The discussion will first address the value of the BCG vaccine. The second subject addresses the efficiency of the drugs and shows that their effectiveness may lead to an immune suppression that may impair lasting recovery, and the last subject of the discussion is the diagnosis policy, which overlooks means allowing taking some of the preventive measures advocated in the Indian Journal of Medical Ethics.[4]

The value of the Bacillus Calmette–Guérin vaccine

With billions of doses of BCG vaccine distributed over the past 50 years, with 122 countries presently covered, with 85% of the world population vaccinated, the epidemiological proof of the failure of the BCG vaccine is given. Warnings were given in 1927 and 1928, during the development of the vaccine, that it was not completely attenuated,[6] but these warnings were ignored. The worldwide coverage of the population with BCG was initiated in the sixties but needed time to reach completion. The first public warning that the mass vaccination with BCG was iatrogenic was given in 1978.[7] The regression of the tuberculous endemy grinded to a halt in France in 1987, followed with a 7% increase of TB cases in 1992 versus 1991. Pr Grosset mentioned 10,000 new cases in 1994 in France and concluded that the fight against TB was a total failure[8] but he did nothing to improve it. Janet Cornwall replied tartly in 1997 that the reason of the failure was the greed and ineptness of the principal TB-actors.[9]

Evidence of inefficacy and infectiousness of BCG. This was exposed at length in Bacille Calmette-Guérin vaccination: Experience from the past and its perspective further. J.Prev Diagn Treat Strat Med 2022: 1: 7-13 and needs not to be repeated here.[10] The vaccine is a fraud.

The efficiency of drugs

The standard operation procedure (SOP) imposed on the treatment of TB cases restricted the primary drug regimen to four (plus streptomycin) without allowance for change, which excluded de facto further research and development of new drugs because the newly developed drugs would find no outlet. The drug makers were not responsible of this situation. Some of the elected chemicals are powerful substances that kill not only TB but also harm the cells involved in the immune defense system. Amikacin, streptomycin, ciprofloxacin, and rifampicin are potent inhibitors of host cellular functions. Inclusion of these cytocidal drugs in a treatment regimen has consistently been shown to be beneficial, with treatment failure occurring in only about 5% to 10% of cases but rises sometimes to 40%. This low number (5% to 10%) represents a therapeutic success but also a failure. Control of the spread of resistant strains[11],[12],[13] is realized by administration of the drugs at their maximal tolerated concentration. These drugs may very well weaken the immune system of the patient to a point where his/her immune mechanisms become unable to dispose of the resident live intracellular mycobacteria after completion of the therapy. In the best of cases, 5% of the treated patients will not be cured and become drug resistant. In the worst case, up to 44% of the patients may turn resistant to one or more drugs and 30% resistant to both isoniazid and rifampin.[14],[15],[16],[17] In this view, the use of bacteriostatic drugs preferably to bactericidal drugs seems advantageous because they do not disable the immune system and will favor the elimination of residual organisms by immunological mechanisms, once the immunosuppression generated by the invading bacteria has been reduced to a manageable level by chemotherapy. The continuous monitoring of the immunoglobulin G (IgG) production at the beginning of the treatment allows the control of the efficacy of this treatment by the visualization of the resuming of the production of specific IgG antibodies, which were down to nearly zero when the patient consulted.[18]

A Belgian team of physicians operating in the Bangladesh ignored the absurd SOP and experimented new drugs with success. On August 2018, the WHO recommended an injection-free regimen and the implementation of a regimen consisting in a number of additional drugs. I give here the [Table 1] of that publication, which lists these drugs:[19]
Table 1: Grouping of medicines recommended for use in longer multi drug resisting tuberculosis regimens

Click here to view


This chart is difficult to read and comprehend. Some of these drugs suffer spontaneous resistance.[20],[21] Besides, these chemicals are expensive and produce so severe side effects (vomiting, liver damage, eye damage, and sometimes death) and demand so many controls during monthly follow-ups that it is not feasible nor realistic to apply them in those countries that need them most. The patient promptly abandons their intake as soon as recovery is noticed. This premature dropout has well documented dramatic consequences. The only way to handle these refractory patients seems to be an immunotherapy[22],[23],[24] and the boosting of the immune system.[25],[26] However, immunotherapy follows an unorthodox path of treatment based on a science that is poorly understood by clinicians who refuse to leave the comfort of their own discipline and, second, it is cheap compared to drugs.

The boosting of the immune defenses of the organism by stimulation of nitric oxide production is a second way to combat recalcitrant cases. It was established in 1994 that synthesis of nitric oxide is impaired in patients with advanced HIV infection.[27] The antimicrobial properties of nitric oxide are well established since 1995.[28] It is synthesized by consumption of L-arginine and O2, with production of citrulline. Synthesis of NO in humans is more restricted than in other mammalian species as mice and rats, and this restriction largely avoids autotoxicity of NO.[29] Food supplements boosting the immune defenses of the organism by promoting the synthesis of nitric oxide via uleine[30] are available and cheap compared to drugs. They were shown absolutely innocuous but efficacious against HIV-infected patients. Since NO is active in vivo against a number of parasites, Mycobacteria, viruses, bacteria and fungi as Mycobacterium tuberculosis, Toxoplasma gondii, Cryptococcus neoformans and Leishmania,[29] the supplement should be active against TB.

Diagnosis

The WHO recommends four sputum tests, i.e., sputum smears, Xpert MTB/RIF, line probe assay, and liquid cultures, also accepted by the RNTCP.[31],[32] To these, two additional diagnostic tests aiming at the detection of the pathogen have been added by the WHO: an interferon test and a LAM test. The WHO claims that new diagnostic tests must meet the level of performance reached by the microscopy taken as the gold standard, i.e., a claimed 75% sensitivity and 98% specificity.[33] The Ziehl–Neelsen (ZN) stain used for smear microscopy stains all mycobacteria. Its specificity is not 98% as claimed but zero. It is, thus, at the same specificity level as serology based on antigen 60, which was the antigen used in the WHO-banned Abbreviated New Drug Application test.[34]

The lower value of the ZN stain reported for the sensitivity (75%) was traced to errors in the manipulation and examination of the microscopic slides. The main reproach advanced by WHO to justify the ban on TB-serology was the spread in sensitivity from 0% to 100%, in different studies. However, the authors of the meta-analysis signaling this spread[35] report a sensitivity for the microscopy inferior to 30% where HIV prevalence is high. The sensitivity of microscopy in very young children and in the elderly is also very low due to their inability to produce the required sample. In addition, microscopy does not detect extrapulmonary cases, which account for at least 30% of all TB patients. These four groups of patients evidently belong to the TB population and their exclusion when determining the sensitivity of a diagnostic test is not justified yet repeatedly done where microscopy is concerned. A realistic evaluation of the sensitivity varies from 20% to 80% in pulmonary cases and is zero in extrapulmonary cases. A progress registered by the Xpert test over other antigen detection tests in sputum is a specificity of 98%. Its sensitivity for smear-positive TB is 98%, which is of no interest and rather a handicap, while for smear-negative but culture positive TB, where it should be dominant, the sensitivity drops to 68%. In other words, culture is superior in all cases and microscopy is slightly superior since the Xpert test is negative in 2% of smear-positive cases. The detection of rifampicin-resistant pathogens in sputum is a valuable progress, but it neglects all other organs and all other drugs susceptible to resistance. Worse still, the test is peppered with crippling inaccuracies, essentially between one third and one half misdiagnoses.[34]

The stated goal of the RNTPC will have better chances to succeed if it is recognized that the Xpert test is wanting just as much as any other test that focuses on only one single organ and neglects the individual immune status of the patient.

The immunopathology of TB is exceedingly complex.[36] Knowledge of the immune status of the patient is obtainable by serological measurements, which give valuable prognostic and diagnostic clues[37] even in BCG vaccinated infants,[38] and detect unapparent infections.[39]

In the meta-analysis that served to ban blood tests, the “experts” applied to the evaluation of the sensitivity and specificity of TB-sero-diagnostic tests, statistics that rely on linear regressions, without accepting the evidence that each patient mounts a personalized immunological response to the TB aggression. Biological understanding played no role in their interpretation of the results. Their paper is typical in that the discussion initiates with a conclusion based on the findings, as though it is derived directly from the results, a mere linguistic transformation of P = 0.05.[40] This is a consequence of a statistical method that eliminated their ability to distinguish between statistical results and scientific conclusions. A huge amount of tables and numbers–a stamp of legitimacy-comforted their misguided approach. The meta-analysis consisted in an evaluation of published studies applying the test (IgG, Immunoglobulin A and Immunoglobulin M) on widely different subjects during extended times after the beginning of the infection, which brings the risk that the patient becomes immune-suppressed by the pathogen and hence turns seronegative, under widely different chemical treatments influencing in different ways their immune reactivity, and drew thereupon conclusions not on the quality of each study analyzed but trying instead to assess the overall number of deviant studies.

Scientific intuition says that, just as a judicial sentence should be concerned with which individual defendant is found guilty or innocent instead of trying to control the overall number of incorrect verdicts, we should try to draw the proper conclusions from individual studies.[38] Their knowledge claims did not stand the test of time: The usefulness of serological measurements, which cannot possibly be assimilated to an antigen-detection test, was demonstrated ad absurdum with an immediate surge of unexpected TB-cases, to the detriment of the patients abruptly deprived of them.

The denial by the WHO of access to blood tests able to demonstrate the positive activity of drugs in immune-depressed patients under treatment, and thus predict the outcome, would be interpreted under various legislations as a refusal of assistance to a person in need.


  Conclusion Top


Janet Cornwall observed in 1997 that: “For the sake of return on investment and for the justification of huge public subventions and lavish expenditures on research and development, the management of the TB problem has chosen to ignore the reality of the situation and the urgency of solutions sensibly adapted to its needs[9] I have shown the numerous deficiencies that the fight against TB endured since the end of World War II, which led to the current disaster. This callous opportunism and disdain for ethics are at work today.

On January 9, 2014, Dr Shyamsunder Panchavati posted on the Linkedin group “Healthcare India:” Ethics take a back seat, as opportunism goes into overdrive and leads from the front). He remarked that “there is a huge possibility of medication or diagnostics being advised disproportionate to the need, and people at large feel that is what is happening.” Dr. Ashok Khandelwal confirmed on February 23 on the same site that the Health Care provider orders unnecessary medical tests. Abundantly produced comments on this discussion strengthen the case. On February 2014, the Indian Journal of Medical Ethics enumerated several breaches of ethical principles committed by the RNTPC.[5]

The recommendation by WHO and imposition by the Indian ministry of Health of the Xpert/RIF diagnostic instrument is such a huge possibility of diagnostics being advised disproportionate to the need. The instrument costs US $ 17,000 or more, the cartridges cost US $60.00 and a 3-year warranty may cost as much as US $18,500–20,950 for the GX XVI 16. The Treatment Action Group observed in an open letter Re: ”Cartridge prices, extended warranties and business in Russia and the People's Republic of China,” sent on 6 January 2004 to Cepheid, the maker of this instrument: ”We are concerned that machines and cartridges are now subject to extortionate prices.”


  Summary Top


Diagnostic tests based on the detection of the pathogen, principally in sputum, have their use but need to be completed with the detection of asymptomatic cases and the monitoring of the immune status of the treated patients, followed by the application of immune-stimulating products to those patients who show a need therefore. In addition, the continuing use of an iatrogenic vaccine and of immunosuppressive drugs defeats the purpose.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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