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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 3  |  Page : 140-146

Evaluation of the therapeutic, diagnostic, and prognostic means currently applied to counter the surge of tuberculosis


Parabolic Biologicals, Rue de l' Ecluse, 2, 1320 Beauvechain, Belgium

Date of Submission15-Apr-2019
Date of Decision15-May-2019
Date of Acceptance11-Jun-2019
Date of Web Publication10-Sep-2019

Correspondence Address:
Prof. 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/bbrj.bbrj_71_19

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  Abstract 


The bacilloscopy and culture, the skin test, the BCG vaccine and the discovery of five powerful anti-TB chemicals were assumed sufficient to win the war on TB after World War II but the enigmas and paradoxes uncovered during treatment were given no heed and the humoral immune capacities of the patient were totally ignored. TB resurged at the turn of the century, with a vengeance. The patient suffering from a TB infection mounts a humoral immune response that is as important as a cellular immune reactivity and is useful as a prognostic of treatment outcome and as a diagnostic of latent infections. The anti-TB chemicals are expensive, highly toxic and some destroy the immunocytes of the patient. Their use may provoke a drastic plunge of antibodies' production, which leaves the patient deprived of immunological resources and exposes the successfully treated patient to relapse. The monitoring of the IgG class of anti-TB antibodies synthetized by a subject suffering from a latent infection prone to convert allows the detection of these cases. At the onset of diagnosed cases, the level of these antibodies is sometimes very low, indicating an immunodepression generated by the pathogen. The monitoring of the rise of their production during treatment permits a control of the efficacy of the treatment. A food supplement consisting of RNA oligonucleotides is available, whose property is to stimulate the multiplication of leucocytes and platelets.

Keywords: Chemotherapy, immunotherapy, latent cases, serology, tuberculosis diagnostic


How to cite this article:
Maes R. Evaluation of the therapeutic, diagnostic, and prognostic means currently applied to counter the surge of tuberculosis. Biomed Biotechnol Res J 2019;3:140-6

How to cite this URL:
Maes R. Evaluation of the therapeutic, diagnostic, and prognostic means currently applied to counter the surge of tuberculosis. Biomed Biotechnol Res J [serial online] 2019 [cited 2019 Nov 20];3:140-6. Available from: http://www.bmbtrj.org/text.asp?2019/3/3/140/266563




  Introduction Top


The biological properties of tuberculosis (TB) and bacillus Calmette–Guérin (BCG) strains, of tuberculin and of immunotherapeutic agents, differ in substantial ways from the properties currently attributed to them.[1] The present review analyses the efficiency of the drugs newly recommended in addition to the five drugs imposed during 60 years by the standard operation procedure (SOP) and verifies the adequacy of the diagnosis and prognosis policies currently applied. It shows that new drugs are a mere pursuit of a policy that proved disappointing and that asymptomatic subjects on the verge to convert have antibodies, whose monitoring improves the diagnostic. A blood test (IgG) of patients under treatment improves the prognostic. Immunodepressed patients can benefit from the stimulation of the multiplication of lymphocytes destroyed by the chemotreatment applied.


  Background Top


Diagnostic

In 1882, Robert Koch observed the presence of the stained tubercle bacillus in sputum under the microscope (bacterioscopy). In 1908, Charles Mantoux improved on the old tuberculin as an effective intradermal test for diagnosing TB infection. Since that time, diagnosis relies nearly exclusively on the detection of the pathogen in a broad sense (X-rays, bacterioscopy, lipoarabinomannan [LAM] test, interferon [IFN] test, nucleic acid amplification, culture, etc.) and on the delayed hypersensitivity observed by a skin reaction to tuberculin.

Treatment

The disease receded in the 20th century. This improvement was attributed to the vaccination of the population worldwide by the BCG vaccine and to a vigorous chemotreatment of the symptomatic patients, relying on 5 drugs: streptomycin in 1944, isoniazid in 1952, pyrazinamide in 1954, ethambutol in 1962, and rifampicin in 1963. This regimen was imposed worldwide as a SOP and remained unchanged for 6 decades. New drugs were introduced these last years with the aim to stop the obstinate progress of TB first observed in France in 1992,[2] and the concomitant rise of drug-resistant cases in 1993.[3]

Paradoxes and enigmas

The existence since 1947 of a simple and apparently efficient chemotherapy induced the TB actors to ignore the dilemmas and paradoxes posed by the therapeutic strategy applied. A vaccination with a BCG strain did not always protect against infection.[1] A drug shown activein vitro may be noneffective in vivo. Atransient worsening of pulmonary tuberculous lesions may appear at any time during treatment.[4],[5] Five percent or more of the treated patients remained unhealed.[3] Attention to these paradoxes was drawn in 1996, and an immunodepression generated by the drugs used to combat the pathogen's multiplication was postulated,[6] in addition to the immunodepression generated by the pathogen. In 1994 and 1998, mention was made of nontuberculous infections in children with cancer[7] and in transplant recipients.[8] In 1999, the need to evaluate the immune status of patients was emphasized.[9]


  The Efficiency of Drugs Top


The standard operation procedure

Once streptomycin, isoniazid, pyrazinamide, ethambutol, and rifampicin were discovered, the SOP restricted during 6 decades the drug regimen to these 5 drugs at their maximal tolerated concentration without allowance for change, which excluded de facto further research and development of new drugs because the newly developed drugs would find no outlet.

This treatment regimen was consistently beneficial, with treatment failure occurring in 5%–10% of cases but which rose sometimes to 40%. In the worst case, up to 44% of the patients turned resistant to one or more drugs and 30% resistant to both isoniazid and rifampicin.[3]

Multidrug-resistant tuberculosis

To meet the surge of multidrug-resistant (MDR)-TB in the immediate term, the “Stop TB partnership” and the WHO advocated bedaquiline, clofazimine, and delamanid on August 22, 2018, in addition to the regular drugs.

Bedaquiline

The drug was shown to elicit mycobacterial drug resistance in 2014[10] and to associate with a disquieting number of dangerous side effects. These were waved away in 2015 in view of the urgency of the problem.[11] The efficacy of a regimen is currently monitored by culture conversion at 2 months (8 weeks). Applied to bedaquiline, the proportion of culture conversion at week 8 was 47·6% in the bedaquiline group and 8·7% in the placebo group, which is good. At week 24 (about 6 months), it was 81% for the bedaquiline group versus 65·2% for the placebo group. Thus, 35% of the placebo group remained infected and 19% of the patients treated in addition with bedaquiline remained infected. The recommendation of bedaquiline for the treatment of MDR-TB was heralded with abundant dithyrambic approval, and the reduction of patient's death obtained by its use was amply emphasized. The cost of this mitigated improvement was crippling multiple side effects, constant expensive monitoring, and death.

Drug side effects linked to bedaquiline include liver toxicity and a potentially serious disturbance in the heart's electrical rhythm. Bedaquiline's long half-life noted by the WHO in 2015[12] means that these and other side effects pose a risk to patients after discontinuation of the therapy. The American Centers for Disease Control warned in 2019: “pooled data from 5 cohorts of patients treated with bedaquiline suggest that this drug is effective and safe,” and concluded “The overall certainty of the evidence is very low.” The words “suggest” and “very low” are tellingly over-cautious.[13] It mentioned a publication of 2014 that reported deaths due to the prolonged use of bedaquiline.[14] In 2015, the BMJ published a note made by Spanish clinicians who remarked that “for every 3.5 cured patients with bedaquiline, one death occurs.”[15] The reports of deaths in excess due to bedaquiline continued to appear.[16] In a randomized, placebo-controlled trial, 10 of 79 patients in the bedaquiline-containing group died (13%) versus 2 of 81 patients in the placebo group (2%). Most of these deaths occurred months after patients received their last bedaquiline dose, but bedaquiline's long half-life means that the drug's possible contribution to the patient deaths cannot be excluded.

Clofazimine

It is known since 1950 as a bacteriostatic antituberculous agent. The drug generates crippling side effects. It was shown in 2014 and 2017 that some MDR-TB patients without prior clofazimine or bedaquiline exposure demonstrated preexisting resistance to these drugs, presumably associated with prior TB treatment.[17],[18],[19]

Delamanid

WHO recommended the use of delamanid for extensively drug-resistant-TB treatment in 2015.[20] An examination of the data given in that communication[20] reveals that 17 patients were treated with delamanid for 6 months in addition to the regular regimen. The failure of the treatment at 24 months amounted to 35%. This is not good.

Conclusion

A single treatment for MDR-TB in the USA costs $294,000 in 2018. This treatment is unworkable in rural areas due to unbearable costs, to crippling side effects (vomiting, liver damage, eye damage, and sometimes death), expensive monthly controls during follow-ups, drug cross-resistance, and a difficulty in tracing patients who escape the harsh treatment as soon as recovery is noticed. It is neither feasible nor realistic to apply it in those countries that need it most. These drugs are merely an extension of former approaches, which have proven disappointing.


  Diagnosis and Prognosis Top


The WHO recommended sputum smears, Xpert/resistance to rifampicin (RIF) test, line probe assay (LPA), and liquid culture for diagnosis. To these, the WHO added an interferon test in 2015 and a LAM test in 2017. It banned blood tests in 2011.[21] The Indian Ministry of Health deemed serology a malpractice in 2012.[22]

The Xpert/resistance to rifampicin test

A WHO policy guideline recommends the Xpert Mycobacterium tuberculosis (MTB/RIF) test be used as an initial diagnostic test in individuals suspected of MDR- or HIV-associated TB.[23] However, a negative Xpert MTB/RIF result does not rule out TB.

According to this guideline, the sensitivity of the Xpert test for smear-positive TB is 98%, which is of no interest. For smear-negative but culture-positive TB, the sensitivity drops to 68%, but Cochrane announced[24] a sensitivity of 88% for this group and of 86% among individuals with HIV infection. This improvement from 68% to 86%–88% still means that 12% of the smear-negative but culture-positive cases go undetected. In another meta-analysis of 15 studies involving 4768 respiratory specimens of 3640 children, the sensitivity of the Xpert MTB/RIF as shown in some studies was 79.9%–98%, with higher values recorded for respiratory than nonrespiratory samples.[25]

However, several studies dispute these optimistic evaluations. They demonstrate that the test performs very poorly in paucibacillary and extrapulmonary cases. Rufai et al. showed in 2014, 2015, and 2017 that the test performed roughly at a 50%–70% sensitivity in comparison with LPA and culture.[26],[27],[28] Reither et al.[29] obtained in 2015 in a low-resource, high TB burden multicenter study, only a 68% sensitivity. Bacha et al.[30] demonstrated in 2017 a poor performance at 8% sensitivity among undernourished children in Tanzania, only half as well as culture. A tertiary care hospital located in Mumbai confirmed in 2018 the inadequate performance of this test and recommended it solely as a complement to culture. It deplored the incapacity of the diagnostic to detect infections by nontuberculous mycobacteria.[31] The poor sensitivity reported in these studies may be a result of variation in resistant strains of MTB Rufai et al.[26] demonstrated in India, where a significant number of rifampicin resistance was not detected due to genetic mutations in the P533 L region of the E probe in up to half of the cases tested.

The interferon test for detection of latent infections

The WHO recommended an interferon test to detect latent infections.[32] The IFN gamma (γ) release assay (test) consists in drawing one cubic centimeter of whole blood from the individual and incubate the sample during 24 h at 37°C in the presence of at least two peptides specific for MTB. These peptides stimulate the production of IFN-γ by the T-cells present in the blood. The plasma is thereafter isolated, and the presence of IFN-γ assessed either by an enzyme immune essay or by a gold reagent.

The IFN test has its uses but is ill adapted to those countries where cheap diagnostic tests are most needed. The interferon test is a very costly substitute to a much cheaper method of assessment of latent infections, obtained by monitoring the humoral immunity. The Anda TB serological test is available since 1989,[33] was shown useful for the detection of latent infections in exposed groups in 1989[34] and 1990[35] and among some cancer patients in 1995, not necessarily TB.[36] The ban of the TB-serology by the WHO in 2011 is not understandable on scientific and medical grounds.[21]

The lipoarabinomannan test

The WHO added this test to the diagnostic panoply in 2015.[37] It is a cheap lateral flow test monitoring the presence of LAM in the urine and can be used with great facility in the field. The WHO recommends its use restricted to AIDS patients with a CD4 count inferior to 100. The considerable advantages that this test presents for use in the field are offset by its very poor sensitivity and the restriction of use imposed.

Serology

The serology has been the object of a violent denigration[38],[39] and was banned by the WHO and India. This policy forbade the timely detection and treatment of latent TB cases on the verge of coming out, and forbade its use in rural areas, where it is most needed.[40] It also prevented the monitoring, via antibodies' surge, of the efficacy of drugs on patients under chemotreatment. This monitoring of IgG antibody production is much cheaper and efficacious than a culture conversion done after 8 weeks of treatment. Most patients who consult have low levels of specific antibodies due to pathogen-induced immunodepression, of which one, two, or all three IgG, IgM, and IgA classes surge during a successful treatment.[41],[42],[43],[44] If the chemotreatment eliminates the pathogen without allowing the antibodies to surge, the chemicals presumably also wiped out the antibody-producing lymphocytes.[45] A boost of lymphocyte multiplication is imperative if one wants to avoid relapse.

The following two figures[40] illustrate these courses of events.

[Figure 1] monitors the output of IgG (▴), IgM (*) and IgA (◾) antibodies against A60 in a patient from 1 month after the beginning of the treatment, for 1 year. After a month of treatment, the level of the IgG and IgM antibodies is still low and those of IgA nearly absent. The IgA titers remained low throughout the treatment, but the titers of IgG and IgM raised, to return to base levels only after 12 months of treatment.
Figure 1: Immunoglobulin G, immunoglobulin M, and immunoglobulin A antibodies' production against A60 by a patient under chemotreatment

Click here to view


[Figure 2] shows a first disease onset, followed by relapse: at first entry, the level of all three antibodies' classes is below cutoff, indicating a severe immunodepression inflicted by the pathogen. All three antibodies' classes enjoy an increased production due to the chemotreatment, that lasted only 2 months for IgM (*) while a steep decline of the IgG (◾) and IgA (▴) antibodies' production occurred after 5 months of treatment, indicating an immunodepression inflicted by the drugs. Relapse occurred 18 months later, with a surge of antibodies similar to the one observed during the first treatment, indicating the absence of memory cells. This patient would have benefited from an immunotherapy consisting in the stimulation of the multiplication of lymphocytes.
Figure 2: Follow-up of a patient under treatment, who suffered a relapse

Click here to view



  Special Applications Top


Serological diagnostic of tuberculosis in children

The need for diagnostics that search for “characteristic markers” or “bio-signatures” elaborated by the organisms to detect TB in other body samples beside sputum, especially among children who often have poor expectorating ability and a predisposition to disseminated TB, was expressed in 2015.[46] The serology fulfills some of these needs.

Child primary TB presents symptoms different from adult secondary TB. A serological search of antibodies helps in the diagnostic. Some early authors found the test defective while others found it useful, no doubt because of a better understanding of the pathological process.[47],[48],[49] Khalilzadeh et al. stated in 2001:[50] “the sensitivity of serological diagnosis of A60 antigen is 77.3% higher than culture (51.2%) and smear test (43.1%). Therefore, use of ELISA tests for the detection of anti-A60 antigen is a simple and rapid diagnostic method, which can greatly facilitate the diagnosis of TB in children.”

Tuberculous meningitis

The diagnostic of tuberculous meningitis in pediatric age[51] is difficult in view of the immunosuppressive properties of the pathogen and the poor synthesis of antibodies. [Figure 3] presents the detection of IgG antibodies in serum and cerebrospinal fluid (CRL) of suspected meningitis, of diagnosed meningitis and of pulmonary TB.[52] The output of IgG antibodies in meningitis cases is much lower than in pulmonary TB cases and is detected at much lower dilutions. In addition, the impact of the immunodepression of the pathogen is visible among the confirmed cases versus the suspected cases. Finally, the level of antibodies is higher in the CRL than in the serum.
Figure 3: Scatter of immunoglobulin G values observed in CRL and serum. Each point represents the positive end-dilution point reached by the patient

Click here to view


Leprosy

[Figure 4] illustrates the fact that the antigen 60 used as capture antigen is not specific for TB and can be used for the detection of leprosy cases.[52] Note that some controls present low levels of antibodies, indicative of an unapparent infection by either leprosy or TB.
Figure 4: Individual immunoglobulin G values in Senegalese tuberculous, leprous, and control populations. The control population shows a large number of unapparent infections

Click here to view


The usefulness of TB serology is so obvious that it is impossible to justify its ban on scientific grounds.

Proliferation of lymphocytes

Fragments of RNA extracted from the bacterium  Escherichia More Details coli inhibitin vivo the multiplication of the Shope fibroma virus and of the vaccinia virus.[53] Oligoribonucleotides restore rapidly and without danger the normal level of platelets and of circulating lymphocytes in the rabbit, when these levels had been drastically lowered by diverse chemotherapeutic agents used in anticancer therapies.[54]

[Figure 5] shows that human patients suffering from a lymphoma and under chemotherapy, treated at regular intervals with oligonucleotides, observe an increase in number of both neutrophils (a) and platelets (b) at each taking of the oligonucleotides.[55] Extracts from the bacterium E. coli. are unsuitable for human use. Extracts from baker's yeast are safe and classify the product as food supplement. It is presented lyophilized and taken under the tongue a day before and the 8 days following the chemotherapy. It is a food supplement that could considerably improve the prognostic of TB and leprosy patients.
Figure 5: Multiplication of neutrophils (a) and platelets (b) in a patient under chemotherapy receiving oligonucleotides

Click here to view



  General Conclusion Top


TB is an immunological chronic disease generated by poverty, unhealthy living conditions, and lack of adequate food nutrients: what one fails to eat is more important than what one eats;[56] food supplements that compensate for a poor nutrition are important. The detection of latent cases prone to convert is hampered by the excessive cost of the IFN-γ detection tool but can be realized by the monitoring of the presence of IgG antibodies. The drug treatment has its uses, but some drugs generate an immunodepression that can be countered by a food supplement stimulating the multiplication of lymphocytes. A monitoring of the production of IgG antibodies during treatment allows a control of the efficacy of the chemotherapy applied, but the bacterium is so universally well established, even among vaccinated infants who all showed IgM antibodies against purified protein derivative that contains factors of virulence,[57] that it is illusory to rely on chemotreatment alone to dominate it.

Considering the immense complexity of the TB problem, Harinath pleaded for an integrative approach.[58] Such an approach may considerably improve our prospects to finally master the disease: A vaccine based on M. chelonae (the Friedman vaccine) was shown effective and satisfactory. It can advantageously replace the BCG. An immunotherapy based on M. vaccae can be applied to resistant cases. Food complements based on uleine and oligoribonucleotides are able to stimulate in an unspecific way the immune capacities of the patients and are available. The serology is much cheaper than inteferon tests and allows the detection of asymptomatic cases prone to convert as well as the monitoring of the effectiveness of the drugs administered to patients. All these existing but neglected and even scorned approaches can advantageously be used in addition to the existing means currently applied.

Financial support and sponsorship

Nil.

Conflicts of interest

I developed the Anda-serological test[33] and the food supplement based on baker's yeast.[59]



 
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