|Year : 2018 | Volume
| Issue : 2 | Page : 87-93
Failing the public health: The ban of tuberculosis serology and the WHO
Department of Research, Parabolic Biologicals, 1320 Beauvechain, Belgium
|Date of Web Publication||14-Jun-2018|
Prof. Roland Maes
Parabolic Biologicals, Rue De L' Ecluse, 2, 1320 Beauvechain
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Maes R. Failing the public health: The ban of tuberculosis serology and the WHO. Biomed Biotechnol Res J 2018;2:87-93
| Introduction|| |
The policy applied by the WHO to fight tuberculosis (TB) is a herd medicine approach: “find the bug, stamp it out and vaccinate the population.” The latest report published in the newspaper “The Hindu” dated March 26, 2018, on TB burden in India says about 1.8 million cases are being treated of which 450,000 are drug-resistant cases. As late as August 1, 2017, “1 Indian dies of tuberculosis every minute” and tuberculosis kills one person every 18 s, worldwide.
TB is handled today with the concepts that were in force during the 19th century, with appalling results.
- The Bacillus Calmette–Guérin (BCG) vaccine against tuberculosis had been shown in 1927 to be inadequately inactivated and iatrogenic. The WHO discovered in 1948 that the BCG it applied in Finland and Denmark favored the spread of TB. Despite this evidence, the French Ministry of Health + WHO recommended in 1950 the vaccine for worldwide application and it is still in use today as sole vaccine against TB. The serology allows a monitoring of the production of antibodies by vaccinees and allows a verification of the protection the vaccine lends.
- A number of anti-TB drugs were elaborated by various pharmaceutical companies after World War II. Yet, the WHO recommended a Standard Operation Procedure that retained only 4 drugs, plus streptomycin for resistant cases. This policy stopped forthwith all drug development for the subsequent 60 years  and favored the rise of drug-resistant TB strains. These drugs are powerful, bordering to extremely harmful [Figure 1]. In March 2018, the TB action group increased the number of drugs for drug-resistant TB cases: Kanamycin, prothionamide or ethionamide, high-dose isoniazid, moxifloxacin or gatifloxacin*, clofazimine, pyrazinamide, ethambutol, i.e., seven drugs during 10–12 months. These drugs create havoc.
Monitoring of the antibody production by the patient applied during such a treatment will considerably improve the prognostic. Persistent absence of IgG/IgA antibodies during treatment is a strong indication that the applied drugs, even if able to wipe out the antigen, have not succeeded in restoring the immune capacities of the treated patient, who is prone to relapse.
- Attention given to a TB patient's natural humoral immune defenses, impacted by undernourishment, pollution, hygiene, foul water, or other crippling agent, is still claimed, against all sound knowledge of mammalian immunology, to be unimportant. An immune-therapy based on Mycobacterium vaccae an immune modulator boosting the production of nitric oxide, another promoting the multiplication of lymphocytes and platelets, a serological blood test allowing the monitoring of the IgG, IgM, and IgA classes of antibodies, were all scorned and dismissed.
|Figure 1: Cutaneous effect of streptomycin, isoniazid, and thiacetazone on an HIV-positive tuberculous woman observed 3 weeks after the beginning of the treatment (Clinical tuberculosis. Ed Davies, Chapman and Hall Medical 1994)|
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Warnings of the looming debacle were abundantly given. Twenty-one years ago, Janet Cornwall observed, in 1997, that the reason for the failure was the refusal to use existing means compounded by the corruption, greed, and ineptness of the TB-actors anxious to earn profits incommensurate with the health benefits they were supposed to provide. I summarized the whole of the TB problem in a book entitled “Is Tuberculosis our new challenge? Reality check on a lost war and a new approach to fight Tuberculosis,” published in 2016 by Lambert Academic Publishing, and available at More Books.
In this communication, I contest the motives that induced WHO to recommend not to use blood tests for TB.
| Development of a Blood Test for Tuberculosis|| |
Several investigators attempted to develop a blood test for TB. To this end, they used a range of antigens, going from crude extracts of TB – as tuberculin – to purified antigens of different types, i.e., proteinic in nature or else glycolipids. All encountered the same drawback: all antigens tested captured antibodies among healthy people and among patients suffering from other ailments than TB. In addition, a severe lack of sensitivity was noted, with some TB patients showing a high level of antibodies while others had none or nearly none. The immense majority of the investigators abandoned their efforts for these reasons.
Harboe et al. used antigen 60 as capture antigen and developed with it an artisanal blood test in 1977. They observed a range of sensitivities among tuberculoid leprosy, lepromatous leprosy and TB patients with some patients very positive and others devoid of antibodies (deficient sensitivity), and positive cases among healthy controls and medical students (deficient specificity) [Figure 2].
|Figure 2: Radioimmunoassay of tuberculosis and leprosy patients and four control groups. AHRI stands for healthy staff members of Armauer Hansen Research Institute|
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Using the same antigen, I developed a blood test suitable for general use. It was applied in 1990 by Wirrmann. He found out that some cashiers of a supermarket, and only these, not the employees shielded from contact with customers, were with low levels of IgG mycobacterial antibodies. Wirrmann thus explained that the origin of the positive cases observed among healthy people was their increased risk of exposure to infection, for example, the group of Norwegian medical students and cashiers in a supermarket. He also showed the usefulness of serological tests to detect these latent infections. Kaustova, analyzing the humoral immune status of cancer patients, arrived at the same conclusion in 1996. A year later, I published the preliminary results obtained by the blood test applied to newborns and elderly, to pulmonary and extra-pulmonary TB (PTB) as meningitis, to primo-infected and active disease, to healthy people, to people at risk and to people suffering from other ailments, all with excellent results. [Figure 3] shows the results obtained with PTB and tuberculous meningitis, which is very difficult to diagnose because sputum is not available and symptoms are difficult to interpret. The IgG serology allows their diagnosis.
|Figure 3: Scatter of IgG values observed in cephalo-rachidian liquid and serum. Each point represents the positive end-dilution point reached by a patient|
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I did not suspect at that time the vigorous immune-depressive activity of the pathogen and attributed the lower levels observed in the confirmed tuberculous meningitis patients to other factors: “Some patients have a low level of antibodies. This anergy may be traced to the formation of immune complexes or else a weak avidity of the specific antibodies produced”. At the end of the resume, and also in the title, I clearly announced that this serology is not suitable as a diagnostic for the detection of active tuberculosis infection.
| The French Blood Test|| |
Philippe Lagrange, working for the Pasteur Institute, published his blood test results in 1995. His stated objective was to replace the smear test with the serology, as announced in the title and also in the statement pronounced at the end of the introduction: “To be of benefit, a serodiagnostic test for pulmonary tuberculosis should be more sensitive and specific than, as well as complementary to, sputum microscopy. The diagnostic value of the EIA were compared with those of the direct smear test”.
The [Figure 4] ruins this hope: negative cases are observed among tuberculous patients and positive cases among controls. These results rejoin the observation made using the antigen 60 as capture antigen.
|Figure 4: Levels of IgG antibodies directed against diacyl trehalose (a) and glycolipid (b)|
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This will to use the blood test solely as a replacement of the smear test for the diagnostic of symptomatic pulmonary tuberculosis, this refusal to admit latent infections in healthy people at risk and in patients suffering from well-defined diseases , flared up again in the meta-analysis published on August 9, 2011 by PLoS Medicine, which led to the ban of blood tests in India.
| The Meta-Analysis Ordered by the Who|| |
This huge study (18) was mathematically rich, but intelligence-poor in that the authors insisted to apply the serology as a substitute for the smear test. The last sentence of the introduction, page 2, states: “Specifically, we were interested in evaluating the use of a serological assay as a replacement test for, or an additional test after, smear microscopy”. On page 8, “Grade evidence profile “, the central question is asked again: “Should commercial serological tests be used as a replacement test for conventional tests such as smear microscopy in patients of any age suspected of having pulmonary tuberculosis?”
Fifteen years earlier, it had been clearly stated that this is not possible because the production of antibodies is hampered by the immune depression induced by the pathogen  and some drugs, and depends on the antigenic load: the heavier the load, the lower the antibodies' level in most untreated patients, hence, the impossibility to use the test in a banal diagnostic manner. In the left column of page 14, the authors state: We did not identify studies with the specific aim of detecting the value of serology over and above conventional tests such as smears.” Of course not, because such an equation makes no sense: a test detecting antigens does not equate with a test detecting antibodies. They have different functions.
On the same page, they conclude: “In conclusion, published data on commercial serological tests produce inconsistent and imprecise estimates of sensitivity and specificity, and the quality of the body of evidence on these tests remains disappointing….”
The same journal published an article by Dowdy and Pai stating the prohibitive cost of the serology in India. An international group of experts endorsed these conclusions in Geneva on July 22, 2010 and the WHO group of experts recommended the ban of serology in 2011. The Indian Ministry of Health followed this WHO recommendation in 2012.
| Was the Ban Justified?|| |
I wrote in 2016 “a critical appraisal of the ban” and drew the following conclusion:
“Reduction of the TB diagnostic problem to antigen detection largely contributes to the current failure to eradicate this disease. If publications on humoral responses are given credit, evaluated properly and integrated, the following conclusions are drawn:
1. The humoral immune response to TB is just as important as the cellular one, and is subject to partial to total suppression by the pathogen. The depression may independently influence production of IgG, IgM, or IgA anti-TB antibodies in different patients. A heavy bacterial load may correspond to a negative serology.”
In 2017, Prof Harinath published an editorial  that spoke in favor of the Indian people suffering from tuberculosis and leprosy, many of them living in rural areas. He asked: “Then, may I ask, why the hurry to ban serological tests and give the impression that serology itself is not useful for TB detection?… Based on meta-analysis by Pai and associates, WHO banned serodiagnostic kits…. The announcement of blanket ban was done without seminar or discussion in different scientific forums.”
He further denied that serological tests are expensive in India. To make acceptable the outrageously expensive Xpert/rif test, the authors of the cost/effectiveness analysis of the serology  evaluated the serology cost based on the simultaneous use of the IgM, IgG, and IgA classes applied jointly for the monitoring of a patient consulting, although it had been abundantly demonstrated that only IgG monitoring is useful in the vast majority of the cases. The authors multiplied unduly by a factor 3 the cost of the serology. Harinath further pointed out that a single test will not answer all the questions posed by clinicians and Public Health Agents: “Probably one test may not answer the diagnosis of active PTB and extra-PTB of clinical (latent, fresh, chronic, relapse, resistant, and pauci-bacillary cases) and public health interests.” Indeed, since inhibition of synthesis of IgG antibodies may occur while IgA antibodies are not, and vice-versa, attentive clinicians observing an absence of IgG antibodies although the symptoms suggest TB, will confirm the diagnostic with an IgA search. IgM antibodies are searched in infants presumably suffering a primo-infection, and a search for IgM antibodies is also recommended for the household of a newly diagnosed TB case. The Association of Diagnostic Manufacturers of India will detail these applications infra.
| The Two Signal Deceptions Committed by the Authors of the Meta-Analysis|| |
“A critical appraisal of the ban”, went through all the errors made in this meta-analysis, and stressed:“the authors of the meta-analysis report results that are sometimes incorrect, drew conclusions on incomplete data, removed publications from their study using dubious reasons.”
The meta-analysis mentions false-positives and false-negatives, although they are not false, as I showed supra. These errors were committed again by the independent tuberculosis experts and by the WHO experts. All they had to do to avoid these errors was to read the reference 16, published in 1991, and reference 26, published in 1994. The results obtained by Zou et al. are summarized in [Figure 5].
|Figure 5: IgG and IgA serological analysis in control and tuberculous individuals|
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Could they have in good faith missed them?
The meta-analysis asserts (methods and findings): “we searched multiple databases for papers published from 1 January 1990-30 May 2006, and in this update, we add additional papers published from that period until 29 June 2010.”
They thus missed Harboe et al., published in 1977, but could not have missed investigations published on year 1990 and later. They listed all the papers that they consulted and rejected for diverse reasons, but they did not list the publications mentioned here above. You can consult the list of the publications consulted and rejected on page 60 (annex 6) of the report published on July 2010 by the expert Group.
In these not-mentioned publications, we find:
- Maes 1991, section “summary”: the test should not be considered to be a diagnostic tool by itself, and concludes: “The demand that a serological test (evaluation of the specific immune status of the patient) competes closely with microscopy (presence or absence of the etiological agent) is unrealistic because it assigns to them the same function, which they do not have”
- What about the results obtained by Zou et al. in 1994? [Figure 5] gives results that confirm what was stated right from the beginning, repeatedly: the serology generates a new concept but is not suited as a banal diagnostic test substitute for a smear test applicable to patients consulting.
A second considerable error in the management of the data the authors of the meta-analysis had collected was their use of statistics relying on P value:
“For each study, the sensitivity and specificity of the serological test along with the 95% CIs were calculated “(left column on page 4).
P value (P stands for Probability) applied for the evaluation of the sensitivity and specificity, and the interval of confidence (CI 95%), spot the values that appear abnormal and reject them. Yet, in serology applied to TB, the values found in TB-certified patients range from zero to strongly positive while positive cases are detected among some non-TB patients and healthy exposed groups. P value and CI 95% will deem these ranges of values abnormal; hence, they will be rejected. All this meta-analysis resting on P value and CI 95% is impertinent, frivolous and meaningless, as stated by the American Statistical Association.,
The American Statistical Association warned that the reliance on statistical analysis using P value to issue policy directives is fundamentally erroneous: “The society's members had become increasingly concerned that the P value was being misapplied in ways that cast doubt on statistics generally. In its statement, the ASA advises researchers to avoid drawing specific conclusions or making policy decisions based on P values alone”. This is however what the WHO, counseled by Mc Gill University and other institutions, did.
It is often said that scientists delude themselves by unduly applying P value to issue policy directives. However, the authors of the meta-analysis, the international TB experts and the WHO TB experts did not delude themselves but deluded their audience, i.e., the mycobacterial community in general and the Indian Ministry of Health in particular: Nandini Dendukuri, Ian Schiller and Madhukar Pai, who coauthored the meta-analysis, are in the Department of Epidemiology, Biostatistics and Occupational Health, McGill University. They could not possibly have ignored this warning which was first given by Goodman in an excellent expose of the problem in 1999 well in advance of the meta-analysis.
| The Response of the Association of Diagnostic Manufacturers of India|| |
In a document addressed to the Indian Ministry of Health, the Association of Diagnostic Manufacturers of India asserts:
- On page 2: the clinical community continues to use the tests successfully and its use has helped diagnose and manage a large number of cases of tuberculosis especially in resource poor settings.
- On page 3: The tests are regularly used by clinicians for two major clinical scenarios:
- Early diagnosis in smear-negative pulmonary tuberculosis: Wherein the tests are used to confirm clinical suspicion of tuberculosis prior to eventual sputum smear positivity thereby saving precious treatment time
- Early diagnosis in extra-pulmonary/occult/pediatric tuberculosis cases: Wherein, the inability to access site-specific specimens for conventional smear, culture or PCRs; leaves the only available option of a serum test to possibly indicate the illness.
- On page 4: Many of these tests have played a stellar role as adjunct to conventional tests in the diagnosis of tuberculosis. This fact is confirmed by the popularity of these serological tests in the Indian diagnostic scenario.
Another document  answers the meta-analysis:
- Meta-analysis: None of the serological tests reviewed could replace smear microscopy, a finding consistent with those reported in a previous systematic review.
- Counterview: None of the tests are meant to replace smear microscopy. The question is, when the smear is negative and clinical suspicion persists, what test to opt for?
What else must be added to defend the serology case? And why did the Indian Ministry of Health pay no heed to this vibrant plea emanating from the civil society, as pointed out by Harinath” The ban on serology provoked in India a disaster from which the country does not recover.
| The Fundamental Reason for the Ban|| |
The interdiction of serology was governed by the will to impose the Xpert/rif test, which evaluates the presence of tuberculosis antigens (nucleic acids).
Harinath  notes: “There appears to be some plan, by intent or accident by commercial interests to promote the molecular assay “XpertMTB/RIF” and remove the opposition from the use of affordable serodiagnostics in rural areas.” It was by intention.
This test is deficient. That the “XpertMTB/RIF” study had been subjected to a manipulation of the conclusions is apparent from the following three studies conducted at the All India Institute of Medical Sciences, New Delhi, India, under the direction of Prof. Singh:
In March 2014, the Institute published: Of 62 rifampin-monoresistant samples by Liquid Probe Assay, 21 (33.8%) were found susceptible to rifampin by Xpert MTB/RIF.
This means that one-third of the drug resistant cases were misdiagnosed.
In August 2015, the Institute published: 162 pleural fluid samples from patients with probable tuberculous pleural effusion were tested by the Xpert MTB/RIF assay and ….a culture system. Of these, 43 (26.5%) were positive in the culture, and 23 (14.2%), in the Xpert MTB/RIF assay. The sensitivity of the Xpert MTB/RIF compared with the culture was 54.8%.
This means that nearly half of the TB-positive cases were free to go home unattended.
In September 2016, (online and Print issue in Jan 2017), the Institute and the Dr. Ram Manohar Lohia Hospital, PGIMER, New Delhi, India, published jointly: Sixty seven patients suspected of probable/possible abdominal TB were tested by culture and by Xpert MTB/RIF assay. Seventeen (25.4%) were culture positive while 12 (17.9%) were detected positive by the Xpert MTB/RIF assay.
This means that a third of the TB patients were free to go home untreated.
The evident gap between this huge healthcare expense and the performance of the Xpert MTB/RIF assay makes manifest our vulnerability to propaganda.
| The Blood Test Developed at the All India Institute of Medical Sciences, New delhi in 2017|| |
Prof. Singh also developed a blood test based on recombinant antigens.
In the following review, I comment on his results.
Here is the main figure [Figure 6] of Singh's results:
|Figure 6: Scatter plots of enzyme-linked immunosorbent assay results using our novel recombinant antigens and the reference antigens. Recombinant antigens assayed are rSS1, rSS2, rSS3, rSS4, rSS5, Esat-6 and 38 kDa Ag). The serum samples used were from of healthy controls, diseased controls, tuberculosis patient (pulmonary tuberculosis, extra-pulmonary tuberculosis, and HIV-tuberculosis) and multidrug-resistant-tuberculosis. The scatter plot indicates the antibody level per subject analyzed. A dotted horizontal line is included to show the cutoff value for individual antigen|
Click here to view
The results he obtained are identical to all the other blood tests devised before him: in all cases, negative results are observed among documented TB patients, and positive cases are observed among controls.
| Conclusion|| |
The WHO insists on the need to use adequate tuberculous antigens to obtain sensitivity and specificity rendering the blood test able to replace the smear test for the diagnostic of active pulmonary cases. This demand is sophomoric. Singh isolated five recombinant specific TB antigens; however, these were similar to those previously used, and could not be better, as I abundantly explained, because they detect latent infections, deviously said by the WHO to be false positive although they are not, and betray the abrogation of the humoral immunity induced by either the pathogen or else the drugs, or both, deviously said by the WHO to be false negatives. Ignoring the WHO, responsible clinicians should exploit serology for diagnostic and prognostic purposes but they would do well to also integrate immunotherapies (e.g. M. vaccae, NO synthesis, and lymphocyte multiplication) within the means they currently apply to win a war that they may in all likelihood otherwise lose.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]