[Show abstract][Hide abstract] ABSTRACT: Worldwide, there are nearly 10 million new cases of active TB and 1.8 million associated deaths every year. WHO estimates that one-third of the world’s population is infected with Mycobacterium tuberculosis (Mtb), forming a huge latent Mtb global reservoir. This renders the prospect of ever eliminating Mtb from the human race almost impossible. Several controversial issues regarding host-pathogen interactions and existing prevention and eradication strategies for latent Mtb infections need to be critically re-examined. In this viewpoint, widely held assumptions on Mtb latency and isoniazid monotherapy and chemoprophylaxis are challenged. We highlight the need for future research to resolve these issues and to develop evidence-based strategies for better understanding of equilibrium and escape of Mtb in the human body, eventually leading to global recommendations for elimination of the latent Mtb state through informed policy and practice. Until such strategies and policies are realized, WHO and TB experts will have to settle for global TB control rather than eradication.
Dans le monde, il ya près de 10 millions de nouveaux cas de tuberculose (TB) active et 1,8 millions de personnes en meurent chaque année, ce qui en fait l’une des plus importantes causes de décès. L’OMS estime qu’un tiers de la population mondiale est infecté par Mycobacterium tuberculosis (Mtb), formant ainsi un énorme réservoir mondial de Mtb. Ceci rend la perspective de l’élimination de Mtb de la race humaine presque impossible. Plusieurs questions controversées concernant les interactions hôte/pathogène et les stratégies de prévention et d’éradication des infections latentes de Mtb doivent être réexaminées de façon critique. Dans ce point de vue, les hypothèses largement répandues sur la latence de Mtb et la monothérapie/chimioprophylaxie à l’isoniazide sont contestées. Nous soulignons le besoin de futures recherches nécessaires pour résoudre ces problèmes et pour élaborer des stratégies fondées sur des preuves pour une meilleure compréhension de l’équilibre et de l’évasion de Mtb dans le corps humain, afin d’aboutir éventuellement à des recommandations globales pour l’élimination de l’état latent de Mtbà travers des politiques et des pratiques éclairées. Jusqu’à ce que ces stratégies et politiques soient réalisées, l’OMS et les experts de la TB devront se contenter du contrôle mondial de la TB plutôt que de son éradication.
A nivel mundial hay casi 10 millones de nuevos casos de TB activa, y 1.8 millones de personas mueren de esta enfermedad cada año, siendo una de las más importantes causas de muerte a nivel global. La OMS calcula que una tercera parte de la población mundial está infectada con Mtb, formando así un inmenso reservorio latente de Mtb. Esto hace que la posibilidad de eliminar algún día al Mtb de la raza humana sea casi imposible. Hay varios puntos controversiales sobre las interacciones huésped-patógeno y las estrategias existentes de prevención y erradicación de las infecciones latentes de Mtb deben ser reexaminadas con una visión crítica. En este artículo, se discuten asunciones ampliamente aceptadas sobre la latencia del Mtb y se plantean desafíos para la monoterapia con isoniazida y la quimioprofilaxis. Subrayamos la necesidad de realizar investigaciones futuras para resolver estos temas y desarrollar estrategias basadas en la evidencia para alcanzar un mayor entendimiento del equilibrio y escape del Mtb en el cuerpo humano, llevando eventualmente a recomendaciones globales para la eliminación del estado latente de Mtb mediante políticas y prácticas informadas. Hasta que se encuentren estas estrategias y políticas, los expertos en TB y de la OMS deberán conformarse con el control de la TB, más que con su erradicación.
Tropical Medicine & International Health 01/2011; 16(1):79-83. DOI:10.1111/j.1365-3156.2010.02665.x · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction
A diverse range of human diseases, including allergy, asthma, autoimmune disease, cancer and chronic neurologic diseases, notably multiple sclerosis and endogenous depression, is becoming more prevalent in industrialized countries. It has been postulated that environmental factors associated with improved standards of hygiene play a leading role in this process since the immune system seems to need extrinsic challenges for its proper maturation.
The inner world
An added dimension has now emerged—the impact on disease of the inner world, principally the numerous endogenous retroviruses (HERVs) within the human genome. Taking melanoma as an example, we propose a framework for understanding how a complex infectious and immunological background can induce or inhibit expression of a HERV-related disease process. The central role of a failure to induce or to maintain certain populations of self-specific CD8+ T-cells mediating immune surveillance, the expression of HERV-encoded peptides on affected cells and pathological mechanisms directly attributable to HERV proteins are discussed.
The presented concepts explain events preceding the clinical manifestation of diseases by several years and provide a rationale for the use of currently available vaccines to protect against certain HERV-induced diseases, especially melanoma. Criteria for establishing the causal role of HERVs in a given disease are proposed.
Journal of Cancer Research and Clinical Oncology 12/2010; 136(12):1787-94. DOI:10.1007/s00432-010-0949-x · 3.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Every year, approximately 250,000 African women die during pregnancy, delivery, or the puerperium. Maternal mortality rates due to infectious diseases in Sub-Saharan Africa now supersede mortality from obstetric causes. Evidence is accumulating that tuberculosis associated with HIV/AIDS, malaria, sepsis, and other opportunistic infections are the main infectious causes of maternal deaths. Screening for these killer infections within prenatal healthcare programs is essential at this stage to prevent and treat causes of maternal mortality. The combination of proven effective interventions that avert the greatest number of maternal deaths should be prioritized and expanded to cover the greatest number of women at risk, and incorporated into a "prophylaxis and treatment community package of care." The effectiveness of these "packages of care" will need to be determined subsequently. Maternal deaths from tuberculosis are now on the increase in the UK, and due diligence and watchful surveillance are required in European prenatal services.
International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics 03/2010; 108(3):181-3. DOI:10.1016/j.ijgo.2009.12.005 · 1.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Progress in TB control has been greatly hindered by a lack of sufficient funding dedicated to priority areas that have been defined many times by international specialist and advisory groups, especially the need for better TB diagnostics, vaccines, drugs and shorter treatment regimens (Donald et al. 2007; Cobelens et al. 2008; Fauci & NIAID Tuberculosis Working Group 2008; Chaisson & Harrington 2009; Dheda et al. 2009). Perhaps, the most striking shortcoming of current TB control efforts is the inability of health care workers to make an accurate diagnosis of TB in a large proportion of patients, particularly in HIV-infected individuals and in children. While several new diagnostic tests are in the pipeline, an improved, rapid, cheap, practical point-of-care test is still eagerly awaited. The major problems associated with current TB therapy are the long duration of treatment that complicates administration, reduces adherence and increases the likelihood of acquiring drug resistance; high rates of resistance to standard first line therapy and the emergence of XDR TB and the frequency of toxic side effects, together with pronounced drug–drug interactions especially with rifampicin. These shortcomings emphasize the need for the development of new drugs and treatment regimens. Large-scale financial investment, both from non-profit agencies and industry, is required to advance new products to human clinical trials. As BCG vaccination has not had a major impact on TB control, the development of new, globally effective, TB vaccines is a major research priority. Development of a novel effective vaccine is, however, complicated by the fact that previous natural infection seems to offer little protection against future TB; most individuals in endemic areas have been primed with BCG or environmental mycobacteria, or they are latently infected with M. tuberculosis. In addition, malnutrition and HIV-infection affect the efficacy and safety of vaccines, especially living attenuated ones.
Tropical Medicine & International Health 03/2010; 15(3):274-6. DOI:10.1111/j.1365-3156.2009.02462.x · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Based on a unifying theory presented here, it is predicted that the immune defects resulting in chronic inflammation rather than effective immune responses could be rectified by the therapeutic use of agents prepared from micro-organisms. With appropriate molecular patterns, these should be able to induce protective immunoregulatory networks or to reprogramme defective ones. In contrast to acute inflammation, chronic inflammation appears to have no beneficial role, but is a state of sustained immune reactivity in the presence or progression of a disease process. This results in an escalating cycle of tissue damage followed by unproductive tissue repair, breaks in self-tolerance, malignant transformation or deleterious changes in tissue morphology and function. Such inappropriate immune reactivity is an underlying characteristic, either in initiation or maintenance, of a diverse range of disease states including chronic infection, autoimmunity, allergy, cancer, vascular disease and metabolic alterations. Evidence is presented that the inappropriate immune reactivity is due, at least to some extent, to failures in the establishment of immunoregulatory networks as a result of hygiene-related factors. Such networks are the result of activation of antigen-presenting cells, principally dendritic cells, by molecular patterns of micro-organisms encountered sequentially during life and establishing the 'biography' of the immune system.
[Show abstract][Hide abstract] ABSTRACT: Tuberculosis continues to be one of the leading causes of morbidity and mortality from infectious disease worldwide. When WHO declared tuberculosis a global emergency in 1993, the initial response from the international community was sluggish and inadequate. A resurgence of the disease, the emergence of multidrug-resistant and extensively drug-resistant strains, and the detrimental effect of the concurrent tuberculosis and HIV/AIDS epidemics on national control programmes in sub-Saharan Africa have all occurred despite the availability of effective combination treatment regimens. On the positive side, funding agencies and donor governments are at long last taking a serious interest in investing in tuberculosis research priorities defined by the Stop TB Partnership. Although this investment introduces optimism for eventual control of the White Plague, past failures remind us not to be complacent.
[Show abstract][Hide abstract] ABSTRACT: The mycobacteria are one of a number of genera making up the aerobic Actinomycetales. Their antigens demonstrable by immuno-precipitation methods can be divided into four groups. The group i antigens, common to all mycobacterial species, cross-react with their counterparts in animal cells, largely derived from mitochondria. Notable amongst these antigens are the heat-shock, or stress, proteins and possibly bacterial sugars. Tests of cell-mediated immunity show that people can be separated by their responsiveness in skin-test, or lymphocyte proliferation techniques, into four categories of responders. Category 1 individuals respond to all mycobacterial reagents through recognition of the group i antigens. Many chronic diseases are associated with a lack of cell-mediated responsiveness to the group i antigens, and have a raised antibody titre to them. This reflects a predominance of T helper 2 activity and reduced T helper 1 responsiveness as part of the pathogenesis of their diseases, which include chronic bacterial, viral and parasitic infections, allergies, auto-immunities and neoplasms. Packaged together, the group i antigens and the cell-wall adjuvants of selected aerobic Actinomycetales make potent immuno-modulatory reagents. An example is heat-killed Mycobacterium vaccae, useful in both prevention and treatment of disease. Treatment with such reagents results in alleviation of disease, restoration of cellular responsiveness to the common mycobacterial antigens and a decrease in antibody titres to them. This new approach to treatment for such a wide range of diseases has few disadvantageous side effects and can accompany other non-immunosuppressive therapies.
Current pharmaceutical design 02/2009; 15(11):1248-60. DOI:10.2174/138161209787846838 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BCG vaccine, vaccinia vaccine and certain pathogens that were shown in previous studies to protect against melanoma have antigenic determinants homologous in their amino acids sequence with the melanoma antigen HERV-K-MEL, encoded by a human endogenous retrovirus K (HERV-K), which is expressed in about 95% of malignant melanocytes. Yellow fever vaccine (YFV) likewise contains an antigenic determinant with a close homology to HERV-K-MEL and might therefore also confer protection against melanoma. To investigate this possibility we carried out a cohort study (28,306 subjects) and a nested case-control study (37 melamona cases and 151 tumors not expressing HERV-K-MEL) in Veneto region (North-Eastern Italy). The standardized incidence ratio was 1.33 (95% confidence interval, 0.84-2.11), 1.59 (0.97-2.59) and 0.59 (0.19-1.84), while the age- gender-adjusted odds ratios were 1.00, 0.96 (0.43-2.14) and 0.26 (0.07-0.96), at 0-4, 5-9, and > or =10 years elapsed from YFV administration, respectively. The risk of melanoma may therefore be lowered 10 years after vaccination with yellow fever vaccine.
[Show abstract][Hide abstract] ABSTRACT: A heat-killed preparation of Mycobacterium vaccae (SRL172) has been shown, in recent studies, to be effective in the treatment of adenocarcinoma of the lung and renal cell cancer. It is postulated that the mechanisms of this form of immunotherapy is, at least in part, due to immune regulation, reflected in the selective enhancement of Th1 and down-regulation of Th2 T cell activity. These beneficial effects are attributed to the ability of adjuvants in the bacterial cell walls to modify and optimise the response to antigens shared by the bacteria and stressed host tissues, resulting in the destruction of cancer cells by programmed cell death or apoptosis. The M. vaccae-induced apoptosis appears to be most effective against carcinomas, perhaps especially those of glandular tissue, in contrast to pyrexia-induced necrosis which is most effective against tumours of mesodermal origin. In view of the great range of adjuvants, especially in the genus Mycobacterium and related genera, it may prove possible to develop a range of immunotherapeutic agents with useful activity against a wide range of cancers.
[Show abstract][Hide abstract] ABSTRACT: Immunotherapy with a heat-killed suspension of Mycobacterium vaccae (SRL172), given with chemotherapy, in a phase III trial against non-small-cell-lung cancer showed no improvement in the primary endpoint of survival over chemotherapy alone in the initial published analysis. Compliance was poor, with on average only 53% of patients receiving more than 2 injections in the SRL172 arm of the study. Quality of life was, however, improved in those receiving SRL172. Secondary analyses based on compliance with therapy showed that immunotherapy led to significantly improved survival times of patients with adenocarcinoma but, by contrast, had no beneficial effect on survival times of patients with squamous cell carcinoma. Survival of adenocarcinoma patients receiving SRL172 was increased by a mean of 135 days (p=0.0009, Kaplan-Meier log rank test) and survival after 4 or 5 doses of SRL172 showed a difference of greater than 100 days (p<0.05, Mantel-Hänszel log rank test) in the group receiving SRL172 in addition to chemotherapy. Despite the problems inherent in a secondary analysis, these results encourage further research on the role of killed preparations of adjuvant-rich micro-organisms, including saprophytic mycobacteria such as M. vaccae, and members of related genera in the therapy of a range of cancers.
European Journal of Cancer 01/2008; 44(2):224-7. DOI:10.1016/j.ejca.2007.08.021 · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is increasing evidence that infections and vaccinations play an important role in the normal maturation of the immune system. It was therefore of interest to determine whether these immune events also affect the prognosis of melanoma patients. A cohort study of 542 melanoma patients in six European countries and Israel was conducted. Patients were followed up for a mean of 5 years and overall survival was recorded. Biometric evaluations included Kaplan-Meier estimates of survival over time and Hazard Ratios (HRs), taking into account all known prognostic factors. During the follow-up between 1993 and 2002, 182 of the 542 patients (34%) died. Survival curves, related to Breslow's thickness as the most important prognostic marker, were in accordance with those observed in previous studies where the cause of death was known to be due to disseminated melanoma. In a separate analysis of patients, vaccinated with vaccinia or Bacille Calmette-Guerin (BCG), HRs and the corresponding 95% Confidence Intervals (CIs) were 0.52 (0.34-0.79) and 0.69 (0.49-0.98), respectively. Joint analyses yielded HRs (and 95% CIs) of 0.55 (0.34-0.89) for patients vaccinated with vaccinia, 0.75 (0.30-1.86) with BCG, and 0.41 (0.25-0.69) with both vaccines. In contrast, infectious diseases occurring before the excision of the tumour had little, or, at the most, a minor influence on the outcome of the melanoma patients. These data reveal, for the first time, that vaccination with vaccinia in early life significantly prolongs the survival of patients with a malignant tumour after initial surgical management. BCG vaccination seems to have a similar, although weaker, effect. The underlying immune mechanisms involved remain to be determined.
European Journal of Cancer 02/2005; 41(1):118-25. DOI:10.1016/j.ejca.2004.09.023 · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several reports indicate that the risk of lung cancer increases slightly for a short period of time after cessation of smoking while the risk of adverse cardiovascular events drops immediately. Recent studies on subjects occupationally exposed to organic dust-containing endotoxin have revealed lower than expected rates of lung cancer. There is experimental evidence that stimulation of the immune system by endotoxin has a protective effect against cancer. Tobacco smoke has been shown to contain high levels of endotoxin. We therefore postulate that cessation of smoking eliminates the protective effect of endotoxin. Any benefit conferred by endotoxin does not, however, justify smoking. As the inverse relationship between exposure to endotoxin and the risk of lung cancer is a strong one, endotoxin-like substances could form the basis of vaccination strategies.
Medical Hypotheses 02/2005; 65(3):534-41. DOI:10.1016/j.mehy.2005.02.043 · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: All the trials of immunotherapy of tuberculosis with killed Mycobacterium vaccae, published or not, that are known to the authors are reviewed here. Following an introduction giving a brief account of some earlier immunotherapies for tuberculosis, the origins of the concept of immunotherapy with M.vaccae are considered. Progress is traced from the early work with irradiation-killed organisms in leprosy to the study in London of modulation of tuberculin skin-test responses, and the first comparative trials in The Gambia and Kuwait. In the last of these studies, dosages and different preparations were compared. As a result of this subsequent studies have used 109 heat-killed organisms, equivalent to 1mg wet-weight of bacilli, as a standard dose. A series of small trials in Argentina, India, Nigeria, Romania, South Africa and Vietnam have pioneered the way forward, disclosing geographic variability, with South Africa as the only country where almost no effects were recorded. Together the studies have shown that a single dose may not be sufficient. These studies have confirmed the mode of action of M.vaccae to be regulation of cell-mediated immunity with enhancement of Th1 and down-regulation of Th2, and they have shown benefits in faster bacteriological conversion, reduction in ESR, recovery of body weight and resolution of radiological opacities, leading to better recovery from the disease even when given to patients receiving directly observed therapy, short-course (DOTS). Three major randomised, placebo-controlled and partly blinded trials have been carried out in Africa. The first, in South Africa showed no M.vaccae-related effects. The second trial, in Uganda, confirmed the observations made in the earlier studies of faster sputum conversion and better radiological clearance. The third trial, in Zambia and Malawi, showed a trend towards benefits in the treatment of HIV seronegative patients but failed to show beneficial effects in HIV seropositive patients. Studies in patients with multi-drug-resistant tuberculosis have shown that multiple doses of immunotherapy are required in most cases, and that these markedly improve cure-rates for these patients. This is especially so when they are also treated with chemotherapy tailored to the resistance pattern of their infecting organisms. A small study has just commenced in which repeated doses of M.vaccae are being administered to a group of patients who have failed treatment with DOTS-Plus (directly observed therapy with drugs selected on the basis of drug susceptibility profiles). Late in the investigation came publications from China supporting and confirming the data in both drug-sensitive and drug-resistant disease, by the use of multiple injections of their own different preparation of M.vaccae. The trial that is now beginning in Vietnam of 3 doses of M.vaccae in the treatment of newly diagnosed pulmonary tuberculosis, is accompanied by a chemotherapeutic regimen with a shortened continuation phase. If this important study is successful, immunotherapy with killed M.vaccae should be introduced into the treatment regimens for tuberculosis worldwide.
Frontiers in Bioscience 06/2004; 9:1701-19. · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A significant correlation between a reduced risk of melanoma and BCG and vaccinia vaccination in early childhood or infectious diseases later in life has already been reported from the FEBrile Infections and Melanoma (FEBIM) multicentre case-control study. This correlation is further evaluated in this study based on 603 incident cases of malignant melanoma and 627 population controls in six European countries and Israel by means of a joint analysis of the influence of vaccinations and infectious diseases. In addition, the previously unconsidered impact of influenza vaccinations is evaluated for the whole study population. The strong effects of the frequently given BCG and vaccinia vaccinations in early childhood, as well as of uncommon previous severe infectious diseases, were apparently not cumulative. With the Odds Ratio (OR) being set at 1 in the absence of vaccinations and infectious diseases, the OR dropped to 0.37 (95% Confidence Interval (CI): 0.10-1.42) when subjects had experienced one or more severe infectious diseases, associated with a fever of > 38.5 degrees C, and had not been vaccinated with BCG or vaccinia. The OR was 0.29 (CI: 0.15-0.57) in those who had had a severe infectious disease and were vaccinated with either BCG or vaccinia and 0.33 (CI: 0.17-0.65) for those with 1 or more severe infectious diseases and who had received both vaccinations. We conclude that both vaccinations as well as previous episodes of having a severe infectious disease induced the same protective mechanism with regards to the risk of melanoma. Because of a 'masking effect' by the vaccinia vaccination, the protective effect of the BCG vaccination and of certain infectious diseases against cancer has remained undetected. The vaccinations contributed more to the protection of the population than a previous episode of having an infectious disease. In view of the termination of vaccinations with vaccinia in all countries and of BCG in many of them, these findings call for a re-evaluation of vaccination strategies.
European Journal of Cancer 11/2003; 39(16):2372-8. DOI:10.1016/S0959-8049(03)00625-7 · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pulmonary disease due to EM occurs worldwide, and its prevalence has increased as a consequence of the HIV pandemic. It is not often detected in the tropics owing to a lack of laboratory facilities, but when sought it has been found. In addition to HIV infection certain occupations such as mining render the work force more susceptible to disease and calls for a revision of working conditions. Resolution by therapy can be achieved in many cases. As the prevalence of TB diminishes worldwide--and hopefully it will in the wake of the resurgence of interest and the widespread application of the World Health Organization's Directly Observed Therapy Short Course (DOTS) strategy--disease due to EM will become relatively more important and will necessitate revised strategies in clinical, microbiological, and public health approaches to mycobacterial disease.
Clinics in Chest Medicine 07/2002; 23(2):369-76. DOI:10.1016/S0272-5231(01)00011-9 · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Many species of mycobacteria that normally live as environmental saprophytes, the environmental mycobacteria (EM), are opportunist causes of disease in humans and animals. Many, but not all, cases are associated with some form of immune deficiency. An increasing number of species and clinical presentations are being described, and advances are being made in the understanding of the underlying predisposing factors. In recent years, four aspects of EM disease have become particularly relevant to human health: (1) the high prevalence of EM disease in patients with AIDS; (2) the emergence of Buruli ulcer, an ulcerative skin disease caused by Mycobacterium ulcerans, as the third most prevalent mycobacterial disease; (3) the effect of infection by EM on the immune responses to BCG vaccination and on the course and outcome of tuberculosis and leprosy; (4) the controversy over the involvement of mycobacteria, notably M. avium subspecies paratuberculosis, in human inflammatory bowel disease. These aspects change the status of EM from mere curiosities to important direct, indirect, and putative causes of serious and increasingly common human disease.
Current opinion in pulmonary medicine 06/2002; 8(3):166-72. DOI:10.1097/00063198-200205000-00003 · 2.76 Impact Factor