Tuberculin Examination Report: Fill & Download for Free

I could locate at least 3 published US BCG trials. Two showed little or no efficacy while the oldest US BCG trial showed efficacy lasting even 50 to 60 years later. How to explain such differences?1. Prior exposure of trial population to Non-Tuberculous Mycobacteria (NTM) could explain non-effectiveness in two of the trials (1, 2).2. The third trial, likely unwittingly but effectively, excluded individuals with prior NTM exposure (3).To fully understand the differences between these discordant US BCG trials, we need to understand the history and details of some of the reagents they used, specifically the materials used in the Mantoux test. In a vaccine trial, how do we decide whom to vaccinate? Typically, we prefer to include only "naive" individuals, i.e. individuals not previously exposed to either the vaccine or disease causing organism. Premise is to be able to attribute trial results solely to the vaccine. This entails some type of pre-screening test to exclude those already exposed. In the case of TB, Mantoux skin tests are used, and responders above a certain cut-off are excluded. The standard Mantoux consists of intradermal injection of 5 Tuberculin Units (TU) on the volar surface of the arm (10). 48 to 72 hours later, the reaction is read as the size of the induration, the hard central nodule of the reaction, excluding the erythema, the redness around the nodule. Obviously, both injection and test reading are error prone. Even more perplexing, different trials used different TU lots and doses, and different cut-offs. Typically cut-off is 5mm at higher latitudes while tropical countries have 10 to 15mm cut-off. What is this Tuberculin and how did these metrics come into existence?What is Tuberculin, the material injected into the skin to assess TB exposure?In 1891, Robert Koch reported his discovery of Tuberculin as a cure for TB (4). His claim was disproved in short order but Clemens von Pirquet speedily recognized its potential value in TB diagnosis (5). This spurred further research into the topic, and Rich and McCordock made the next key observation (6), namely, individuals with small or moderate skin reactions to Tuberculin were less likely to develop TB disease compared to strong reactors. Thus, BCG trials typically pre-screen with Tuberculin and exclude strong reactors.Koch's Tuberculin, later called Old Tuberculin, was eventually phased out of use because it gave too many variable skin test results. Consensus arose around the need to improve its preparation method to yield a more consistent product. Intensive research on Tuberculin preparation ensued, with Florence B. Seibert, then a young biochemist at the University of Chicago, at the forefront.New Tuberculins, the Purified Protein Derivatives (PPD)Seibert precipitated Koch's Old Tuberculin with a variety of chemicals to derive products she called Purified Protein Derivative (PPD) (7). However, these products were neither pure nor entirely proteins, rather they are protein-polysaccharide mixtures of varying degrees (8).Pure or not, in 1952, the WHO adopted a crude mixture prepared from heat-sterilized Mycobacterium tuberculosis culture filtrates, Seibert's lot 49608, also called PPD-S (S for Seibert), as the international reference standard for all PPDs (9). The International Unit (IU) for PPD is defined as the biological activity contained in 0.000028mg of PPD-S consisting of 0.00002mg of PPD and 0.000008mg of salts. 1 Tubeculin Unit (TU) is thus defined as 0.00002mg of PPD-S (9). The WHO adopted 5TU as the standard screening dose of PPD from the practical necessity of using a single concentration, and also because almost everyone reacts to Tuberculin if given large enough doses (9). So much for Mantoux skin test specificity! The US BCG trials we discuss here pre-date these guidelines.Two US BCG trials showed little or not efficacyGeorge W. Comstock initiated and/or was involved in two US BCG trials (1, 2). Both trials pre-screened with a Mantoux skin test using the same PPD batch, lot RT19-20-21.One trial (1) was conducted in 1950 in Muscogee County (and Russell County, Alabama) using BCG Tice on a total of 64136 persons over the age of 5 years (16913 vaccinees, 17584 controls, 29369 Mantoux positive reactors). Pulmonary TB rates were similar between vaccinees and controls at a 20 year follow-up.Another trial (2) was conducted from 1949 to 1951 in Puerto Rico using BCG Birkhaug on 191827 children. Pulmonary TB rates were similar between vaccinees and controls over a 18 to 20 year follow-up.The many differences (population ages, BCG sub-strains, TU used for skin test, and test cut-off size) between these two trials don't matter much since neither trial showed BCG protection against pulmonary TB. What else? Something about the trial location? The Georgia trial had almost as many pre-trial PPD responders (29369) as not (16913+17584 = 34497) as not, suggesting strong mycobacterial exposure among the trial population. Could NTM prevalence at these trial sites explain the data? Two kinds of data sets support this idea.1. In later studies, individuals at some of these trial sites responded more strongly to skin tests with PPDs made from NTM compared to TBPPD (PPD-S).2. More NTM were found at some of these trial sites compared to elsewhere.Location Does MatterI. Skin Test Responses to NTM in one BCG trial location (South-Eastern US) are stronger compared to elsewhereIn the 1950s, two microbiologists/epidemiologists, Lydia B. Edwards and Carroll E. Palmer were trying to develop a diagnostic tool for atypical (non-TB) mycobacterial infections. Taking a leaf out of Koch-Siebert, they prepared PPDs from a number of mycobacterial species. They had the key insight that simultaneously testing with two or more PPDs, one from TB and the others from NTM, could differentially diagnose NTM versus TB exposure. How did they do this? They isolated NTM from nasal swabs of volunteers and dual tested them with TB or NTM PPD. The largest reaction was usually to the antigen prepared from the isolated NTM (11, 12). With this insight, from 1958 to 1969, Edwards and Palmer undertook an extensive study (13) of Mantoux skin test patterns to two PPDs, PPD-S and PPD-B, in a very large group of individuals (all male naval recruits numbering about 100000 per year). We already know PPD-S. They prepared PPD-B from an NTM they called the Battey strain. We now call it Mycobacterium avium. As the name suggests, it was first isolated from a bird. The Edwards-Palmer study incontrovertibly showed that place of origin predicted skin test response patterns. Strongest PPD-B skin test responses were from those who came from the South-Eastern US.Edwards and Palmer also found organisms responsible for such sensitivity were not transmitted from human to human but were readily isolated from the environment (13). Palmer was also among the first to speculate that NTM could influence response to BCG (14). In 1974, in an extensive study of patients and employees in hospitals spanning 8 US states (15), Wijsmuller and Erickson also found stronger skin test responses to PPD-B from people from the Southern US states. In 1970, Abrahams replicated this result in Queensland, Australia. He skin-tested school children with PPD-S and PPD-B. Those who originally responded more strongly to PPD-B retained same response pattern 4 years later, prompting him to coin the phrase Original Mycobacterial Sin, i.e. primary mycobacterial exposure imprints a stable (skin) immune response pattern (16).Location Does MatterII. Are there more NTM in Southern US compared to elsewhere?NTM are found in mud, compost, wet soil, surface water, rivers, estuaries, piped water supplies, taps and shower heads (17). Some species are more hydrophobic and can readily aerosolize to sensitize people who inhale them (17). A study particularly relevant for the US BCG trials is part of a series of studies done by a group led by Joseph O. Falkinham, III, at the University of Virginia Tech, Blacksburg, VA. Following up on the Edwards-Palmer skin test study (13), Falkinham's group compared NTM distribution in South-Eastern and North-Eastern US soil and water. They found NTM species were more abundant in the South (18, 19).NTM prevalence and exposure could explain the Georgia BCG trial. What about the Puerto Rico trial? Here the clue comes from examining the war of words (20) that broke out between Comstock and Sol Roy Rosenthal, another prominent US TB researcher, when these trial results were published. The key text from Rosenthal is, "Puerto Rico has a high incidence of atypical mycobacterial infection". Today we call Rosenthal's atypical mycobacteria NTM. Thus, as with Georgia, we can safely infer high NTM prevalence in Puerto Rico as well.Final WordIs BCG ineffective against TB in the US? No, it worked in the earliest US BCG trial.The last US BCG trial (3) I discuss was actually the first one undertaken in the US. From December 1935 to February 1938, 3025 American Indians and Alaskan natives with normal chest radiographs and skin test response to 250TU of PPD (yes, 250TU!) got one dose of intracutaneous dose of BCG in a placebo-controlled trial. Study area included southeast Alaska, Arizona, North Dakota, South Dakota, and Wyoming. They used early BCG strains obtained directly or indirectly from Calmette or Guerin. In a 1992 to 1998 follow-up, they found a vaccine efficacy of 52%. Not bad for a 50 to 60 year follow-up. How to explain this baffling result? By pre-screening with an extremely high (250TU) PPD dose, they likely excluded from vaccination those with prior NTM exposure. I interpret this to suggest that even with a sub-optimal (skin) route, BCG can protect against TB when given to people previously unexposed to mycobacteria.Bibliography1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1439003/2. http://ajph.aphapublications.org/doi/pdf/10.2105/AJPH.64.3.2833. http://jama.jamanetwork.com/article.aspx?articleid=1986814. http://www.ncbi.nlm.nih.gov/pubmed/70417195. von Pirquet, C. Verlauf der tuberkulose allergie bei einem fälle von masern und miliar tuberkulose. Wien Klin. Wschr., 1908; 21: 861-865.6. Arnold Rice Rich, and Howard A. McCordock. "An enquiry concerning the role of allergy, immunity and other factors of importance in the pathogenesis of human tuberculosis." Bull. Johns Hopkins Hosp 44.273 (1929): 228.7. Seibert, Florence B. "The isolation and properties of the purified protein derivative of tuberculin." Am. Rev. Tuberc 30 (1934): 713-720.8. http://www.ncbi.nlm.nih.gov/pubmed/61761569. http://www.ncbi.nlm.nih.gov/pubmed/811095410. http://www.ncbi.nlm.nih.gov/pubmed/823141111. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475851/pdf/bullwho00619-0114.pdf12. Palmer, C. E., and L. B. Edwards. "Geographic variations in the prevalence of sensitivity to tuberculin (PPD-S) and to the Battey antigen (PPD-B) throughout the United States." Bull Int Un Tuberc 32.July (1962): 373-383.13. http://www.ncbi.nlm.nih.gov/pubmed/576760314. http://www.ncbi.nlm.nih.gov/pubmed/592421515. http://www.ncbi.nlm.nih.gov/pubmed/480916216. http://www.sciencedirect.com/science/article/pii/004138797090026717. http://www.ncbi.nlm.nih.gov/pubmed/178415018. http://www.ncbi.nlm.nih.gov/pubmed/648656219. http://www.ncbi.nlm.nih.gov/pubmed/741659320. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1778044/pdf/amjph00790-0085.pdfThank you for the A2A, Ian York.

Short AnswerThe difficulty is not so much with tuberculosis (TB), the disease, as with obfuscating dogma that has prevented Mucosal Immunity taking center stage in TB research and vaccine development. Further, over the past century, even as biomedical research and development expanded exponentially, TB's domain shrank to primarily encompass the poor who also tend to be the dispossessed and malnourished. Careerist Science and Economics of science then amply filled the ensuing lacuna in scientific prestige attendant to TB.Long Answer1. Post-1970s scientific fashion has emphasized reliance on poorly predictive animal models, such as the mouse, which do not recapitulate human TB disease (1).2. We use unsuitable vaccine routes of administration such as intradermal, which do not recapitulate natural TB infection which is airborne. Are we using the currently available vaccine BCG vaccine (Bacille Calmette Guerin) appropriately? BCG vaccine's history is an important guide for novel TB vaccine development. Different countries administer different BCG vaccine sub-strains, and even use different routes, potentially resulting in different immunogenicity and efficacy. An examination of BCG vaccine suggests that if we misread its history and abandon it wholesale, we might be throwing the baby out with the bath water.3. We have forgotten the object lesson of the Original Mycobacterial Sin (2), i.e. immune response imprinting by Non-Tuberculous Mycobacteria (NTM). An evocative phrase, it's a riff on the older phrase, Original Antigenic Sin (3, 4). Today, we would conceptualize similar ideas under the rubric, Hygiene hypothesis. More narrowly, with reference to T and B cell responses, we would call the phenomenon Cross-reactivity. Different parts of the world harbor different NTM in their environment. Some are prevalent in soil, others in water (5), some even form biofilms in man-made structures such as showerheads and plumbing. The degree and route of our exposure to NTM depends on our geography. How does NTM influence anti-TB immunity?4. We have under-explored the biology of TB latency. What is the biology of long-lived TB infection in the absence of overt disease (latency)? A third of the human population is presumed infected with TB. Is this accurate? If so, what is different about latent TB infection? How do human genetic polymorphisms and NTM exposure differences influence the ensuing immune responses associated with conversion of latent infection to active disease?5. Why have we still not predictably characterized protective human immune responses against TB? Why is TB biomarker development languishing? We rely on poorly predictive tests such as the outdated skin-associated Mantoux test (Tuberculin Sensitivity Test; TST) and the irrelevant systemic Interferon gamma release assay immune response readouts. Assuredly, the long shadow of Robert Koch, the discoverer of TB, and recent Immunology dogma about the so-called Th1 response (T helper cell) impede our efforts to identify and develop qualified biomarkers for predicting TB infection, TB disease, and (lung) TB control.6. TB is typically a disease of poverty and attendant malnutrition, ergo the afflicted population has little political traction to dictate better science.7. Expanded and more stringent (Western) regulatory environment mandates testing a whole range of vaccine candidates (subunit, live attenuated, non-replicating vector-based). Each requires different efficacy assessment and biomarker approaches.Even Longer Answer (Proceed with caution. Not for the faint-hearted. You will need time and patience from hereon).If you're up for it, let's take a roller coaster ride through TB land.TB by the numbersIt's common to see estimates suggesting a third of the human population is infected with TB. What's the real risk of TB? About 10 to 20% of individuals do not become infected even after sustained high-level exposure, 5% develop clinical TB within 2 years of exposure, and the remaining do not develop overt disease but are considered to have latent TB infection (LTBI; Latency). Among the latter, 5 to 10% develop clinical TB in their lifetime, typically due to some kind of immunodeficiency (e.g. HIV infection, anti-TNF treatment). Thus, in 2012, there were approximately 8.6 million new TB cases and 1.3 million deaths (6).Ref 6.However, the numbers hide a much more tragic story and as the cliche goes, a picture speaks louder than words.Today, TB is largely a Third World disease propagated by poverty, its attendant malnutrition, and the unregulated practice of medicine in many poor countries (7, 8, 9).TB GenomeA journey through the TB genome is to witness a counter-intuitive exercise in minimalism. Here's an organism, a rarity within its genus, being an obligate pathogen among mainly saprophytic species (34), and yet it harbors fewer, rather than more, genes (35).TB-Human Co-AdaptationsAt least 6 different TB lineages appear to have co-evolved and adapted to human populations (36, 37, 38, 39). Circulating TB strains could be different in their virulence and induction of immunity (40, 41). Natural human mutations reveal that mutations that impair IFN-g immunity may be important for opportunistic mycobacterial disease control (42). However, natural human mutations have so far yielded no clear insight into human susceptibility for pulmonary TB (6). Typically, persistent bacteria tend to rely on a ploy called Antigenic Variation to evade the host's immune responses (43). As the term suggests, Antigenic Variation refers to gene sequence modifications, specifically of sequences that are the target of host immunity. This does not appear to happen in TB. In fact, CD4 T cell epitopes, sequences that are the target of a host's CD4 T cell response, among 21 TB strains showed the opposite, being highly conserved (44). Unfortunately, Immunology easily lends itself to military terminology. In that light, pathogen-host relationships are couched as evolutionary arms races. TB genome analysis runs somewhat counter to this, similar to the case with another intracellular bacterium, Salmonella eneterica serovar Typhii (45). How to explain this? Within the dogma of an arms race, options become severely truncated at this point, and authors postulate that more conserved sequences drive host-beneficial immunity while diverse ones drive pathogen-beneficial immunity (44, 46). What if the selection were elsewhere, not on CD4 T cell epitopes? Maybe on B cell epitopes? Maybe on gamma-delta T cell epitopes? Maybe the scenario is not an arms race so much as an entente between TB and humans? Maybe even a detente?TB LatencyLatency refers to the capacity for the TB bacterium to remain viable within the host without overt signs and symptoms of active disease. Usually latency is inferred by the http://en.wikipedia.org/wiki/Mantoux_test. Newer tests such as http://en.wikipedia.org/wiki/Interferon_gamma_release_assay do not offer substantial improvement (47), and neither test accurately distinguishes latent infection from active disease, nor reactivation of latent infection from reinfection (48). Recently, a blood-derived genetic signature claims to distinguish latent infection from active disease (49). However, this signature overlaps with that of another disease, Sarcoidosis (50), disease of unknown etiology thought to be related to TB.Vitamins and TBVitamin D deficiency increases susceptibility to TB (62). Vitamin C recently showed direct anti-TB bactericidal activity (63). Such studies emphasize the link between poverty, its attendant malnutrition and TB, and suggest simple dietary improvements such as vitamin sufficiency among poverty-stricken populations could greatly ameliorate TB resistance.A Novel Model upends Century-old TB dogmaOver the past decade or so, among others, Lalita Ramakrishnan at the University of Washington in Seattle has developed a Zebrafish model of mycobacterial infection (Infection with the fish pathogen, Mycobacterium marinum). This model has thus far upended one of the central dogmas of TB. Since the days of Robert Koch, we have believed that the Granuloma, or walling off, response is a host protective response designed to imprison whatever induces the Granuloma, be it indigestible material or bacteria like TB. However, this zebrafish model (74, 75, 76) instead suggests that Mycobacterium can actively sculpt the host’s Granuloma response, ensuring it be populated with precisely those host cells most amenable for bacterial invasion (a particular subset of host macrophages), proliferating within them and using them to spread even as they deliberately evade those endowed with the capacity to kill them.What is protective anti-TB immunity?Can it be assessed in the blood? Should it? Why, if the action is taking place in the lung? The following table highlights perils attendant to these differences (51).Ref 51.Mouse knockout studies place T cells center stage in TB control (52, 53, 54). Why does TB cause mortality? It does not secrete toxins. We deem an exuberant, poorly regulated immune response, i.e. immunopathology, the culprit. This umbrella term encompasses a variety of tissue destructive processes by the host's own immunity that cause irreversible damage, especially to delicate lung parenchyma in pulmonary TB, eventually leading to death. In humans, circulating blood-derived CD4 T cells from active TB patients but not from asymptomatic latently infected, appear to have a propensity for exuberant anti-TB TNF-a (55). In the past, IFN-g response to the same antigens could not make the same distinction. However, this study has three caveats. One, they examined circulating blood mononuclear cells, two, they stimulated with peptide pools. The latter bypasses complex biological processes (Antigen Processing and Presentation) with the potential for artifacts (56). Three, anti-TB CD4 T cells are sparse, not abundant, in circulation (51). This necessitates overnight stimulation. Such an assay is not a snapshot of in situ immunity. On the other hand, contacts of active TB patients have robust TB-specific responses in their bronchoalveolar lavage (BAL) but not in their peripheral blood (57). Rapid recall responses are also seen in BAL (58). Maybe we should also examine local lung immunity and not just peripheral blood? Why then are such studies rare and not the norm (51)? Is it because examining peripheral blood is much easier even if the ensuing information is less relevant?Is There A Role for B cells and Antibodies in TB?TB is an obligate intracellular organism. Dogma dictates B cells and antibodies are irrelevant against it. Yet circulating antibody titers correlate with disease prognosis for other intracellular bugs such as Chlamydia, Leishmania (70) as well as with BCG. BCG also elicits long-lived memory B cells (71) and oral BCG induces an antibody switch from IgG to IgA (72). B cells and antibodies remain controversial topics in TB (73) yet how to explain this phenomenology? Could an effective antibody response prevent TB spreading from one infected cell to another? Could anti-TB IgA prevent TB spreading from one infected individual to another?How Do Co-Infections Influence TB outcome?Here too, some data flout dogma. Dogma states that an effective anti-TB response is Th1, i.e. a response dominated by mediators like IFN-g and TNF-a. The same dogma states that certain organisms like the helminthes drive a Th2 response, dominated by mediators like IL-4 and IL-13, with Th1 and Th2 working against each other. Thus, if BCG infected the lung at the same time that the lung was acutely infected with a helminth, the BCG infection should do worse. Yet the opposite happened in a mouse model study (67). Contrary to dogma, T cell responses are much more complex and inherently more plastic than previously envisaged. A single measure such as the capacity of circulating CD4 T cells to make anti-TB IFN-g does not correlate with protection (68). However, neither does expanding from single to multifunctional circulating CD4 T cell capacity (69). Again, maybe we need to comprehensively examine anti-TB immunity in the airways and lung secretions?BCGBCG vaccine is the live, attenuated vaccine approved for TB. The development of this vaccine reads like a Rafael Sabatini adventure novel with the attendant highs and lows. The developers were Albert Calmette and Camille Guérin. In Lille, France, starting in 1908 with a virulent bacterium (Mycobacterium bovis, not Mycobacterium tuberculosis) isolated from the udder of a tuberculous cow, and donated to them by Edmond Nocard, they diligently, methodically, and heroically sub-cultured this bacterium every 3 weeks in their special glycerin-potato medium, adding ox bile to the mix when they noticed their bacterial cultures tended to clump, which fortuitously led to a reduction in virulence. Why heroically? Heroic because they continued their sub-cultures unabated through the German occupation of Lille, even through increasing scarcity of potato and ox bile! By 1919, after about 230 subcultures over 11 years, they had in their hands a tubercle bacillus that did not cause TB in guinea pigs, rabbits, cattle, or horses (10). Starting in 1921 and continuing to date, it's estimated that more than 5 billion people got the BCG vaccine.The Lubeck disasterIn 1930, in Lubeck, Germany, 250 infants were given oral BCG. 73 developed TB and died within a year (10). How did this happen? Unfortunately, in the Lubeck laboratory, BCG and virulent TB were accidentally cultured in the same incubator with the tragic consequence that the children got vaccinated with TB-contaminated BCG (10, 11).Lubeck was however only a temporary setback. Resurgence of TB during the 2nd World War restored public confidence in BCG by inducing its massive scale use. Starting in 1974, intradermal BCG vaccination at birth has resulted in an estimated 3 billion cumulative vaccinations worldwide and approximately 100 million vaccinations per year (12, 13). However, BCG efficacy in vaccine trials ranges from 80% in the UK to 0% in South India (59). Why is BCG vaccine efficacy so variable?Could BCG sub-strains explain differences in vaccine efficacy?Albert Calmette and Camille Guérin supplied their BCG to various laboratories around the world. Unfortunately, freeze-drying technology only emerged in the 1960s so early cultures were maintained by repeated sub-cultures, leading to differences over time. Substantial differences have been documented between the different BCG strains (13). Today, we mainly use five BCG strains, Pasteur 1173 P2, Danish 1331, Glaxo 107, Tokyo 172-1 and Russian BCG-1 (11, 13), while Brazil uses Moreau RD (14). BCG sub-strains can be grouped by date:Group 1: 1921-1925; BCG Moscow, BCG Moreau, BCG TokyoGroup 2: 1920-1931; BCG Sweden, BCG BirkhaugGroup 3: 1931; BCG Glaxo, BCG Copenhagen (also BCG Danish)Group 4: 1934; BCG Tice, BCG ConnaughtData suggest that early BCG is more immunogenic (14, 15). A criticism of BCG refers to documented differences and deletions (11, 31, 32) in BCG compared to TB, deletions which house immunodominant TB proteins such as ESAT-6 and CFP-10, purported important in driving anti-TB immunity. However, tweaking BCG to express such TB antigens doesn't seem to improve upon BCG either (33). On the other hand, in another Sabatini-esque twist, BCG Tice and Connaught are used for bladder cancer treatment in Europe and US (16). We don't know how it does it but it works better than existing chemotherapy (17, 18). Yet another intriguing mystery in TB land.Maybe we should consider administering BCG to mimic the natural route of TB infection?Initially, Albert Calmette chose to give BCG orally because he believed infection occurred through that route. Brazil continued oral BCG vaccination until the mid-1970s using BCG Moreau (11). From the beginning, oral BCG vaccination was under pressure from the need to generate an "allergic" skin response as evidence of vaccine "take", which doesn't happen with oral BCG. Why the need for this skin response? Here looms the long shadow of Robert Koch, who spent the latter part of his scientific career in the quest for a magic bullet cure for TB. His idea for a cure was a purified extract of TB, Tuberculin, injected into the skin. This "treatment" itself ended in disaster but its legacy survives as the Mantoux test, used till date as a "biomarker" for mycobacterial exposure, for TB infection and for BCG vaccine "take". This skin response is actually a certain type of immune response called the Delayed Type Hypersensitivity (DTH; Type IV hypersensitivity). Today, we know that a BCG-induced DTH does not correlate with protection against TB (19) because the cells and antigens involved in this response are different from those suspected to be involved in protection, and yet, we don't have a more accurate test for vaccine "take". Again, maybe we should examine immune responses to TB, to BCG, to novel TB vaccine candidates at more relevant sites, say in the lung airways and in lung secretions, perhaps?TB is an airborne pathogen. A remarkable series of experiments (20) in the 1950s proved that TB spreads through Infectious Droplet Nuclei (coarse respiratory droplets expelled by an infected person in an enclosed space and breathed in by another). They housed colonies of healthy guinea pigs in a separate room on a separate floor in a hospital ward housing highly infectious and very sick TB patients. The room housing these uninfected guinea pigs received its air supply directly from the hospital ward housing the sick TB patients. Most of these guinea pigs developed TB but not if the air from the sick patients' room was pre-treated with ultraviolet light that killed the TB bacilli. What is the point of this anecdote? It emphasizes we get TB from breathing in infected air. Yet, BCG vaccination does not mimic the route of TB infection. Why? Would BCG work better as an aerosol or orally? I am not alone in posing this question (21). Since BCG is a live, attenuated bacterium, TB aficionados would warn that a potential danger of oral or any other mucosal route targeting the upper airways is risk for cervical adenitis. However, this danger is well allayed by the fact that no cervical adenitis cases were ever reported from Brazil where BCG Moreau was given orally to newborns from 1945 to 1977 (11, 19). In fact, aerosol BCG protects monkeys from airborne TB (22) and aerosol BCG can even be safely given to humans (23). Even though these latter groundbreaking observations date back 40 years or more, we have apparently made little subsequent effort to capitalize on them.Mucosal vaccination has several advantages for TB:1. Easy to administer.2. More practical since it does not need trained personnel, and there's no risk of contaminated needles.3. Easier for people so it would engender greater compliance.4. Easier to produce. Injectables need to be highly pure and need to be especially free of microbial products such as endotoxin. On the other hand, mucosal surfaces already abundantly harbor microbes. Thus, mucosal vaccines need not be highly pure. This leads to enormous cost savings in manufacturing and quality control.5. Mucosal vaccination induces both mucosal and systemic immunity (24). On the other hand, systemic immunization such as intramuscular and subcutaneous, do not trigger robust mucosal immunity (25). Mucosal vaccination also offers many choices such as oral, intranasal, pulmonary, rectal and vaginal (11, 26).Ancillary advantages of BCGBCG and Trained ImmunityBCG appears to improve immunity against other microbes such as Staphylococcus aureus, Candida albicans, and unrelated neonatal and infant vaccines such as Hepatitis B vaccine, Polio Vaccine, Tetanus Toxoid (28, 29).BCG can be given at birthBCG is one of a handful of vaccines given at birth, others being Hepatitis B and Polio. This is an enormous advantage because in large parts of the world, birth is the single most reliable point of contact of an individual with the public health system. Inability to vaccinate at birth is a huge missed opportunity for many vaccine preventable diseases. Such is obviously not the case with TB. Babies vaccinated at birth with BCG make robust, polyfunctional anti-TB CD4 T cell responses (30). So much for the idea that babies have an immature immune system!NTM (Non-Tuberculous Mycobacteria) or EM (Environmental Mycobacteria)There are at least 55 species of NTM (34). The largest human trial for BCG in Chingleput, South India, showed 0% efficacy against adult pulmonary TB (59). Local prevalence and ensuing early life exposure to NTM were largely implicated in these results (60). Since then, prior exposure to NTM has been extensively explored (61), as an immunomodulator, either blocking (preventing) or masking (doing the job itself) BCG. NTM are differentially distributed around the world, being more prevalent closer to the equator (60). However, even after decades of research on this topic, we have more questions than answers about the role of NTM in anti-TB immunity.1. Which NTM species are important for protective anti-TB immunity?2. Exposure how? Oral, nasal, other?3. Starting when? At birth?4. Do different NTM species and/or routes imprint different types of anti-TB immunity? Are some imprints beneficial, others harmful? How does nutritional status influence this imprinting process?Here is another intriguing tale from TB land. In the 1970s, John Stanford, a British microbiologist, traveled to Uganda, where BCG proved quite effective. There, he isolated from the "hippo" mud on the shores of Lake Kyoga, an NTM he named Mycobacterium vaccae (http://www.amazon.com/Epidemic-Absence-Understanding-Allergies-Autoimmune/dp/1439199396/ref=sr_1_1?s=books&ie=UTF8&qid=1414433518&sr=1-1&keywords=the+epidemic+of+absence). Testing suggested it could cure autoimmune disease, no less! In 1994, with his student, Graham Rook, he established a biotech company, Stanford Rook, to capitalize on this fortuitous finding. However, the product failed initial test as a TB drug (http://www.independent.co.uk/news/business/stanford-rook-slumps-70-as-tb-product-fails-trials-1233329.html) and share prices plummeted. This product or others like it may yet succeed in re-calibrating immunity gone haywire. In the meantime, their early promise as BCG replacements has faded.How Does Microbiota influence TB and vice-versa?Studies are just beginning to map this terrain (64, 65, 66).Bibiography1.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952977/2. http://www.sciencedirect.com/science/article/pii/00413879709002673. http://annals.org/article.aspx?articleid=6753544. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2138235/pdf/331.pdf5. http://www.ncbi.nlm.nih.gov/pubmed/57676036. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024222/7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501509/8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1858706/9. http://whqlibdoc.who.int/hq/2005/WHO_HTM_TB_2005.352.pdf?ua=110. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC459668/11. http://www.scielo.br/pdf/mioc/v109n6/0074-0276-mioc-109-6-0838.pdf12. http://whqlibdoc.who.int/publications/2011/9789241502412_eng.pdf13. http://genmico.unizar.es/PDF/Marinova%20et%20al%20Expert%20Rev%20Vaccines%202013.pdf14. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187452/15. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1838518/16. http://www.ncbi.nlm.nih.gov/pubmed/2404256317. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1862178/pdf/canmedaj01349-0047.pdf18. http://www.the-scientist.com/?articles.view/articleNo/32194/title/TB-Vax-for-Bladder-Cancer/19. http://www.ncbi.nlm.nih.gov/pubmed/1897726920. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC441100/pdf/bactrev00130-0080.pdf21. http://www.ncbi.nlm.nih.gov/pubmed/1732179722. http://www.ncbi.nlm.nih.gov/pubmed/463222123. http://www.ncbi.nlm.nih.gov/pubmed/566610724. http://www.ncbi.nlm.nih.gov/pubmed/2446296125. http://www.ncbi.nlm.nih.gov/pubmed/2282891226. http://www.ncbi.nlm.nih.gov/pubmed/2252438727. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491454/28. http://www.jimmunol.org/content/168/2/919.full.pdf+html29. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943168/30. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842001/31. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984997/32. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC177799/33. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906398/34. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066954/35. http://www.ncbi.nlm.nih.gov/pubmed/963423036. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184389/37. http://www.ncbi.nlm.nih.gov/pubmed/1921369938. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2976975/39. http://www.ncbi.nlm.nih.gov/pubmed/1851377340. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048359/41. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1622867/42. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315101/43. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354987/44. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2883744/45. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652037/46. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4043303/47. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016555/48. http://www.ncbi.nlm.nih.gov/pubmed/2439613449. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492754/50. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262024/51. http://jid.oxfordjournals.org/content/205/suppl_2/S316.long52. http://www.ncbi.nlm.nih.gov/pubmed/1190581153. http://www.ncbi.nlm.nih.gov/pubmed/1503259054. http://www.ncbi.nlm.nih.gov/pubmed/1124403255. http://www.ncbi.nlm.nih.gov/pubmed/2133628556. http://www.ncbi.nlm.nih.gov/pubmed/1718254757. http://www.jimmunol.org/content/165/3/1479.full.pdf+html58. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715303/59. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2395884/60. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2895%2992348-9/abstract61. http://www.ncbi.nlm.nih.gov/pubmed/1144355862. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3223428/63. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698613/64. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3862690/65. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164332/66. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018338/67. http://www.ncbi.nlm.nih.gov/pubmed/2325027468. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098235/69. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2970848/70. http://www.biomedcentral.com/content/pdf/1471-2334-14-S1-S1.pdf71. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3519837/72. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1569376/73. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760469/74. http://www.ncbi.nlm.nih.gov/pubmed/1913588775. http://www.ncbi.nlm.nih.gov/pubmed/1949422576. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961847/Thank you for the A2A, Anonymous. Your well-phrased question helped me get this answer out.

Q. Is it ethical for a doctor to treat war criminal/terrorist in conflict zones? Aren't they helping terrorist to get up and kill more people?They are treating those who are responsible for the killing of civilians, for them to get well soon and pick up weapon to kill more civilians. I don’t think this is more ethical at all than those who sell weapons to terrorists.A2A:The Geneva Convention for the Amelioration of the Wounded and Sick in Armed Forces in the Field states that belligerents must care for the sick and wounded without any adverse distinction founded on sex, race, nationality, religion, political opinions, or any other similar criteria. Only medical urgency can justify priority in the order of treatment.Medical care and treatment must be provided with impartiality and without discrimination. This means that detainees must be given the same quality and standard of care as all other patients. In accordance with the principle of equivalence, the ethical standards required of doctors apply equally to the treatment of detainees as to all other patients.Care of Enemy Prisoners of War/Internees (US Armed Forces)IntroductionHealthcare personnel of the armed forces of the United States have a responsibility to protect and treat, in the context of a professional treatment relationship and universal principles of medical ethics, all detainees in the custody of the armed forces. This includes enemy prisoners of war (EPWs), retained personnel, civilian internees, and other detainees. For the purposes of this chapter, all such personnel are referred to as internees. Department of Defense (DoD) healthcare personnel should make every effort to comply with “Principles of Medical Ethics Relevant to the Role of Health Personnel, Particularly Physicians, in the Protection of Prisoners and Detainees Against Torture and Other Cruel, Inhuman, or Degrading Treatment or Punishment”—adopted by the United Nations General Assembly Resolution 37/194, December 18, 1982 (see Appendix 1 in this book)—and all applicable DoD policies.The Geneva Conventions Define medical personnel as those individuals “exclusively engaged in the search for, or the collection, transport, or treatment of the wounded or sick, or in the prevention of disease; and staff exclusively engaged in the administration of medical units and establishments” (Geneva Convention for the Amelioration of the Wounded and Sick in Armed Forces in the Field [GWS]). Medical personnel of enemy forces are not considered internees, but are classified as “retained” in order to treat other EPWs. Internees are also entitled to the protections afforded under the provisions of the Geneva Convention Relative to 462 Emergency War Surgery the Treatment of Prisoners of War (GPW). Detained persons who are not protected under GWS and GPW, may be protected under the provisions of the Geneva Convention Relative to the Protection of Civilian Persons in Time of War. The Geneva Convention for the Amelioration of the Wounded and Sick in Armed Forces in the Field states that belligerents must care for the sick and wounded without any adverse distinction founded on sex, race, nationality, religion, political opinions, or any other similar criteria. Only medical urgency can justify priority in the order of treatment.The signing of the Geneva Convention of 1864.WorkloadThe number of internees and retained/detained personnel requiring medical in-processing and/or medical care can be staggering. Coalition forces captured over 62,000 internees during Operation Desert Storm.During the 1-week ground war, until the end of March 1991, 8,979 internees were treated. The most common internee medical condition reported during Operation Desert Storm was dental disease (24%). Other common medical illnesses were unexplained fever, nephrolithiasis, peptic ulcer disease, and malaria. Wounds in internees may be different than those seen in friendly forces due to differences in personal protective gear, preexisting diseases, malnutrition, and neglect.Medical Care of Internees Healthcare providers have a responsibility to report information that constitutes a clear and imminent threat to the lives and welfare of others. Whenever possible, internees should receive medical care equal to that given to our own troops. o Providers should report any suspected abuse or maltreatment of an internee. o Providers should inform the theater internment facility chain of command of internee physical limitations. Medical recommendations concerning internee activities are 463 Care of Enemy Prisoners of War/Internees nonbinding. Decisions concerning internee activities are made by the chain of command. Healthcare providers charged with the care of internees should not be actively involved in interrogation, advise interrogators how to conduct interrogations, or interpret individual medical records/medical data for the purposes of interrogation or intelligence gathering. Healthcare personnel ordered to perform duties they deem unethical should request to be recused through his or her chain of command. If the situation is not resolved satisfactorily, healthcare providers may contact their Command Surgeon or the Inspector General. Requirements for internee care are provided in AR 190-8/ OPNAVINST 3461.6/AFJI 31-304/MCO 3461.1. Internees must have an examination upon arrival at the detention facility, as well as a chest radiograph (tuberculin skin test for children up to age 14 years). Sick call must be available daily, and each internee must be weighed at least once per month. Sanitation and hygiene must be maintained at all times (AR 190-8). Medical records.o Internee medical records are the property of the US Government. Internees are entitled to a copy of their medical records upon release. Original records are retained.o The Health Insurance Portability and Accountability Act (HIPAA) does not apply to the medical records of internees (DoD Instruction 6025.18 and DoD 6025.18R). However, the handling, disposition, and release of all types of medical records are governed by regulation. Commanders and others who have an official need to know can access information contained in internee medical records by following the procedures given in AR 40-66, using DA Form 4254. Patient consent is not required. The medical treatment facility commander or designee, usually the patient administrator, determines what information is appropriate for release. Only specific medical information required to satisfy the terms of a request will be disclosed. Healthcare providers should expect that released medical information will be used by the chain of command, to include interrogators. Medical information. o Releasable medical information includes that which is necessary to supervise the general state of health and cleanliness of internees, to detect contagious diseases, and to provide for the safety and security of the facility.Setup/Planning Develop plans for prisoners on a hunger strike or who refuse treatment. Enemy forces may have preexisting medical conditions requiring medication. Ensure that any internee/retained/detained person evacuated to the medical treatment facility for treatment is escorted by an armed guard, as designated by the nonmedical (echelon) commander. The guard must remain with the patient while in the medical evacuation and treatment chain. When possible, keep internees segregated from friendly forces patients. Internees requiring evacuation will receive an internee identification number upon entry into the detainee reporting system. Medical personnel do not search, guard, or interrogate internees. It is critical that medical personnel not enter the general EPW holding area, but have patients brought out to them for sick call and any medical treatment. NATO STANAG 2131, Multinational Phrase Book for Use by the NATO Medical Services—AMedP-5, provides basic medical questions in a number of NATO languages. Use other retained persons/internees (especially medical personnel) as translators. Detainees may feign mental illness to avoid interrogation.Screening Guards should ensure internees are screened for hidden weapons and other potentially dangerous materials. Medical personnel, however, must remain vigilant of these threats and mentally prepared should a threat or attack occur.Care of Enemy Prisoners of War/Internees During transfer, release, and/or repatriation, another medical examination should be performed. Final documentation of any ongoing medical, surgical, or wound care problem is completed and forwarded to the gaining facility or to the appropriate medical records repository.Supply The internment facility must enforce field hygiene and sanitation principles. Plan for personal hygiene requirements and protective measures (insect netting, insect repellent, sunscreen). Coordinate with the supporting medical headquarters for additional preventive medicine support (pest management, potable water, dining facility sanitation, and waste disposal) and Veterinary Services support for food safety as required.Medical Staffing The facility should be staffed to ensure that detainees receive the same standard of care as US forces. Retained medical personnel should be utilized for care of their compatriots in conformity with the Geneva Conventions.Legal When possible, signed permission should be obtained for all surgical or invasive procedures. The patient’s identity should be absolutely clear in each photograph. Photographs are invaluable should there be a claim of unnecessary surgery or amputation. A high-quality camera is important. Any patient who requires amputation or major debridement of tissue should be photographed (face as well as wound images).Internee Advocate The military physician is often the commander’s advisor for medical ethics. The physician should be alert for potential and actual ethical conflicts, and make efforts to resolve them. They must also strive to maintain a “moral distance” from participating in any proceeding potentially adverse to the patient’s interest. Personal safety should never be taken for granted by the medical team, regardless of familiarity with internees and surroundings.Security There is always an element of danger to the medical staff in treating internees.  Physical security will be provided by nonmedical personnel designated by the appropriate leadership. It is the capturing line unit’s responsibility to provide security for EPWs/detainees until arrival at an internment facility. Security personnel must accompany all internees whenever they are in a treatment or holding area. In forward areas, it may not be possible to have separate and secure medical treatment/ holding areas for internees. When possible, internees should be segregated from allied, coalition, and US forces. When possible, avoid taking medical equipment into the patient wards for security reasons (ie, bring the patient to the equipment). Following treatment, the provider should alert internment medical personnel of any special needs the internee may have.For Clinical Practice Guidelines, go to http://usaisr.amedd.army.mil/clinical_practice_ guidelines.htmlhttp://www.cs.amedd.army.mil/FileDownloadpublic.aspx?docid=8ee7a717-3fd1-4395-9371-063b3917d21fBritish Medical Association GuidanceWhat are doctors’ responsibilities in providing medical support to detainees?Medical care and treatment must be provided with impartiality and without discrimination. This means that detainees must be given the same quality and standard of care as all other patients. In accordance with the principle of equivalence, the ethical standards required of doctors apply equally to the treatment of detainees as to all other patients.A doctor’s role in relation to detainees should be restricted to assessing, protecting or improving the physical and mental health of patients. As well as providing direct medical support to detainees, doctors also have responsibilities in monitoring the standards of health and hygiene within a detention facility, such as access to food and water, sanitation, heating, lighting and ventilation.Whenever a doctor considers that a detainee’s physical or mental health will be harmed by continued detention, or by the conditions in detention, this should be reported to the commander.Ethical decision-making for doctors in the armed forces: a tool kit of the detention facility and to the medical authorities.Doctors also have a duty to ensure that their patients are not being abused while in detention, and to act on any evidence of abuse.The Duty to Provide Care for a Wounded or Sick Enemy