‘Asymptomatic TB’ in the latest Global TB Report – is it something needing really serious new attention, or is it just a red herring?
Tucked away (in full sight) within the most recent Global TB Report is a section on ‘asymptomatic TB’.
Asymptomatic TB, as far as we are concerned, is an entirely new category of TB disease as presented in these report so it caught our attention immediately. Of course, the general idea of ‘asymptomatic transmission of an infection’ (courtesy of COVID-19 disease when the disease is not expressed symptomatically although signs of infection are bacteriologically confirmed) will be familiar to most of us, though it has to be said that it has also been disputed by some COVID-19 experts.
In this second blog in a series of three, we’ll dive into what ‘asymptomatic TB disease might mean and imply, and also try to tease out exactly why this term has appeared in this recent Report.
Picking apart the process of TB infection - in particular when TB becomes infectious
First let's set the scene by stating that this territory is now worryingly uncertain.
Here's what the National Institute for Health Care and Excellence currently states in the UK[i], for instance. defining (possibly simplistically) an infection of TB in two clear states – either active (or reactivated), or latent:
Active disease describes symptomatic or progressive disease of the lung (most common) and/or other organs (extrapulmonary TB).
Latent disease occurs when there is no clinically active TB (the person is asymptomatic and not infectious).
(we have emboldened the type where important because it makes it clear that the asymptomatic patient is believed to be non-infectious)
In the U.S., the CDC is even more specific (in this case in defining both ‘inactive’ and ‘latent’ TB together)[ii]:
Tuberculosis (TB) germs can live in the body for years without making you sick. This is called inactive TB or latent TB infection.
People with inactive TB do not feel sick, do not have symptoms, and cannot spread TB germs to others.
Let’s be clear. Up to this month the orthodox consensus has been exactly this - that latent or inactive TB cases, despite being bacteriologically confirmable as being courtesy of the TB pathogenic mycobacterium, have no symptoms and are of no risk to anyone apart from themselves (since their disease has a small chance of maybe 5% of subsequently erupting into active or reactivated disease which would of course then be active and infectious). The issue to appreciate at this point is that there are so many latent cases out there (globally about one-in-four-of-us if the most recent estimates are to be believed, each one effectively a possible landmine of active disease and ongoing infection waiting to be trodden on by fate to reactivate). This potential for reactivation is why targets for preventative TB treatment have been set since 2018 (and annually abysmally missed. These targets realte to finding those latent cases most at risk of reactivating (principally close contacts of known infectious cases, children in particular, and people living with with HIV) and then treating them with 6-9 months of isoniazid treatment (most commonly) to sterilise their latent asymptomatic infection and so stymie the risks of reactivation.
So what’s changed in this Report?
In this Report, the WHO is identifying TB as being more complex than just being a simple dichotomy of either/or ‘active/infectious’ and ‘latent/non-infectious’ TB infection. Almost certainly quite correctly, they suggest that the condition of latency is probably more nuanced than is popularly assumed and that the orthodox dichotomy between latency and activation is an oversimplification of what is more probably a spectrum of infection which might even be bidirectional[iii]. Here’s what the WHO now has to say on the matter in this Report[iv]:
'The natural history of TB remains incompletely understood. Current thinking sees asymptomatic TB as a stage on a continuum that moves from infection with Mycobacterium tuberculosis complex to clinical disease.'
This is not that controversial a statement – in fact, it’s been proposed and discussed at TB conferences for about a decade, with some experts proposing that latent TB should be more accurately redefined as ‘sub-clinical TB’ for instance (still asymptomatic, of course, since no symptoms might still indicate active disease with a dynamic potential that might be invisibly moving both towards activation or away from it at any given time). In most respects, these definitions may seem semantic and of interest only to experts and inconsequential to disease burden – which is probably why it’s been largely ignored in the WHO Global Reports until now, and initially the Report is similarly reassuring:
'If a large proportion {of asymptomatic cases) resolves spontaneously, then the burden of illness associated with asymptomatic TB may be minimal.'
This Report, however, does then add something cautiously, which is a little more concerning, that:
'Conversely, untreated asymptomatic TB may contribute to the pathology associated with severe clinical TB (e.g. cavitation); therefore, delays in starting treatment will influence outcomes in such patients.'
There is still appropriate caution around the degree of lung damage in a ‘latent’ infection, in other words, some asymptomatic cases may well become more serious if they reactivate following cavitation in the lungs.
But then comes the Report's bombshell:
‘Another key question is whether asymptomatic TB matters for transmission of TB.’
With the idea of a spectrum of disease development in mind, such a question certainly seems reasonable to make, though up to this point no WHO Report has seriously suggested that latent TB (subclinical, asymptomatic, call it what you like) is also potentially infectious. (Note the CDC specification above, and the NICE one, for instance – with neither authority considering latent/asymptomatic/subclinical TB to be any sort of infectious threat) - and up to now, the WHO was apparently of the same opinion. But a sentence later they throw serious doubt on this idea (emboldening of text is ours for emphasis), by identifying that:
There is uncertainty about the duration of infectiousness of asymptomatic TB and therefore about its contribution to transmission if it is not treated. It is likely that individuals with asymptomatic, pulmonary, bacteriologically confirmed TB contribute substantively to TB transmission and the global burden of TB disease, even if they have minimal or no cough.
Here is a table from the 2024 Report with the new definitions of TB disease added
As we will soon see, these changes have truly seismic implications if seen in the context of the current failing strategies to end TB.
So what is the WHO’s evidence for there being a ‘likelihood’ of asymptomatic TB contributing ‘substantively’ to the global burden of disease?
The Report refers us firstly to a 2023 paper that reviewed old data from Vietnam extracted from a 2007 tuberculosis prevalence survey[v]. In particular, the reviewers assessed the infective effect of individuals with clinically active tuberculosis who shared the same household as children aged 6–14 and did this based on tuberculin skin testing (TST) of the children (assuming that TST positivity indicated that they may well have been infected by the ‘index’ household case who was almost certainly infectious).
They divided a cohort of children into three groups – the first were living with a bacteriologically diagnosed (sputum positive) TB case with a cough of 2 weeks’ duration; the second living with a bacteriologically diagnosed (sputum positive) case who didn’t have a cough of 2 week’s duration; and a third cohort which was a simple control group of children not living with a known TB case of any sort at all. They then compared each children’s group’s respective prevalent rates of being latently infected with TB (determined by the tuberculin skin testing).
The results were concerning though it has to be recognised that there are limiting factors relating to drawing any firm conclusions from it, because generally the paper concludes that the “findings of our study support the hypothesis that subclinical TB contributes to the transmission of Mtb.” Please note that the WHO Report reflects this conclusion slightly more strongly, suggesting from this paper that “it is likely” that asymptomatic TB contributes “substantively” to TB transmission. Is this the same thing as this study supporting a hypothesis that it might do? Not quite we would suggest.
You can probably tell that we were a little sceptical at first about this – not least because the ‘asymptomatic’ determinant of this paper specifically relied only on cough and not on reporting or exhibiting other TB symptoms (like fever, night sweats etc.) which are also common TB symptoms. In other words these supposed ‘asymptomatic’ cases may not have been without symptoms at all – particularly because it’s well known that it is not just droplets from a cough which spread respiratory infections, it can also be from inhaling the aerosols from normal respiration.
But we then took a look at the second paper that was referred to in the Report. This paper is referenced at the end of a sentence in the WHO’s Report which baldly stated that “about two thirds of global TB transmission may be from asymptomatic TB” which amounts to a truly stunning statement because of what it implies. We looked at this second paper and found it to be a very detailed technical paper which does states things just as alarmingly as the WHO Report – stating that its raw data “do not suggest [that] subclinical TB is substantially less infectious than clinical TB”. In fact they reckon that some of their data suggest that it may be actually “more infectious”!
As ever there are limitations to any single paper (although it is supportively referenced and meticulously reported). Unfortunately, we also recognise that there is some telling corroborative evidence that supports these general suggestions as well – in particular the general findings of prevalence studies which often reveal a lot of bacteriologically confirmed TB that can be defined as being asymptomatic at the time of bacteriological testing. TB mycobacteria have to be expressed in some quantity in the sputum of the suspect case for bacteriologically confirmation, so it’s actually not a big step to realise, then, that even in small quantities it must also be potentially expressed in normal exhalations from the lungs through the same respiratory passageways that the sputum had passed through. But the numbers exposed in these prevalence studies do suggest that many must not go on to reveal more activated disease.
The baffling percentage anomalies
With all this in mind, we couldn’t help ourselves from wondering how many infectious cases might really be out there totally invisible in respect of their asymptomatic status? All (10.8 million) current symptomatic TB ‘cases’ are already being estimated and epidemiologically assessed based on current definitions of their living with ‘active’ disease – though we at least know that most of the 8 million already on drug therapy should be bacteriologically negative within two months of starting drug treatment. We now, however, must now suspect that the total sum of bacteriologically diagnosable (and infectious) disease might actually be twice whatever this infectious cohort might up till now be believed to consist of at any moment or more… which has enormous implications.
A frank discussion
As you’ve probably realised, we were initially sceptical about this statement of asymptomatic TB infection contributing significantly to disease burden, not least because there are still differences of opinion about asymptomatic COVID-19 (with the coronavirus being an infinitely faster moving and more infectious pathogen), about whether transmission actually exists at all in any asymptomatic phase beyond the first couple of days after infection before symptoms develop). There are varying opinions now that the claims that asymptomatic disease was ever as big a component of COVID-19 transmission as was officially explicated. Certainly not enough was understood at the time these claims were made for them to have been made with confidence - and so it must be similarly reasonable to say the same thing about TB despite it being an ancient disease – particularly note the quoting in the Report that points out that ‘the natural history of TB remains incompletely understood’.
So is promoting the possibility of there being a previously unconsidered ocean of asymptomatic infectious cases out there even helpful? It may not be, certainly if we consider the existing abysmal record of failing to find and treat those most at-risk - i.e. close contacts of known infectious cases.
After 6 years of not meeting this UN target by the same countries which set it, are we now seriously considering going looking for, finding, and treating upwards of 11 million asymptomatic cases (effectively hidden away within a global cohort of latent disease that is about 2 billion strong)? Should we seriously expect any great success if we do so? The WHO itself must recognise this challenge, of course – not least because there is nothing in the current End TB strategy that remotely resembles such a plan. So is this mention of asymptomatic infection some sort of ploy, or an act of courage on their part?
Might this announcement, for instance, amount to some sort of smoke screen in advance of 2025 and 2027 when the health ministries of all TB endemic countries (and their leaders and the global authorities responsible) could and should be exposed as negligent in respect of their social contracts with their peoples? In these crazy times when few seem to ever be held to account for the problems they cause, this is certainly a possibility.
But what if this phenomenon is real? Then, despite the obvious lack of resource that might even remotely begin to address the issue, it is surely the responsibility of the WHO to promote public debate on the issue, the Global Report must be the prime place for this to be expressed. And following that process, if it is then still seen as a potential reality, then more focused research and a better strategy will both need devising, because this host of invisible infection will have to be determined one way or the other as to whether it is a significant persistent factor that may be stymying efforts to end TB.
What is also staggeringly ironic (and depressing) in this respect is that currently only 62% of the cohort of notified cases (those TB cases who are found, reported and put on treatment) are prescribed 6 months plus of challenging medication after being bacteriologically confirmed to have the disease anyway (the rest are given the same medication based only on presenting symptoms and/or X-ray analysis). In other words, if we’re looking for more bacteriological diagnosis to identify subclinical cases who may well be contributing to more than half of ongoing disease transmission, it looks like we have a terrifying amount of catching up to do. This, at the same time that budgetary targets are being so appallingly missed.
But one further question deserves to be asked still.
If this aspect of asymptomatic infection, which was not even known about or even guessed at a decade ago (and is now suspected as being a factor for persistent prevalence of TB in endemic countries) does exist, how did such high rates of pre-war TB almost disappear in 25 years in Northern Europe and North America? Particularly given that in the immediate post-war period in which the disease declined the drugs that were available were in short supply, and also were less effective that those available since the 1970s?
It certainly seems a valid question to ask at this stage of discussion because, of course, all of these same countries were TB-endemic themselves in the pre-war period. It’s even more valid, moreover, because this was a period where the roll-out of TB drugs was in its absolute infancy, and those first drugs were far from as effective as the current crop and were far harder to endure (and of course the efficacy of the BCG vaccine was just as equally ineffective as it is today).
Two things help explain this, we think.
Firstly, there was active case finding back then – health authorities went looking for TB (largely helped by mobile X-Ray facilities) in the places they most expected to find it – and, wat's more, when they found it and treated it. This may not be an insignificant observation in light of this fresh concern about asymptomatic spread because almost certainly they found and treated a massive proportion of asymptomatic TB as defined above in the process, so effectively treated not just active TB but also asymptomatic TB without having the faintest idea of the potential importance of doing so.
The second factor, of course, is socio-economic and we will look at these two factors in more detail in a final blog on this Report and its unexpected very serious revelations.
[iii] This spectrum stretches from implicit resistance to the TB bacillus (prpbably because of activity in the upper respiratory tract that finishes the infection on exposure, through a latent stage, to a subclinical stage and then on to an active or reactivated stage. For anyone interested in this complex filed, please take a look at Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection. The Journal of Clinical Microbiology (2018).
[v] Clinical Infectious Diseases, Volume 76, Issue 11, 1 June 2023, Pages 2000–2006, https://doi.org/10.1093/cid/ciad027
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