If ‘asymptomatic TB’ really 'substantively' provokes TB transmission...

In the last blogs we discussed some general content in the WHO’s most recent TB Report, and most particularly we identified one additional unexpected proposition - that asymptomatic TB “substantively” contributes to ongoing transmission of TB to the tune of at least half of all new incident cases (if not more).

We should add that this remains a hypothesis, but it seems that the WHO is taking it seriously enough to redefine its definitions of asymptomatic TB in order to allow for its possibility (and the Stop TB Partnership is implying 'watch this space...').

As we interpret this hypothesis, we see that it effectively undermines the current END TB Strategy which depends on stemming the ongoing pipeline of transmission that was up until now believed to have been fed by symptomatic cases. It also means that defeating TB will probably require new approaches.

Up until now the general strategy has been founded on the principle that the bigger the percentage of estimated TB cases out there that you successfully treat, the more you will squeeze the pipeline of ongoing transmission: eventually as the percentage of cases found and treated will reach a critical mass, the 'R' number will drop below the magical ‘1.0’ and the global incidence of new cases will start to tumble.

What’s more, if, at the same time, we can find and preventatively treat as many close contacts of diagnosed active cases (especially those considered at highest risk of contracting an activated infection) before any of their infections reactivate, then that pipeline can get squeezed a little harder still, and so the current stream of new cases that perpetuates this plague year-on-year will begin to become more like a feckless dribble.

This certainly made epidemiological logical sense – at least it did in an era in which it was assumed that those active cases with the highest bacteriological count of TB bacteria in their sputum were the prime transmitters of this ancient disease. But this may have just changed, because we now have a new idea being proposed - that more than half of the new incident cases are being infected by effectively invisible 'asymptomatic' cases, only a small proportion of whom will ever present to a TB clinic for treatment. If we apply the existing logic, what this means is that the ongoing transmission valve will remain stuck in the open position and R1.0 will remain a pipedream, unless the strategy is adjusted towards somehow finding these invisible infectious cases. This existing policy of depending on symptomatic cases presenting for treatment, incidentally, is known as ‘passive case finding’ and it's been a consistent aspect of global TB control since the Global TB Emergency was first officially declared back in 1993.

What this new hypothesis suggests is that the End TB Strategy needs to be reconsidered – including urgently implementing a policy of ‘active case finding’.

Finding those invisible ‘typhoid mary’s’

It's a historical fact that 'active case finding' was something that was vigorously implemented in the post-war years in Western Europe and North America in a period when TB levels in these regions declined to their lowest in recorded history. The health authorities simply went out looking for TB in the places they most expected to find it, deploying an army of mobile X-ray lorries and radiographers in the process – and (unsurprisingly) they found a lot, not least because we can now presume that a lot of them were unsuspected and unsuspecting asymptomatic cases who may have been silently seeding their local epidemics like an army of ‘typhoid Mary’s’.

What's interesting is that during this same period of active case finding, the numbers of new TB cases in these countries declined to become the minimal national epidemics that remain in these same countries today.

QED - (that active case finding might make all of the difference)? It’s very tempting to say so, though it’s a sad reality that such an initiative is way beyond the resources currently allocated to TB control in all high-burden countries. In other words, there's a mountain of paradigm to both climb and shift if this policy is adopted

A broader perspective on those historical reductions in industrialised countries

It may not be epidemiologically that simple, anyway, because the numbers of TB mortalities had already very substantially declined before they rolled out those X-ray wagons and, given that the estimated annual global incidence of TB is currently sticking so stubbornly at around 10 million a year (10.8 million this last one, in fact) it strongly suggests that we might be missing something else that may be even more important if we just focus on active cases as we have been doing.

In fact, on reflection, we wonder whether this unexpected re-categorisation of ‘asymptomatic’ TB towards being a substantive vector for infection now offers global authorities an interesting opportunity – to review the whole End TB Strategy in the light of something even more pervasive than global TB - .global poverty and national inequalities.

Up until now, the End TB strategy has been primarily based on increasing and improving resources, on developing both a new vaccine and faster more sensitive diagnostics, and on developing new drugs, as well as seeing as many as possible of those infected with TB (whether symptomatic or asymptomatic) put on treatment – and lives saved. Certainly we can say that the END TB targets are tied in with the Sustainable Development Goals, but this is only the case in a secondary capacity. (TB doesn't even have its own designated SDG, in fact). Maybe it's time to turn this on its head?

To help us orient ourselves, we need to step back and look at registered TB deaths recorded in the hundred years before those first TB drugs were developed - in the first instance looking at a graph of registered TB deaths over a hundred years in Boston, Massachusetts, USA during all of which which TB was a notifiable disease.

Graph showing TB deaths in Boston 1860-1971 and in the USA 1900-2018

It’s an extraordinarily interesting graph. You can see, for instance, that the peak of TB deaths was around 1860 - when it was still called ‘consumption’ because it was still twenty years before the TB bacillus was even first identified and any bacteriological diagnosis was possible (that was in 1882 as the graph shows). This same peak at around 1860 was also a full sixty years before the BCG vaccination was first used (that was in 1921, though in this graph it shows it as being 1954 because the USA chose not to introduce the vaccine until then). And, astonishingly, it was around ninety years before the first successful TB drug was used (and actually over a hundred years before Rifampicin was discovered - which was the drug which facilitated a shorter treatment course and more effective drug treatment.

In other words, this graph shows very clearly that the largest portions of reduction in TB mortality all occurred before diagnosis, drugs or vaccination were available, and so also before any find-and-treat strategy could have been even conceived of ... something which surely begs some questions about the current strategies given that each Global Report still estimates stubbornly persistent numbers of new cases each year.

Of course, you might be thinking – twell, his was just in Boston – but for most of this graph (between around 1900 and 1975) there are actually two lines on the graph, the second (telling) one picking up death rates from TB in the whole of the USA - and you can easily see that these lines are almost indistinguishable from each other. So what does this suggest? Well, we can say for sure that after 1850 TB deaths in Boston had reduced by about half before any vaccination was available (if it had been available in Boston in 1921) and astonishingly by almost 7/8 by the time the first TB drugs were available – and we can suggest that the same reductions may well have been the case in the whole of the USA (and probably were).

But was this just an American phenomenon?

The fact is that this is unlikely because here's a second graph showing registered TB deaths in London after 1900 through to 1970, and we can see almost the same pattern in it.

Graph showing TB deaths in London 1900-1970

This time we can also see clear ‘up’ turns during and after each world war (which is exactly what we would expect because of rationing and tough times affecting population-wide host immunity). And in this second graph of TB deaths we can see that mortality rates in London were down about 2/3 of their 1900 level by the time when the first TB drugs arrived and were in single figures by 1970, just before Rofampicin was discovered and the DOTS short course multi-drug chemotherapy was possible to conceive.

It’s important to add here, of course, that in both graphs the drugs clearly did help to drive mortality down further - to a very low rate indeed by 1970. This is clear - and also to stress that they have saved millions of lives since then. But they have so far failed to drive down the incidence rate of infections, and also, it has to be added, have implicitly created a secondary pandemic of airborne drug-resistant disease (because you can't have a drug-resistant pathogen with a drug for the pathogen to become resistant to).

so What does this all add up to?

Well, there’s a lot to think about here, and a few telling bullet points should help us figure this all out and hopefully add a fresh realistic perspective.

• In 1882 (when the TB bacterium was formally identified by Robert Koch on a stained plate under his microscope in Berlin) about one-in-seven of all European deaths were reckoned to be caused by TB.

• At the end of the 19th century, infection rates in some cities in Europe and North America were thought by most public health officials to be at almost 100% [i.e. almost every urbanite was latently infected at that time].

• At this same time, tuberculosis was also considered to be either a sign of poverty or an inevitable outcome of the process of industrial civilization - or both.

• And about 40% of working-class deaths in cities were from tuberculosis.[i]

• Since 1990, meanwhile, it has certainly been the case that TB incidence in both Europe and the U.S. has slightly increased, but mortality rates from TB in both regions is significantly less than 1 per 100,000 (in America recently it's been pegged at just 0.2 deaths per 100,000 population).

• In contrast, the global TB mortality rate is currently around 17 deaths per 100,000 population (which is probably around the same rate as it was in the U.S. and Europe when the first TB drugs arrived, incidentally[ii] - though the truth is that we suspect for various reasons that it may be a little higher than currently estimated and reported, and, of course it’s unquestionably significantly higher in some countries.

• Mortality rates in high burden countries, however, are often much higher than this: Indonesia, for instance, was recently estimated to have a TB mortality rate of 51/100,000; this was 90/100,000 for South Africa; and was a staggering 156/100,000 for the Central African Republic (which is roughly the same as was occurring in London and Boston in 1900).

So what made these dramatic differences in the industrialised nations between 1850 and 1950?

The answer obviously has nothing to do with TB drugs, nor has much to do with vaccines. The most probable reasons (although difficult to differentiate in respect of discrete impact) were:

the use of sanatoria (though later discredited as being effective);
a reduction of abject poverty,
general better nutrition,
improved sanitation,
and better living and working conditions

(It’s largely forgotten that it was the sorts of death toll identified above (40% of all working class deaths, for instance) which drove a raft of legislation that improved the living conditions of those most vulnerable to this ancient plague – the poor.)

Take a look at that first graph again and now consider these dramatic reductions while considering the simultaneous reductions of abject poverty in the cities, the better nutrition, improved sanitation and better living and working conditions. Could these be suggested to have reduced mortality rates from tuberculosis by 90% in Boston, and similarly probably the whole of the U.S. and indeed norther Europe? It seems reasonable to do so, and indeed they have been.

And given this probability, is diverting our attention towards considering asymptomatic spread as being a “substantive” driver of ongoing transmission going to be any significant help in ending TB unless similar changes also occur that benefit those most vulnerable? There certainly doesn’t appear to be sufficient resource willingly available to clinically address the problem already (only 22% of the budgeted annual target being met in the last year), so if active case finding is seen as the only available answer, this is a challenging option to consider.

The most challenging option of all for us to consider (which is actually the only realistic one)

Perhaps this aspect of asymptomatic infection as identified in the most recent TB Report suggests that it’s time to address some fundamental aspects of this disease which TB has been telling us about all along – that the pernicious influence on TB mortality is primarily that of chronic poverty and structural inequalities.

And perhaps it’s time to also ask ourselves why we appear to be so reluctant to really address this issue despite it being so clear – not least because it doesn’t just drive TB transmission and mortality.

It also drives migration. We, in our post-industrialised corners of the world, may not feel that TB touches us today as it touched our forebears, and this may well be one reason why it no longer strikes fear in our hearts. But migration certainly does touch us, more and more - destabilising our societies and threatening international relations - and this also is driven by structural socio-economic inequality and chronic poverty.

We need to wake up and smell some coffee, and just maybe TB is telling us that we can't put this off any longer.