World TB Day 2023 – getting back ‘on track’

The optimistic theme of this year’s World TB Day is ‘YES - WE CAN END TB!’ and of course we could do (although realistically it will take at least a decade because of the nature of this disease), but only if an awful lot more effort than is currently the case is expended on the project. An awful lot…

Today’s strapline from the WHO is officially intended to ‘convey a message of hope’ in respect of ‘getting back on track’ largely because COVID-19 threw everything TB-related into such disorder for a while. We certainly know that this has resulted in increased incidence and higher mortality, for instance, because it's been reported as such by the WHO (for 2021) – but the sorry truth is that things were far from being anywhere near ‘on track’ before COVID arrived as we will explain below.

So let’s review some of this off-track lack-of-appropriate effort that’s been out there since COVID but which also has been out there throughout all of the last thirty years, well before we ever heard of SARS-CoV-2.

Diagnosis

Seventeen years ago in 2006 Dr Peter Small, then the senior program officer for the Gates Foundation, bewailed the fact that TB was taking a fresh victim every 20 seconds, at the same time as TB control was relying on a principle diagnostic tool that was biomedically archaic being (now today) 141 years old. Not only that, he added that only half of all TB cases were being found (and not much more than this are reckoned to be being found today), with the pharmaceutical response relying on one of the biomedicine’s oldest and least effective of vaccines and on what are now sixty-year old first line drugs. We can at least report that since 2006 a new modern diagnostic (beyond the ancient basic ‘sputum microscopy test’ that was being referenced by Peter Small) has finally been approved, but apart from that, seventeen years later, and appallingly little has changed.

Most worrying of all, though, is that the toll of one death every 20 seconds is reported as being exactly the same today in 2023 as it was in 2006.

And all through this period, TB has been officially classified by the WHO as a Global Emergency. Happy World TB Day.

The importance of bacteriological confirmation of disease for safe and proper drug treatment

Bacteriological confirmation of disease is critically important for TB but there are now several options available that weren't approved in Peter Small's time. According to the WHO, anyone diagnosed by ‘culture, rapid molecular tests recommended by WHO, lateral flow urine lipoarabinomannan (LF-LAM) assays or sputum smear microscopy are defined as “bacteriologically confirmed” cases of TB’. Please note that the last of these, ‘sputum smear microscopy’, is the most basic and was the archaic technique that Peter Small was referencing in 2006. It was, in fact was how Robert Koch first identified the TB mycobacterium on this same day (March 24th) in Berlin in 1882 exactly141 years ago.

The WHO importantly further qualify the importance of bacteriological confirmation as follows: ‘The microbiological detection of TB is critical because it allows people to be correctly diagnosed and started on the most effective treatment regimen as early as possible.’

But here’s a thing. In 2021, 5.3 million people were officially ‘notified’ to the WHO as having pulmonary TB (P-TB) with most of these put on treatment – i.e. they were identified and reckoned to have tuberculosis in the lungs, which happens to be the easiest place of the body for bacteriological diagnosis. But astonishingly, ONLY 63% of these notified cases (3.3 million) were actually ‘bacteriologically confirmed’ to have the disease (this number comprising around a third of the estimated total global incident cases for the year - a total which includes the millions who are reckoned to still be being missed). So only a third of the total global case load benefitted from what is officially defined as the ‘critical’ diagnosis that might mean they could quickly be put on ‘the most effective treatment regimen’. What this also means, of course, is that the other 2 million notified TB cases were put on strong drug treatment without any bacteriological confirmation of their disease which, given the nature and duration of the treatment, is astounding in its implications. These folk probably did have TB (maybe based on X-ray analysis or simply on symptoms) but equally they may not have done (and TB drugs are no fun to take)! But more worrying still, they may well have been infected but also carrying an unidentified infectious drug-resistant strain (a pathogen which is infectious through being airborne which makes TB unique amongst drug-resistant disease because of its risk of community spreading).

But it's actually even worse than this. Here is a summary of the actual diagnostic resources that are actually available.

The WHO further reports that in 2021 only 25% of 'TB diagnostic sites' (i.e. clinics where symptomatic cases might be bacteriologically diagnosed) had any access at all to the newer ‘critical’ WHO-recommended rapid diagnostic tests (those that could not just bacteriologically diagnose TB more accurately, but also potentially provide the first indication of drug-resistance) – which means that, as a global average, three out of four TB diagnostic sites globally were inadequately equipped according to WHO recommendations and were only using sputum microscopy (that old test that is 141 years old today). Even worse, only a paltry 7 of the 30 so-called ‘high TB burden countries’ (where most TB is believes to be circulating) reported that more than half of their TB diagnostic sites had access to these same rapid diagnostic tests. In other words, the modern more critically important diagnostics simply don’t exist in most of the places that they are most needed and this deficiency pre-existed any COVID-19.

So is this any sort of track record that we need to get back to? Of course it isn't: it is totally unacceptable that around 4 million cases were reckoned to have been missed completely, that 2 million sick people were diagnosed in 2021 without any bacteriological confirmation at all at the outset of their treatment; and that at least a million more cases (quite possibly many more) were still being diagnosed using the 141 year-old technique of sputum microscopy.

What's more, only 70% of those so tested with the sputum test were then subsequently diagnosed for Rifampicin resistance (Rifampicin being the strongest existing TB drug) by the newer rapid molecular tests that have been being recommended by the WHO for getting on for a decade for identifying possible drug-resistance (and therefore preventing further spread). ‘Bacteriological confirmation of TB is necessary to test for drug-resistant TB’, the WHO reminds us. Damn right it is – and has been for three decades.

This all points to just how sluggish the response has been to this pandemic well before COVID: the WHO’s own numbers furthermore confirm that this dreadful 63% proportion of notified P-TB cases being bacteriologically confirmed has only improved by a paltry 13% in the past twenty years - less than one percent improvement annual improvement in this period. Is this sort of stagnant response any sort of ‘back-on-track’ to aspire to in respect of ‘ending’ TB? It is obvious that much more is needed now - and it still can be done if there is political will to do so..

Persistent over-reliance on sputum smear microscopy

The WHO certainly doesn’t disguise the potential problems that the persistent reliance on sputum smear microscopy is creating, though they could make a far better job of highlighting it because it is so critically important. Here is what they say: ‘Over-reliance on direct sputum smear microscopy is inherently associated with a relatively high proportion of pulmonary TB cases that are clinically diagnosed [i.e. assessed from signs and symptoms], as opposed to bacteriologically confirmed’', adding the crucial rider that ‘in general, levels of [bacteriological] confirmation are lowest in low-income countries and highest in high-income countries where there is wide access to the most sensitive diagnostic tests’. But this issue here really isn’t properly identified for us as it should be because of what this last sentence actually means. Just think about it for a minute: there is invariably much less TB incidence in high-income countries, so this precious bacteriological resource is patently in the wrong place. And the consequence of this? Well it's been being reported for years that anywhere between 95-98% of those who actually die from TB are impoverished and/or live in lower income countries, so it’s fairly obvious now why this has been the case: the world’s poorest and most vulnerable are not benefitting from any plausible proper diagnostic response and are dying as a result. In fact, since these resources are available (but in the wrong places, then arguably these folk are actually being physically deprived of proper diagnosis.

This does not amount to a co-ordinated or coherent response to a pandemic.

And then there are the cases that are simply still being missed

Meanwhile a further estimated 4 million-ish TB cases in 2021 weren’t notified nor received any approved drug therapy at all… and these appalling statistics persist a full 30 years after TB was officially declared a ‘Global Emergency’.

Vaccine protection

Those living in TB endemic countries 30 years into a Global Emergency also still rely on the questionable protection of a vaccine that is now 102 years old.

What makes this sentence worse is that it’s been known for nearly half this time that the BCG vaccine offers little or no protection beyond infancy (when it does definitely help protect). In 2012 Peter Small was heard once again out there lamenting in the public sphere, this time about the lack of TB vaccine research. He reckoned that ten years previously (i.e. in 2002, already 9 years into the official ‘Global Emergency’) ‘all of the TB vaccine researchers in the world would have fit into the back of a minivan’. Twenty years later and this situation has certainly improved some, but still no vaccine has emerged, and currently none is expected before 2027 at the earliest.

Yes, you’re ahead of us probably – now just consider this for a minute in the light of the rapid vaccine research response to the coronavirus with all its more obvious incumbent associated profit potentials.

Drugs

Rifampicin, the most recent first line drug that was developed and approved for TB, and still the strongest, is now 59 years old. Yes, there have been two new drugs approved a decade ago specifically for treating drug-resistant TB, but neither are appropriate for first line drug use, nor have they been rolled out as widely as had been hoped for MDR-TB, nor are they are easy to manage, and anyway both are far too expensive to be practically employed as first line drugs anyway.

So, 59-plus-year-old medication still being employed a full 30 years after TB was officially declared a ‘Global Emergency’ and 17 years since Peter Small first woke us up to the issue – is this any sort of prior track record to aspire to?

Death rates

Active TB, if left untreated, is accompanied by a case fatality rate of between 50 and 70% (the estimates vary). If treated appropriately, however, (i.e. following a bacteriological confirmation of disease, of course) the global death rate really should now be less than 5%. In other words, if 10 million new active cases occurred each year, at the most half a million lives maximum should be lost to this disease each year.

Disturbingly, even with effective drugs available, the current estimated death toll remains three times this number. It's stubbornly sticking at around 15% (and unfortunately we believe this may well be even higher). Consider this for a minute in reference to COVID-19 disease with a case fatality rate of less than 1% without any drugs, and compare the quantity and quality of the global response to each, particularly the scale of mobilisation of funds and general resource. But we need to repeat something important in relation to this: that this unacceptable TB death toll of at least a million annual excess deaths is still occurring a full THIRTY YEARS AFTER THIS DISEASE WAS OFFICIALY DECLARED A GLOBAL EMERGENCY.

This surely makes TB both a public health and political scandal by any measure - and it's one which reflects shamefully on all of us, but most of all it reflects appallingly on:

· the global authorities entrusted to control this disease. The WHO, for instance, was founded in 1948 with the specific original aim of controlling TB along with malaria and sexually transmitted disease. Plainly it is still failing in its mission with regards to tuberculosis 75 years later despite drugs being available for at least two-thirds of this time;

· the political leadership of the world. It was, after all, the UN’s own World Health Assembly that collectively declared TB to be an Emergency back in 1993 and which has continued to set targets for TB every few years that invariably are subsequently serially missed

· and specifically the health ministries of all high burden TB countries who for many reasons (some, but not all of them, bad) have failed in their implicit social contract to protect so many of their most vulnerable citizens.

What next?

Some time in September a major review meeting (following up on the UN’s Special Meeting on TB in 2018) is to be held in New York. It will be attended by world leaders and will review how the targets for 2022, all set unanimously by the leaders of 192 countries in 2018, have or haven’t been met. Sadly, we already know that actually none of them will have been met by September, but worse, that some important ones will have unfortunately been missed by staggeringly large percentages. But sadder still, we fear that next September much of the blame for this will be being erroneously and expediently allotted to the coronavirus. If this happens it will be a duplicitous review because these targets were already way off track before the coronavirus emerged, and in any case 30 years is at least two decades too long for a Global Emergency to persist and it has been neglect in world governance that has allowed this to happen.

It's worth adding that in this same thirty year period TB has lost but then twice taken back its unholy crown of being mankind’s most lethal infectious foe (once from HIV/AIDS, and the second time from COVID-19). So it is still wearing this crown today, this World TB Day.

So the informed response to today’s strapline message of ‘We can end TB!’ is surely this: yes, we can indeed end TB, but only if those entrusted with the capacity to make the necessary changes start taking appropriate action. Much more and much better diagnosis is needed, along with much more case finding, much more funding for both national TB programmes and for research, and a new safe and effective vaccine is of course also needed, along with much better drug treatment administration and shorter drug regimens – all of these will help. But even this will only take us so far, because TB is well recognised to be suffer from significant socio-economic factors, well evidenced by the epidemiological record. And because of this, the only way that TB will in any real sense truly ‘end’ is when the world’s appalling inequalities are levelled up at the same time as a proper biomedical response is finally implemented. This is how this awful disease will stop reaping its appalling ruthless annual harvest on the world’s poor.

And it's not just by a little levelling up.

It's a lot of levelling up that's needed now.