Latent TB (Part 4) – acquired immunity and mixed infections
Let’s set the scene by starting with some much-needed good news.
Protection from further infection afforded by a TB infection
In the process of writing these blogs we’ve come to a new appreciation of how the risk of a re-activated infection following an initial latent infection falls so ‘precipitously’ after the first twelve months after infection[i]. Put in the simplest of terms, this means that if you’re unlucky enough to have spent some limited time in the presence of an infectious TB patient and a year later you haven’t developed any signs or symptoms of disease, then your chance of developing TB is generally pretty slim.
What this further suggests is that, after a certain delay, the host immune response to TB may well manage to literally sterilise the infection, and could even do so in the vast majority of cases – so (in the simplest of terms), while all of those current 1.7 billion latent infections worldwide might still test positively for latent disease, only those most recently exposed to the disease (i.e. who have recently been in close contact to a probable cohort of about 20 million prevalent potentially infectious cases[ii]) are at significant risk of developing disease. In fact most of the rest may be harbouring no real risk at all.
That has to be good news. Essentially it makes it a numbers game with risks significantly reduced by the elapse of time. But of course, this assumes that the infectious exposure was only ever a one-off event – and this very clearly isn’t the case at all in countries with high rates of TB, particularly in their hotspots. In these places exposure to infectious TB may be regular - even daily. So this changes things: in these environments an existing latent case is being inevitably exposed to more TB (of potentially different genetic strains of disease), and this may even continue for a lifetime simply though breathing in the neighbourhood air. And the truth is that no-one has a real idea of what this really means – except that it makes things a lot more complicated. And in the 12 months after first infection things aren’t just the same – they turn out to be more complicated still…
So does a TB infection confer meaningful protection against further infection?
This is an important question for us to consider: does an original primary infection that remains latent (and may even be sterilised) provide protection against further infection(s)? Well the general consensus is that it does offer some protection, though this appears to be very variable, and may in some instances even do the opposite (defaulting to become a ‘super-infection’ as a result of further infectious assault).
A 2012 paper attempted to collate all the available data and put a figure on this and its conclusion was that a primary infection provided a significant and very encouraging protection of 79%.[iii] But this conclusion (developed from a mathematic model as is normally the case with these sorts of papers) equally concluded that 90% of the new infections among the latent infections were as a result of a new infection, and so weren’t from the original infection that had resulted in the initial latency. The data they used was old (i.e. it was using historical TB data) and certainly couldn’t have included anything that actually measured this in terms of DNA fingerprinting since all the data reviewed predated this technology.
This 90% percentage did seem to us to be unexpectedly high: surely it would have been much lower if the protection from a latent infection really was so significant? In the paper itself this apparent anomaly was simply explained away as being as “a consequence of the high annual risk of infection”, but to us this still doesn’t seem a sufficient explanation.
So we picked the data apart further as best we could. It turns out that the cohorts that this paper had considered were all “young healthy individuals” (mainly they were healthy disease-free nursing students, medical students and “young women” assessed at the start of their training and then later on) and they were all reviewed between 1929 and 1954. In other words, these cohorts weren’t composed of individuals with any particular compromised immunity with accompanying high risks of developing TB. This review was, in essence, assessing healthy individuals who were likely to be exposed to TB as part of their work which in turn implies that the significant 79% protection would hardly be typical of the pandemic today. In fact, it might well be significantly less in a typical TB infection in any low-income country, particularly in one with high rates of HIV/AIDS.
We found some support for this more cautionary perspective in a recent study which identified a much lower risk reduction (of 35%) in a high risk setting in Lima, Peru. So perhaps this much lower percentage might be nearer the ‘real world’ measure? It does seem possible.
It’s worth noting that the authors of the 2012 paper themselves went a lot further themselves, adding that, “In high HIV-burden communities, the negative impact of HIV on immunity likely outweighs possible protection afforded by latent infection”. With such a proviso, it’s possible that only a little protection is afforded by a first latent infection in many African communities, but then even this would be subject to the level of anti-viral therapy available to those same communities so could be better with good HIV support.
But let’s at least accept this much: that an infection of latent TB does confer some protection in many cases, but that this needs to be carefully considered in the light of the amount of prevalent disease that the case is continuously exposed to along with the socio-economic environment – and the truth is we still don’t know enough to be definite about it.
What we think we can still be definite about, though, is that the risk of disease progression does fundamentally depend on the state of the host immunity.
Secondary infections
But what was also clear from the 2012 paper was that 90% of the reactivated disease that emerged was not a result of the original infection. If this is generally true, then it would seem that most reactivated TB that emerges in high incidence environments isn’t the original infection at all – it’s actually a secondary one, and this has all sorts of implications.
To help us understand this better, we can consider a paper from 1999[iv] which took a different look at this issue of protection and secondary infections, looking this time at contemporary cases from the end of the 90s (not historical ones), and it drew slightly different conclusions as a result. It also used modern technology to do so, using DNA fingerprinting to identify whether TB disease which re-emerged in patients who had already been ‘cured’ of their TB was of the same strain as the original infection. Their findings were revealing: 75% of these ‘relapsed’ disease was not of the same strain as the original infection indicating that their so-called ‘relapse’ wasn’t a relapse at all but was a reinfection.
They then added the following text which adds an extra layer to this complexity: “In areas with a high incidence of tuberculosis, exogenous reinfection might also be a cause of the first episode of post-primary tuberculosis, since the immunity that develops after primary infection followed by a period of latency cannot be expected to confer more protection against exogenous reinfection than the immunity that develops after an episode of active disease.”
And what this in turn implies is that there also may be many cases of mixed infections even while the disease is still latent.
Mixed infections
So now we have two caveats to apply to the capacity of a TB infection to provide protection: first, it may well not provide sufficient protection during a latent infection to prevent a second infection from provoking a primary reactivation; and second, a reactivated infection may well not provide sufficient protection to prevent a second episode of reactivated TB as a result of a fresh infection.
We will pick this up again in more detail shortly. But initially we should be careful about drawing too broad a conclusion about this, particularly about that 75% of ‘relapsed’ cases actually being new infections because this study used data from South Africa from a high incidence area with an incident rate of 251/100,000 at the time. Similarly to the 79% protection rate discussed above, it seems unlikely that this would be typical of the wider pandemic. In fact, in this case, it might be much lower globally.
In relation to this, another paper published two years later took another look at this which supports this idea.[v] This time it monitored TB patients in an island (Gran Canaria) with a much lower incident rate of TB of only around 31/100,000 (or an eighth of the previous study) all of whom were monitored after relapse. Again they used DNA fingerprinting, and their results were more modest than those from South Africa, but unfortunately are still pretty alarming. They suggest that 44% of recurrent TB is from a second infection, and isn’t an endogenous resurgence of the original one (so again is not a relapse). Not three-quarters, as in South Africa, but nevertheless still nearly half.
One further paper came to similar conclusion.[vi] It reviewed 90 years of historical TB data in the UK from 1900 onwards in the light of a current understanding of the mechanisms of disease progression in TB. Broadly speaking they found themselves unable to make coherent sense of their review unless they allowed for re-infection having played a significant role. They even concluded that re-infection “made an important contribution” to the UK’s TB epidemic over this period.
But let’s go back for a minute and consider that earlier quote from the 2012 paper: “In areas with a high incidence of tuberculosis, exogenous reinfection might also be a cause of the first episode of post-primary tuberculosis” because this has implications as well.
Exogenous (new) reinfections and reactivations
So what exactly does this mean? It means that what was believed to be a simple progression of a primary infection from latency through to re-activation may not be so simple at all: in fact the reactivated disease may be from a secondary infection.
It further means that an initial primary infection with strain ‘Y’ (which has already been rendered by host immunity to sub-clinically latent) may not provide sufficient protection to prevent a second infection with strain ‘Z’. And so, at a particular point of time, both might be technically latent (and the latent infection can then be classified as ‘mixed’ or polyclonal), but at this stage this can’t be determined – that is unless the case died and an analysis was carried out post-mortem. But if the patient remains alive then at a later point of time either one of these two strains might reactivate. In fact it’s quite possible that both might do so (but do so at different rates depending on their relative virulence). And shortly we’ll see that this seems to be happening in a substantial proportion of cases.
Of course, if both strains are drug-susceptible it shouldn’t make that much difference anyway, but what if one isn’t? And anyway, is this a risk worth worrying about?
Polyclonal “mixed” infections
Well it turns out that a surprising number of studies have reported that individuals with reactivated disease can simultaneously harbour more than a single strain of TB. In fact this has been known over many years. A review study, published in 2012 in the Journal of the American Society of Microbiology[vii], attempted to make sense of exactly these studies, and its conclusions are certainly thought-provoking.
The study first confirmed that a “substantial fraction” of first-time disease may be the result of instances of re-infection rather than from primary ones, and furthermore added that (in certain settings) 10 to 20% of cases are probably infected with multiple strains. The review went even further, in fact, suggesting that (given significant limitations in the capacity of current techniques to identify them) such mixed infections may even be “very common”.
All the studies they reviewed had identified mixed infections in cases of reactivated TB, of course, because it’s only in this active state that identification of such strains is possible. No-one yet has taken a stab at how many latent infections may be mixed, by the way, though a recent study reckons that they may only account for a “low proportion”.
Whether this is accurate or not (or whether this is even of any epidemiological significance) is frankly anyone’s guess at this point of time. Our own guess would be that wherever there are high rates of TB and also an average incidence of mixed infection then they are most probably similar to that 10-20% referred to above – and if these mixed infections involve one strain that is drug-resistant and one that isn’t then they must surely be epidemiological significant.
The review paper, meanwhile, also took pains to identify that the most significant obstacle to developing any accurate data relates to the limited sensitivity of the methods of measurement (they reckoned, for instance, that a minority strain would need to be present in “extremely high numbers (of between 10 to the power of 7 to 10 to the power of 9)” at the time of sampling for them to be detected at all, so many mixed infections would be missed as a result). They therefore suggested that all current estimates of the prevalence of mixed-strain infections should be treated as “a lower bound”, and that the actual proportion of cases with mixed infections may be significantly larger, not least because this wasn’t the only limitation to accuracy that they identified in their review.
Meanwhile another study from Capetown, South Africa, from way back in 2004 generally confirmed the higher estimate, recording that 19% of all patients tested had multiple strains, including 17% of new patients (only 10% of whom may have also been HIV positive).[viii] It’s worth further noting that this percentage of polyclonal cases could actually have been even higher since they were only testing between two drug-susceptible strains of TB of ‘different evolutionary lineage’, and were not differentiating between strains that might be differentially resistant to TB drugs. This also, of course, further confirms that the rate of reinfection in high incidence areas may be frighteningly high.
A study in Uganda came to not dissimilar conclusions, but added a further perspective relating to the impact of HIV coinfection. It reported that a significantly higher proportion of patients with mixed-strain infections were HIV positive rather than negative (37.5% in HIV positive cases versus 16.6% in HIV negative). This finding begs the logical question as to whether impaired cell-mediated immunity of any sort (not just from HIV) might increase the probability of harbouring multiple infections, and this does seem likley. It has to be added, though, that the progression of disease in such cases is well known to be complicated, and may in any case be fundamentally dependent on whether the patient is at the same time being treated for their HIV (adding to the importance of treating HIV and TB together).
But the possibility for huge challenges for treatment of TB is not hard to imagine. So let’s imagine one specific possibility.
A polyclonal case with one strain that is MDR
Let’s assume that our patient has a mixed infection with two strains, one of which is more virulent and is drug-susceptible, and the other which is less virulent but is MDR. (This is the classic picture of the nature of MDR-TB, of course – believed by many to be less virulent when drug-resistant). And for this to occur, our patient will also almost inevitably live in a high incident environment where there is also above average MDR-TB.
The patient first develops symptoms that are easily recognisable as potentially tuberculosis and so, exactly as encouraged by her National TB Program (NTP), she takes herself promptly down to her local TB clinic for a check-up. Two sputum tests quickly confirm that she has TB and she’s immediately put on first line drugs and her symptoms quickly reduce in a few weeks. She’s even checked again at two months and happily there are no signs of disease in her sputum (why should there be? – the dominant strain has been hit hard by the TB drugs, and the available sputum microscopy is nowhere near sensitive enough to spot the secondary strain). But she’s a well-managed patient, and she perseveres with the treatment for the full six months so that at its end she’s confirmed as ‘cured’ having further final bacteriological confirmation of clearance of disease by microscopy.
But two months later her symptoms return, and she takes herself back to the clinic. Thankfully her NTP has the capacity to carry out a check for Rifampicin resistance, and so they check her sputum again (this time by GeneXpert) and she’s confirmed as being proxy-MDR by default of her infection being Rifampicin resistant.[ix] The clinic staff now admonish her because they figure that she can’t have taken her TB drugs properly first time round (because otherwise how could she have relapsed to be MDR?). The clinic superintendent meanwhile admonishes the nursing staff for not having managed her properly (because otherwise how could she have relapsed to be MDR?).
But, of course, the truth is that no-one was at fault. What had happened was that the dominant strain had indeed been treated successfully, but that this had allowed the sub-dominant strain to slowly proliferate to the extent that, not that long after the patient had been declared cured, there were sufficient numbers of drug-resistant mycobacteria to provoke a new set of similar symptoms.
But now our patient is on a harder road – unless she’s in South Africa (where she’ll get an all-oral regimen which includes bedaquiline) she’s faced with daily injections for six months and around 1400 pills over the next two years. And she faces only a 55% chance of successful outcome and a good chance of permanent debilitation as a result of side-effects of the toxic second-line drugs. In fact, she may be even more unlucky and have to wait haplessly for treatment at the end of a lengthening queue because there aren’t enough drugs available for her, possibly getting no further treatment at all.
She did nothing wrong, of course, and the NTP did nothing wrong. So might this exact scenario account for some of the low success rates when treating TB?
Of course there are other possible scenarios that our patient faces:-
There may have been no facility to test for drug-resistance at all, so she remains classified simply as ‘failed’ or ‘relapsed’ (probably the most likely) and will get no further treatment and will probably die after infecting others with a programmatically untreatable disease.
Or the initial virulent strain wasn’t completely cured and then regroups as the second line drugs take their toll, and the patient becomes sicker and more and more unable to cope with the second line drugs.
In either case her prospects are very poor.
Mixed infections in extra-pulmonary TB
Since we’re talking mixed infections it’s also worth bearing in mind that they don’t only occur in the lungs (as is also the case with TB generally – which will be the subject of another future blog).
When it doesn’t do so, it’s termed as extra-pulmonary TB, and this can occur pretty much anywhere in the body, in which case it can be very difficult to spot, and is also challenging to treat (though thankfully it’s not often infectious). This most often occurs in folk with HIV, or in kids (i.e. it’s more frequent when the immune system is particularly vulnerable to the disease).
How many TB cases are EP is very questionable (this will be the subject of our future blog on it) – but, of course, what’s also questionable is whether TB can occur simultaneously in both a lung and another organ but consist of two different strains (i.e. be polyclonal but separately so in each location). Unfortunately, it looks like it can do, and what’s more it can do so at some scale. A Ugandan study from 2015[x] took a careful look at this in HIV positive individuals with CD4 counts that were lower than 200 (i.e. with advanced HIV) and who also had evidence of TB in both sputum (pulmonary) and blood (extra-pulmonary). Their results were concerning: a substantial 51% of them were shown to have different strains in TB in their lungs and internal organs, and the study generally concluded that the majority of co-infected cases with advanced HIV infection might have mixed infections.
Conclusions
One conclusion is obvious. TB is a complex disease, not helped by its capacity to become resistant to the drugs designed to treat it.
It's also obvious that frighteningly little confidence can still be given to much of the general understandings of the progression of this disease, exactly because of this complexity (but also because of the shameful neglect that has been awarded it since the 1960s.
But our final conclusion to this four-part blog is that the host immune response is key to much of the known progression. And we remain fundamentally convinced that a broad low-level stoking of the human system may help make a difference to any stage of disease progression.
What's more, we think that small cone direct moxa may do exactly this, and we are more committed than ever to figuring how true this is conviction is.
[i] https://www.bmj.com/content/362/bmj.k2738
[ii] This is an educated guess because the WHO no longer publish estimates of prevalence in their annual reports.
[iii] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3284215/
[iv] https://www.nejm.org/doi/full/10.1056/NEJM199910143411602
[v] https://www.atsjournals.org/doi/full/10.1164/ajrccm.163.3.2003070
[vi] https://cmr.asm.org/content/25/4/708
[vii] 2012 journal society of micribiology
[viii] https://www.atsjournals.org/doi/10.1164/rccm.200305-714OC
[ix] They had no reason to do so originally according to her NTPs national guidelines because she had responded positively to her original first line medication and didn’t fall into any risk category that suggested she should be further tested,
[x] https://www.ncbi.nlm.nih.gov/pubmed/26176604
