Leprosy Mailing List – January 4, 2022
Ref.: (LML) Doing what works
From: Joel Almeida, London and Mumbai
Dear Pieter & colleagues,
It is helpful to understand how the world was mobilised against other diseases, and how stagnation was transformed into widespread effective action.
In TB, the 1980s saw the declaration of victory. It was a mistaken declaration. The real battle was yet to begin. Bactericidal regimens had been defined through clinical trials and some projects used them to achieve consistent "sputum conversion" (from bacillated to non-bacillated). These successful projects were the exceptions. The rest of the world continued to drag its feet. Most endemic countries used ineffective interventions. One or two of those countries even declared that TB was no longer a problem. It emerged later that many of their citizens were being killed by TB year after year.
When we (WHO team) tried to introduce a more effective intervention into Bangladesh, it was derided as a "Sheraton program". That is, fancy but unworkable methods fit only for discussion in five-star hotels by well-fed people who did not understand the realities of life. Only when pilot projects demonstrated consistent sputum conversion, instead of the usual 50% conversion or worse, were the sceptics somewhat shaken. Some local organisations adopted the more effective interventions and even tweaked them. Illiterate village women were allocated the central task of ensuring regular ingestion of drugs. These illiterate women produced the world's best outcomes in TB (matched only in China and Vietnam).
We compared the outcomes from various countries across the globe, and identified the key ingredient for consistent success. This was the action taken when a dose was missed. Wherever swift follow-up was done after a missed dose, with resulting ingestion of the missed dose, sputum conversion approached 100% (well over 90%). In nearly every other circumstance, sputum conversion fell away to the sub-50% to 80% level. This critical ingredient (or the absence of it) continues to influence outcomes today.
I visited these village women in Bangladesh and asked them what happened when a patient under their supervision missed a dose. One of them told me, "He comes regularly at about 8am. If he doesn't come by 8:30 am, I find him and scold him severely." That's how near-100% sputum conversion was being achieved. Nowhere else was follow-up so prompt, within only half an hour. Decades of research had gone into identifying the potent molecules, but the magic at the front line was indispensable. The same woman explained, "I tell my villagers that if they start coughing and go to the doctors in the town, they will die. If they come to me, they will live." This was, roughly, true. Without prompt follow-up for missed doses, even people who started treatment were dying of TB.
That strategy, labelled the DOTS strategy, was introduced in one country after another with the help of highly successful pilot projects. The sceptics found it increasingly difficult to resist. (Incidentally, the DOTS strategy included more than just supervision and follow-up for missed doses. It includes generation of political commitment, uninterrupted drug supplies, quality-controlled microscopy and a reliable recording & reporting system).
TB was once a neglected disease, because victory had been declared prematurely and mistakenly. As the DOTS strategy started producing good outcomes, TB control moved higher up in the world's agenda. TB research too got a boost. Now TB work is an important global priority, with all sections of society being roped in to fight TB. Successful projects are the key to mobilising the world for effective action. Successful pilot projects create oases of success. These oases open our eyes to a vision of a transformed world, where gardens replace deserts.
Did the world know everything there was to know about the TB bacillus and its epidemiology? No. We continue to learn. Did that stop the DOTS strategy from saving lives? No. There will always be room for further knowledge. However, that is not a good reason for dragging one's feet. Austin Bradford-Hill wrote, wisely: "All scientific work is incomplete - whether it be observational or experimental. All scientific work is liable to be upset or modified by advancing knowledge. That does not confer upon us a freedom to ignore the knowledge we already have or postpone the action that it appears to demand at a given time." We drive cars without knowing what is under the bonnet. The car works if we know only how to find the starter key, steering, brakes, gear stick and accelerator. We plug holes in dams without fully understanding the routes by which towns were flooded. We do that because it works. More knowledge is always desirable, of course. It can enable breakthroughs. But effective action does not depend on having perfect knowledge.
HD
In HD (leprosy), we know that victory is in the future and not in the past. There are millions living with the sequelae of HD, and those with polar LL (lepromatous) HD in endemic areas are at risk of reinfection. Reinfection converts previously treated but genomically anergic LL HD patients into factories for astronomical numbers of viable bacilli. Recurrent LL HD often goes undiagnosed for years, because the signs are masked by sequelae of previous infection, and annual skin smears are rarely done. This allows HD bacilli to keep spreading to children and others even in well-run programs where active case-finding has been practised for years. Bacilli do not care how they find a new home. They will spread through the nose, through the skin, through the soil, through all channels available to them.
The main thing is that we can stop transmission at source. We can achieve this by prompt diagnosis and prolonged anti-microbial protection of LL HD patients in endemic areas. Then LL HD patients no longer can keep replenishing the environment with bacilli. LL HD patients are uniquely important because careful studies revealed that the nasal discharges of even BL (borderline lepromatous) HD patients did not contain such astronomical numbers of bacilli, whether before or after anti-microbial protection. When LL HD patients were granted prolonged anti-microbial protection, a demonstrable16% to 20% annual decline in the incidence rate of MB HD was achieved even in places that had low incomes at that time (e.g., Uele/DRC, Karigiri/India, Weifang/Shandong/China). Careful surveys demonstrated that these were real declines in incidence rate, not just artefacts of case-finding methods.
Transmission continues in even well-run programmes because we are late in diagnosing LL HD patients and hasty in withdrawing anti-microbial protection.
Further, if MDT is withdrawn at 12 months from LL HD patients instead of being continued, these patients suffer a 600% increase in the risk of ENL neuritis during months 13 to 24 (as discussed here previously). ENL neuritis is an excruciatingly painful condition that drives many LL HD patients to the verge of suicide. It is not in the patients' best interests for us to allow a 600% increase in the risk of ENL neuritis.
Instead of championing anti-microbial neglect of LL HD patients in endemic areas, we could champion prolonged anti-microbial protection for them. That would be not only humane and ethical but also transform our epidemiological impact.
What works in HD?
What is the equivalent of the DOTS strategy in TB? The DOTS strategy had 5 points. The corresponding strategy in HD would appear to have 4 points. It is even more effective than the DOTS strategy in TB, because the HD strategy produced rapid and measurable epidemiological impact..
1) Expert skin camps to ensure that LL HD patients with only subtle signs are diagnosed promptly. Wherever local expertise is scarce, telemedicine allows experts to participate. They can instruct frontline staff how to pinch skin, examine ears & eyebrows etc. Otherwise, we keep diagnosing all types of HD except LL HD, the most highly bacillated and infectious type. Smear microscopy reveals the astronomical numbers of bacilli in nasal discharges (or skin fluid) of unprotected LL HD patients.
In places where finance and technicians are available, further tests can be used. They reveal that up to 50% of randomly selected school children in endemic areas have IgM antibodies to phenolic glycolipid-1, an antigen specific to HD bacilli. Such further tests are not a substitute for smear microscopy, however. Microscopy uniquely allows direct visualization of the astronomical numbers of bacilli present in nasal discharges (or skin fluid) of unprotected LL HD patients. The key distinction to be made is between LL HD and non-LL HD. Then appropriate case management of LL HD becomes possible.
2) Prolonged anti-microbial protection for anergic LL (lepromatous) HD patients. MDT followed by post-MDT chemoprophylaxis in LL HD patients is used in centres of excellence in endemic countries including India and Brazil. Destitute LL HD patients who cannot afford combinations of bactericidal drugs would have to rely on prolonged free-of-charge MDT. We know that about 17% of previously treated homeless and destitute patients in two south Indian towns had bacilli in skin smears. There is no reason to keep offering genomically anergic LL HD patients as fodder for the bacilli in endemic areas.
There are options for post-MDT chemoprophylaxis with combinations of bactericidal drugs. Monthly ROM (rifampicin + ofloxacin + minocycline) was demonstrated to be roughly as effective as MDT. Monthly rifampicin + moxifloxacin + minocycline (RiMoMi) is likely to be even more effective than monthly ROM because moxifloxacin is more bactericidal than ofloxacin. Where finances permit, daily regimens can replace monthly regimens to maximise the area under the curve (AUC) of drug concentration over time. This AUC generally is correlated with the bactericidal effect of drugs, and increasing it helps to eliminate endogenous mycobacteria (as observed in TB). Even when highly bactericidal daily and high-dose regimens are used, however, prolonged anti-microbial protection for anergic LL HD patients remains important. That is because sources of infection in endemic areas can keep reinfecting genomically anergic LL HD patients.
Those LL HD patients who do not have genomically related anergy and "de novo" LL HD but instead "downgraded" from inadequately treated BL HD tend to respond well to MIP vaccine (Mycobacterium w vaccine) Typically, about 70% of LL HD patients in India respond well to MIP vaccine, as demonstrable by accelerated clearance of bacilli from skin and conversion of lepromin status. The remaining 30% of LL HD patients may be taken to have genomically related anergy. Even where MIP vaccine is used, this 30% of LL HD patients is capable of shedding astronomical numbers of bacilli and suffering excruciating ENL episodes if anti-microbial protection is withdrawn.
Where smear microscopy is unavailable, patients in need of monthly post-MDT chemoprophylaxis (and/or MIP vaccine) can be identified by widely distributed, bilaterally symmetrical signs. This is not as specific as measuring the BI (bacillary index) under the microscope. However, it is good enough to protect nearly all genomically anergic patients against reinfection. Otherwise, transmission continues even in well-run programmes because of undiagnosed or belatedly diagnosed recurrent LL HD.
These 2 points above (expert skin camps and prolonged anti-microbial protection for anergic LL (lepromatous) HD patients) can yield a 16 to 20% annual decline in new MB (multibacillary) HD cases as observed in Karigiri (India) and Weifang/Shandong (China). Such declines probably occurred elsewhere too, wherever LL HD patients were protected against reinfection by allowing them prolonged anti-microbial protection. 16% to 20% annual decline is better than the sub-10% decline achieved in Norway or the sub-7% decline being achieved in Yunnan (China) with 24 months of MDT (despite vast increases in income since the 1990s) or the sub-3% decline being achieved globally. It is much better than the near-zero decline of new HD cases observed in the Indonesian LPEP projects that for several years supplemented 12 months of MDT with single dose rifampicin among contacts of newly diagnosed HD patients.
3) In high endemic hot spots in addition to points 1) and 2), add the following
Mass multi-drug administration (e.g., ROM) at intervals of less than a year. Repeat until no child case is found for a few years. This was used alongside points 1) and 2) above in FS Micronesia with remarkable success. It achieved a decline of about 40%/year in new HD cases. Unfortunately, the intervention was discontinued after only two annual rounds of mass multi-drug administration, and prolonged MDT was replaced by only 12 months of MDT.
Which high endemic hot spots could be first in the queue for exemplary projects? Former HD "colonies" are prime candidates for mass multi-drug administration alongside expert skin camps and prolonged anti-microbial protection for LL HD patients. For example, Vila Santo Antonio do Prata in Para, Brazil, showed enrichment of genetic risk factors among the residents. Former HD colonies can rapidly become transmission-free zones. They can be the oases of success that demonstrate how the desert of stagnation can be transformed. Persons affected by HD, in partnership with expert clinicians, and supported by philanthropic organizations, can lead the way out of epidemiological stagnation.
4) Political commitment, generated on the basis of rapid decline in new MB cases resulting from points 1), 2) and 3) above. Successful projects are the best answer to scepticism. No politician can resist success.
(If I may be pardoned a personal story relating to TB, President Clinton visited only one health project in the course of an official visit to India. This was to a Public-Private Mix project in Hyderabad that I had designed and supervised. It was implemented by local professionals who I had trained during a field visit to the illiterate village women in Bangladesh. The outcomes in the project had been transformed from 56% sputum conversion to consistent 100% sputum conversion, with the participation of private practitioners, then an unprecedented step. The President's visit helped change the world's perception of TB and of Public-Private mixes. Successful projects are magnets for political commitment. Real political commitment yields adequate financing).
The fifth point in HD is not part of the strategy. It consists of delaying drug resistance. Avoiding the use of single drugs (e.g., avoiding single dose rifampicin) is very important to delay drug resistance and keep MDT effective. Mass multi-drug administration of ROM enabled a 40%/year decline in new HD cases without rapid selection of rifampicin-resistant mutant bacilli. Regressing to the use of single drugs seems unduly reckless because multiple drugs delay drug resistance while single drugs select drug resistant mutants.
2022 is a turning point. We can progress rapidly with booster rockets attached, in the shape of the four points above (the "HD strategy" that works). There is no reason to remain trapped in epidemiological stagnation, selection of rifampicin-resistant bacilli in undiagnosed LL HD contacts, and increased risk of ENL neuritis. Those adverse outcomes accompany SDR-PEP for contacts and fixed duration MDT for LL HD patients. That does not work. Success seems preferable to stagnation.
We are a community of integrity, justice, compassion and science. In 2022 we can be a community of highly effective action, steadily creating oases (successful projects) that keep transforming the desert of stagnation into a garden of epidemiological impact. Step by step, other areas & countries will join in. Eventually, the whole world will cheer us on & assist this noble effort.
1) Expert skin camps for prompt diagnosis
especially of LL HD patients (highly bacillated) with new or recurrent HD
2) Uninterrupted MDT for all patients plus prolonged anti-microbial protection for LL HD patients in endemic areas
3) In high endemic hot spots (e.g., former "HD colonies) mass multi-drug administration (e.g., ROM) at intervals of less than a year
4) Generate political commitment & adequate financing based in part on genuine decline in new MB cases
Alongside this, we can monitor nerve function especially in MB HD patients & intervene promptly with prednisolone when needed, boost respect for the inalienable dignity of every human being, replace public misinformation & fear with facts & understanding, help persons affected to advance socio-economically & cope with distress, promote inclusion & respect.
This is the future we care about. This is the world we want to create. It is great work, worth doing..
Happy New Year to all.
Best,
Joel Almeida
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << editorlml@gmail.com
--You received this message because you are subscribed to the Google Groups "Leprosy Mailing List" group.
To unsubscribe from this group and stop receiving emails from it, send an email to leprosymailinglist+unsubscribe@googlegroups.com.
To view this discussion on the web visit https://groups.google.com/d/msgid/leprosymailinglist/c3582b99-a1ba-45c4-a6f3-78b6c4b53f1en%40googlegroups.com.
No comments:
Post a Comment