The Leprosy Mission Research Magazine - July 2022
The 4th edition of TLM's Research Magazine looks at transmission research, the latest on drug resistance, the history and future of PEP and treating ulcers
TLM's Research Magazine
Issue 4: July 2022
Leading the charge towards the last ever case of leprosy
Leading the charge towards the last ever cases of leprosy
Eliminating a disease is not something that happens thanks to one organisation or one group of people in isolation; eliminating a disease requires partnerships across the world from all levels of society. But, leading the charge towards a world where leprosy has been eliminated are the scientists that are cracking the codes of leprosy transmission.
The researchers at the Stanley Browne Research Laboratory in India are working on three key research projects that are driving us towards zero transmission. One focuses on epidemiology, another is concerned with a PCR test for leprosy, and the last is about mud.
Genotyping is the key to identifying the source of transmission
Our scientists in India have been tracking the spread of leprosy within an eight block radius of high leprosy transmission in Purulia, India. They have taken samples from 112 people who have been diagnosed with leprosy and their close contacts. The team have extracted the leprosy DNA from these samples so they can be tested for genotypes.
Genotyping is the process of determining differences in the genetic make-up of an organism. It is how we can see the genes that have been passed on from your parents to you. In the case of leprosy, it allows us to see which strain of leprosy a person has and where that has come from.
How does that help us end leprosy transmission? Imagine a mother and daughter living in a home in Purulia. The team have taken a swab from both the mother and the daughter. The mother’s swab contains leprosy DNA, as does the daughter’s swab. However, the genotyping reveals that the leprosy DNA in the two swabs is different – it has different genes, so it must be a different strain. This tells us that the daughter did not contract leprosy through her mother; she must have contracted leprosy elsewhere.
This knowledge could then direct our field teams to determine the real source of the transmission. Perhaps there is a classmate at the daughter’s school who has undiagnosed leprosy. Perhaps it is one of the children from a neighbouring home that the daughter plays with regularly.
Genotyping will allow our teams to narrow down the source of transmission. Their contact tracing does not stop simply with the mother, but extends until the index case is identified. Through this, we are in a better position to look for signs and symptoms, to provide treatment, and to provide post-exposure prophylaxis (PEP) in the form of one or more antibiotics.
As leprosy programmes across the world look to expand their PEP, contact tracing, and active case finding efforts in line with the new WHO leprosy strategy, this technology will allow them to be more targeted than they ever could have been before.
This is true on a local scale, like within a household or neighbourhood, and also on a much larger scale. Certain strains of leprosy are more common in particular parts of India and our scientists are now better equipped to identify how these strains are spreading, where they are starting, and if there are interventions we could be making to interrupt this transmission.
PCR Tests for leprosy: a game changer
At some point in the last two years, all of us will have taken a PCR test for Covid-19. A PCR test allows researchers to make copies of a small section of DNA or RNA, which means they can produce the large amounts of DNA they need to perform molecular and genetic testing.
Over a number of years, our team in India have been testing one gene marker of leprosy at a time to determine which of these genes have the most sensitivity to tests. In October 2021, the Stanley Browne Research Laboratories were in a position to combine three of the most sensitive gene markers into one multiplex PCR test.
This test is 90 percent successful at diagnosing cases of leprosy, including the really early cases of PB leprosy. Previous tests have only been 60 percent effective and this test is nearly at a stage which could see it rolled out as a field-friendly, small, battery-operated testing machine that works through nasal swabs.
This multiplex PCR test is being perfected and prepared for an initial pilot within India’s leprosy programmes. By 2024, it could be ready for a global rollout that would make leprosy diagnosis faster and more effective than ever before. It could be a game changer in our fight to end leprosy transmission by 2035.
Mud is more important that you know
The Stanley Browne Research Laboratories are world leaders in the understanding of environmental reservoirs of leprosy bacteria.
The leprosy bacteria, M. leprae, is most commonly understood to be transmitted from human to human. However, leprosy has also been identified in armadillos - who are known to transmit leprosy to humans. The UK’s Red Squirrel population, and a wild chimpanzee population in West Africa have also been identified as carriers of leprosy bacteria, although there is no evidence of transmission between these animals and humans.
Our researchers in India have been looking at the extent to which leprosy bacteria can also be found within soil and water.
They have been looking at remote villages in India where there is a high level of leprosy transmission and only one water source per community. They have tested both the water and the soil surrounding this water source to identify leprosy DNA and, where viable leprosy bacteria is found, they have used genotyping to compare this to leprosy DNA from the recently identified leprosy cases in the village. Through this, they can draw a direct link between new cases of leprosy and leprosy DNA that is found in water and soil.
So far they have identified a link between leprosy DNA that they found in soil and water and new cases of leprosy that have been identified in 20 separate families.
This research has been conducted within Purulia and Chhattisgarh, where communities are underdeveloped and suffer from poor WASH facilities.
If we can identify that viable leprosy bacteria from water sources in these villages is leading to members of the local population developing leprosy, we can take this knowledge to local governments. We can make the case for new wells in these communities so that people can access clean water, which will not bring the risk of leprosy transmission.
The knowledge from this project could be used across the world, it can focus our WASH efforts, and it can be another tool in our advocacy toolbox.
Photo credits: Ruth Towell
What is drug resistance and should we be worried about it in the leprosy world?
What is drug resistance and should we be worried about it in the leprosy world?
In this video, Dr Deanna Hagge, Senior Research Advisor for The Leprosy Mission International, speaks about drug resistance and the impact it will have on leprosy.
Deanna considers:
- What drug resistance is
- Why drug resistance is having an impact on leprosy patients today
- How drug resistance is being tracked across the world
- How drug resistance is affecting leprosy transmission
- What work TLM is doing on drug resistance
- What leprosy treatment could look like in the years to come
How scientists created a watershed moment in the fight to defeat leprosy
How scientists created a watershed moment in the fight to defeat leprosy
Post-Exposure Prophylaxis (PEP) has become big news in the leprosy world over recent years. A post-exposure prophylactic is a medicine that prevents people from developing a disease after they have been exposed.
In practice for leprosy, PEP means that we identify people who are close contacts of someone who has recently been diagnosed with leprosy and we give them a single dose of an antibiotic called Rifampicin. This single dose reduces the likelihood that they will go on to develop leprosy by as much as 60 percent. In people who are already vaccinated against TB, the risk is reduced by as much as 80 percent.
PEP is not the tool that will single-handedly end leprosy transmission, but it has unlocked a world of opportunity.
So what has gotten us to this point? For decades, scientists have been working hard to get us here and even now they are working to improve and perfect PEP to make it more effective.
We talk to Professor Jan Hendrik Richardus, who has been there for much of that journey, to find out how we reached this point.
PEP for leprosy is a much older idea than we might realise
“The idea of a post-exposure prophylaxis is not unique to leprosy and is used in a lot of other illnesses (for example, HIV). In the leprosy world, PEP was already been considered as early as the 1970s. At that time, they were using Dapsone and variations of Dapsone as the prophylactic.
“They could see that this was having an impact, but it was far from a perfect scenario. Patients had to take Dapsone for years before they could be sure that leprosy had been prevented.
“Not long after this, MDT was developed and rolled out and people thought this would be the ‘silver bullet’ that would end leprosy transmission once and for all. Because many scientists held onto this belief, PEP was de-prioritised. We were very happy to see that MDT was curing patients, but ultimately there was an acknowledgement that it was not interrupting transmission. That is when PEP was revisited.”
The early days of PEP as we know it today started in the 1990s
“Of the three medications that make up MDT, Rifampicin is the most potent by some distance. Dapsone and Clofazimine slow down the growth of the bacteria, but they don’t kill the bacteria; it is Rifampicin that kills bacteria. Even one dose of Rifampicin can kill up to 99 percent of leprosy bacteria in the body.
“Because scientists could see the potency of Rifampicin from the very beginnings of MDT, Rifampicin became the obvious drug to start using for PEP.
MDT Distribution in Mozambique (Photo credit: Ricardo Franco)
“In the 1990s this was trialled in a few places in the Pacific, but the studies had not been designed in the most rigorous way and so the results were inconclusive.
“Next, the Royal Tropical Institute in Amsterdam began working with Indonesian partners in a PEP trial. The study was quite an elegant one and was trialled on five small Indonesian islands with high levels of leprosy.
“On two of the islands, everyone received a single dose of Rifampicin. On another two islands, only the close contacts of leprosy cases were given a single dose of Rifampicin. On the final island, no one was given Rifampicin as PEP. The researchers saw that PEP was quite effective on the island where everyone received a single dose of Rifampicin but less effective on the island where only close contacts received a dose.
“These were interesting results, but these were very small islands and so you could argue that everyone was a close contact of a new leprosy case. The idea of giving a single dose of Rifampicin to everyone in a country is also both highly impractical and would increase the risk of drug resistance.
“This was the point when it was decided that we needed a properly designed, thorough, Randomised Controlled Trial (RCT) with high numbers of participants.”
The watershed moment
“The COLEP study took place at TLM’s Nilphamari centre with funding from American Leprosy Missions. This was an easy choice of location. There were high numbers of cases and a well-trained network of field staff who could implement a project like this. We also didn’t face significant problems in accessing the communities involved; they weren’t too far away or difficult to reach.
“The study began in 2002 and by the end there were over 20,000 contacts involved in the trial. Because this was a Randomised Controlled Trial, the methodology was as solid as it could be and the results were as statistically significant as we could hope for.
“The COLEP study showed that after two years there was a 60 percent drop in the number of leprosy diagnoses among individuals who received a single dose of Rifampicin. This increased to 80 percent for individuals who had received the BCG vaccine for Tuberculosis as a child.
“It became a watershed moment in the movement towards establishing a post-exposure prophylaxis for leprosy. The COLEP study showed that PEP was cheap, feasible, and an effective way to prevent leprosy.
“The results from COLEP were published in 2008 and by 2018, PEP was adopted into the WHO’s guidelines for leprosy control. That might seem like a big gap, but it is quite common that new approaches take around a decade before they are adopted into official guidelines.”
The future for PEP
“PEP is the most effective preventative for leprosy that we have right now. That is not to say that it is perfect. There are two problems that we need to consider.
“The first problem is that PEP is not effective for all individuals. People who have been exposed to high levels of leprosy bacteria do not respond as well as we’d like to receiving a single dose of Rifampicin. Because they already have a high bacterial load, the single dose simply isn’t sufficient.
“What these individuals need is something that is halfway between a single dose of Rifampicin and receiving a full course of Multi Drug Therapy.
“That is what the PEP++ project is hoping to determine. In Indonesia, India, Nepal, Bangladesh, and Brazil, a trial is underway to see if there is another antibiotic that people could take after they’ve been exposed to leprosy. Or perhaps they need to take more than one dose. Or perhaps they need a combination of Rifampicin and something else. These trials are aiming to help us find the right combination of medication to prevent leprosy.
“In the future we can use improved diagnostic tests to identify who has a high bacterial load so that we can give them the enhanced PEP regime and everyone else can receive a single dose of Rifampicin.
“The second problem with PEP at the moment is the complications around implementation. How do we get preventative antibiotics into the hands of everyone who has been exposed to leprosy? No NGO has the capacity to make that happen. It will certainly require us to work in partnership with national health systems.
A participant in the LPEP study in Nepal
“The LPEP project looked closely at this issue of implementation in Indonesia, India, Nepal, Myanmar, Sri Lanka, Tanzania, and Brazil. They wanted to create rigorous, best-practice systems for implementing PEP. This means identifying new cases, conducting surveys to identify their close contacts, and getting PEP to those close contacts. This requires precise thinking and a degree of health systems strengthening. The LPEP project got us a long way towards getting this right.”
Is PEP the key to ending leprosy transmission?
“No. But no single thing will ever be the key to that.
“PEP is an enormous step forward, but it has to work in tandem with a number of different things. We have to have effective programmes for active case finding and contact tracing. These two interventions on their own are vital to interrupting transmission. PEP, when used in combination with these things, is going to even further interrupt transmission.
“New diagnostic tools, vaccines, and PEP will all be crucial interventions that scientists will make in the coming years, but they will have very limited success if we don’t make the move from passive case detection to active case finding.
“My team are currently mapping the extent to which these interventions can impact transmission rates in contexts around the world. It’s hard work, but it’s giving us significant reason to be hopeful.”
Front cover photo credit: Sabrina Dangol
Read Professor Jan Hendrik's paper, 'Protecting people against leprosy: Chemoprophylaxis and immunoprophylaxis' >
The next tool we can use against leprosy ulcers?
Honey.
The next tool we can use against leprosy ulcers? Honey.
Leprosy ulcers are well documented as being among the most challenging and serious complications of leprosy. Around 1 in 5 leprosy patients will suffer a foot ulcer and many of these people will suffer multiple ulcers over their lifetimes.
As well as being very unpleasant, ulcers often require patients to spend time in hospital so that infections in the wound can be treated and a saline dressing can be applied to heal the wound. For many patients who are already working hard just to feed their families, this time away from the communities and their livelihoods is most unwelcome. But if they do not receive this kind of treatment, potential infections can become so serious that they can lead to amputations.
TLM Nigeria are currently working on a new research project, the HELP (Honey Experiment on LeProsy Ulcer) Study, which is taking place under the RIGHT CALL-1 project. This project is attempting to confirm whether honey could be used to make life easier for leprosy ulcer patients.
We talk to Mr Israel, who is a physiotherapist in the TLM Nigeria team to find out more.
Honey is known to have healing qualities
“Although using honey to treat ulcers might sound unusual to people who do not have a scientific background, it makes a lot of sense.
“Honey produces small amounts of hydrogen peroxide in a slow release manner, which serves as an antibacterial. It is currently being used in many skin clinics to treat burns and skin ulcerations that have been caused by accidents, so it is not a new concept. The HELP Study is aiming to clarify the efficacy of using honey to treat leprosy ulcers so that clinicians can have a scientifically proven basis for using honey in their own ulcer treatment practices.”
There are serious advantages to using honey
“The standard practice for leprosy ulcer treatment today is to apply a saline dressing to the wound. This is an effective way of treating the ulcers and has been for decades.
“However, there are reasons that honey could be a better option and they mostly relate to accessibility.
“Normal saline is only readily accessible in hospitals and through pharmacies. It is created by pharmaceutical companies and sold for use on ulcers and in other medical contexts. That means that a patient must come to the hospital or clinic in order to be treated. Treatment can last for months, so patients have to be away from their homes and families for long stretches, sometimes for 12 months or even longer. This is particularly tiresome for patients when the ulcers happen again and again.
“Honey is different, however. Many patients can access the honey in their community. In fact, much of the honey we are using in this Study is being sourced from some of the more remote communities in Nigeria where there are a number of leprosy patients.
“Patients will still need to attend hospital when they first develop an ulcer because the medical staff need to ensure that any potential infection has been cleared. However, once the wound is clear of infection, the patient can return home and apply the honey dressing on their own using the honey supplies that are available in their community. This is going to cut down significantly the amount of time patients spend away from their homes in hospital.
“There is also a chance that the honey will heal wounds faster than a saline dressing because the honey has a natural and healing drying effect, which is better than saline dressings, which keep wounds wet, which in turn slows the healing process. Honey effectively pulls water out of the wound and allows them to heal faster.
“There are a number of different ulcer studies happening right now as part of the RIGHT-CALL project. One of those includes the LPRF Study that is being conducted by Dr Indra Napit at TLM Nepal. We are very excited about the potential of LPRF to heal wounds far quicker than the saline dressings.
“The LPRF treatment could revolutionise ulcer care in leprosy, so the honey dressings would not replace that. However, in low resource settings, where LPRF is not possible and where honey is a natural and readily available product, we are hoping the honey-based dressing could be particularly transformative for those patients.”
The study is taking place throughout 2022
“Our plan is to recruit 130 patients to take part in a Randomised Controlled Trial at the Leprosy Referral Hospital in Chanchaga, Niger State. Each patient will have up to 30 dressing changes over a three-month period. The patients will still be discharged if the wound is healed before the completion of the 30 dressings. We will track their progress over this time and compare with the outcomes of the control group, who will use traditional saline dressings.
“We will also follow up with the patients after six months to see if the honey dressings have also reduced the number of ulcer recurrences for these patients.
“We hope that we will be able to publish some findings in 2023.
“We hate seeing patients stuck in our hospitals for months at a time on end while their ulcers are treated; it’s heart breaking. Our sincere hope is that this study will provide the scientific basis for clinicians to begin using honey in contexts where traditional saline dressings are not serving patients well. We hope honey dressings might allow patients to spend much more time at home, with their families, earning a living, and living full lives."
