The Leprosy Mission Research Magazine - Jan 2021
The Leprosy Mission's Research Newsletter looks at ENL reactions, leprosy and the link to mental health, treating leprosy ulcers, and a new diagnostic test
The Leprosy Mission's Research Magazine
My name is Dr Deanna Hagge, and I am TLM's Senior Research Advisor and the Director of Research and Laboratories at Anandaban Hospital in Nepal.
I'd like to thank you for taking the time to read our first research newsletter. This is a new initiative that we plan to send out to you twice a year.
Through the research newsletter, we hope to keep you up to date on some of the many exciting projects that are happening across the TLM world.
Often this work goes on behind the scenes, but our research is a crucial part of our efforts to achieve zero leprosy. Hopefully, this newsletter will equip you with new knowledge of how we partner with you to defeat leprosy and to further empower you to pray and be champions of a world without leprosy.
In this issue of the newsletter, we have details on our mental health research in Nigeria, our ground-breaking ulcer research in Nepal, updates on our research into diagnostic tests in Bangladesh, and a longer interview between Tim Burton and myself about research into devastating Type 2 Reactions.
I hope it is an enjoyable read for you.
Dr Deanna Hagge
Front page image copyright: Tom Bradley
Tackling the worst that
leprosy has to offer
An interview with Dr Deanna Hagge
Type 2 Reaction (ENL) is one of the worst complications that leprosy has to offer
Leprosy, if spotted and treated quickly, is easily curable and need not have serious consequences for a patient. However, if the disease is not treated quickly, the bacteria in the body are allowed to build up so high that even after antibiotics, bacterial residues can remain for years. These residues extend the risks of inflammatory episodes, called leprosy reactions, which are the main cause of nerve damage and disability development – such as foot drop, clawed hands, a collapsed nose, the loss of toes and fingers, eye damage, and pressure ulcers. Type 1 Reactions cause inflammation only where leprosy bacteria are located; while Type 2 Reactions, often called ENL (for Erythema Nodosum Leprosum) can affect the whole body – often with worse symptoms and for a much longer time.
A group of scientists and clinicians from across the leprosy world have joined together as an ENL International Study Group called ENLIST. This group aims to provide answers to some of the key questions the disease poses, crucially: how can we treat ENL better than we do currently?
Dr Deanna Hagge, TLM’s Senior Research Advisor, spoke to Tim Burton from TLM’s International Office to explain why ENL is such a pressing issue and how ENLIST is going to make a difference.
Tim Burton: What is ENL?
Dr Deanna Hagge: It’s horrible, just horrible. That’s the short answer. It’s the worst kind of reaction that a leprosy patient can experience.
Leprosy reactions occur in up to 30-50 percent of all leprosy patients at some point before, during or after antibiotic treatment. Reactions are an unpredictable, sudden shift in the immune system’s response to leprosy. White blood cells in the body suddenly change in how they respond to leprosy bacteria. If there are not many leprosy bacteria in the body, often Type 1 reactions develop.
Type 2 Reactions, or ENL, develop in cases with the highest levels of leprosy bacterial load; which means white blood cells have not restricted bacterial growth much or at all for many years. When ENL develops, the whole body develops symptoms. Patients have a fever and incredibly inflamed skin lesions all over their body. They can experience severe pain in their skin, bones, muscles, eyes and/or testicles. Due to this variety of symptoms, they often experience delays in diagnosis because health providers are not familiar with leprosy and suspect other diseases. For example, a man in Nepal spent two years in extreme pain going from doctor to doctor before he arrived at Anandaban, where he received proper diagnosis and treatment.
At times I have heard men sobbing in pain because their skin is so inflamed that even taking a blood sample is agony.
TB: What is the treatment for ENL?
DH: There are currently two drug treatments recommended for ENL: corticosteroids (prednisolone) and/or thalidomide. Approximately three quarters of patients become chronic and require more than 6 months of treatment and half of ENL cases require up to 18 months of treatment to stop having their first reaction. One Anandaban patient’s ENL episode lasted 7 years. Half develop multiple ENL episodes. Most are in and out of hospital for years, with an average of 3 years of total drug treatment.
TB: What are the biggest ENL problems that need addressing?
DH: There’s lots of problems we need to address with regards to ENL but two big problems are: one, finding a treatment that works and doesn’t cause serious side effects; and two, how we can stop ENL from devastating people’s lives.
So, the first big thing we need to consider is ENL treatment. Both recommended treatments have problematic side effects and may not be able to completely stop ENL or nerve damage from occurring. Thalidomide has an infamous history associated with risks for serious birth defects; however, it works wonderfully for subduing ENL symptoms.
"I will hear men sobbing and in tears on the ward"
How much do you know about ENL?
- I know a lot
- I know a bit
- I know nothing
Unfortunately, it is often restricted or banned entirely across many leprosy-affected countries. For instance, in Nepal, a patient has to be in hospital while they are taking it; and that can be a long, long time. It is also a sedative and can itself cause peripheral nerve damage. Therefore, thalidomide is rarely used as a first treatment option because of availability, cost, the patient’s household factors, and potential side effects.
Prednisolone is available worldwide and is the most common treatment for ENL. However, as a corticosteroid, it is not meant to be used long-term. Long-term use in treating leprosy reactions can lead to serious side effects such as blindness, diabetes, and joint and bone problems. We had a young man in his thirties with ENL travel from a nearby country just so he could access thalidomide treatment at Anandaban Hospital. He had already had long-term prednisolone treatment, which had failed to control his ENL and had wrought havoc by causing diabetes, blindness and fractures in his spine. Leprosy and ENL had not caused those permanent outcomes. The ENL treatment did.
Prednisolone causes such severe side effects that it can even lead to patients dying.
Prednisolone causes such severe side effects long-term that it can even lead to patients dying. A study in Ethiopia (where thalidomide is banned) showed that, of 99 ENL patients, eight patients, aged between 19 and 45, died. The researchers recorded four of those deaths as definitely related to ENL and four of them as possibly related to ENL.
But, even for patients who survive, this long-term treatment is causing enormous problems.
Which brings me to the second serious problem we need to consider: the effect that ENL is having on patients’ lives. Remember that it takes half of patients up to 18 months to get over their first ENL reaction. Imagine being away from your home, your family, your work for that length of time. That kind of interruption is devastating in a person’s life.
A London School of Tropical Medicine and Hygiene study in partnership with TLM suggests that an ENL reaction is likely to cost a patient’s household around 40 percent of their income. Not only do these patients have to sit in hospital, experiencing a prolonged and incredibly painful illness, they have to do so while knowing that their family is being buried under catastrophic economic failure.
We have to find better treatments for ENL so that we can stop patients from dying and households and generations from being thrust even deeper into extreme poverty.
We have to find better treatments for ENL to stop severe side effects, deaths, and to prevent family incomes from spiralling.
TB: What is ENLIST and how is it going to make a difference?
DH: ENLIST is a group of specialists that have been brought together from across the world through Dr Steve Walker and Dr Diana Lockwood of the London School of Tropical Medicine and Hygiene. This global partnership includes doctors from TLM hospitals in India, Nepal, and Bangladesh, as well as experts from Brazil, Sri Lanka, Ethiopia, the Philippines, another Indian partner, and myself. It’s been very important to work as a partnership because it’s almost impossible for any one site to perform a large, comprehensive study. Through ENLIST, we can design and conduct ENL studies that need to happen, involving expertise from around the globe.
Through Leprosy Research Initiative funding, we’ve been able to develop an ENL Severity Scale to grade 10 major symptoms of ENL. This provides a global tool for measuring and comparing ENL patients to each other, understanding how symptoms change with treatment, and allowing us to classify a patient’s condition as mild or moderate-to-severe ENL.
This severity score is a really important starting place, because now we have a method of testing new ENL treatments and getting an accurate assessment of how well they are working.
We are now using this tool to conduct a trial which will see us combine Prednisolone with another drug called Methotrexate. The hope is that, by using the two together, we can slowly wean a patient off Prednisolone. This may be possible for some but perhaps not for very severe ENL cases.
We are also at the very early stages of looking at whether an entirely new drug (so new that it doesn’t yet have a name) could be used to treat ENL. The early results are hugely promising and suggest we may be able to treat ENL with perhaps only a month of drug treatment with no major side effects. That would be revolutionary! One of the patients in the trial felt so good after treatment, that he did not want to take time from work to come in for a follow-up appointment. While this was not a positive for the study, it reminded me that this is what we want for our ENL patients. To receive short, effective treatment such that returning to the doctor’s office is truly unnecessary.
But, it will take time for us to trial this drug at every level, generating data to pass through all the regulatory standards and checkpoints required for international drug approval. In all, it could be mid-way through the 2020s, or even later, before it is ready to be used clinically.
With every ENL patient that walks through the door, there is a definite urgency to see change happen; and there are real reasons for hope. Please remember to pray for us as we go about our work, and pray for the patients we are trying to help out of dire situations.
What are you taking away from this interview and how will it change the way you go about your work?
Leprosy and mental health in Nigeria
A video interview with Dr Paul Tsaku
What can we do about the link between leprosy and depression and anxiety?
In this video, Dr Paul Tsaku, Research Advisor at TLM Nigeria, guides us through the latest mental health research that he is conducting. He talks about the aims of the research and what this could mean for persons affected by leprosy and for our work.
The right path to solving
leprosy's ulcer problems
A look at the latest research by
Dr Indra Napit in Nepal
TLM Nepal are on the right path to solving leprosy’s ulcer problems
Ulcers are very common amongst leprosy patients, with up to 20 percent of people affected by leprosy being at risk of developing an ulcer. These are wounds that occur because people lose feeling in a part of their body - in other words, communication is disrupted between the brain and, most commonly, the foot.
This means they may not feel, for example, if there is a stone in their shoe that is damaging the skin. Even the sweat glands lose communication, and the skin of the foot dries and easily cracks open, becoming vulnerable to infection.
After the first ulcer, it is likely that ulcers will recur for the rest of a person’s life, causing devastating disruption. In places where walking is central to transport and work, leprosy ulcers can lead to a downward spiral of losses over time including income, job, community, home, family and even limbs. When placed in hospital wards alongside these patients, first-time ulcer patients can develop suicidal thoughts, because they see the other patients’ stories as their own unavoidable future. We need to change that outlook.
TLM Nepal, India and Nigeria are working on a large ulcer project, which includes lots of smaller projects, with partners from across the world.
In Nepal, Dr Indra Napit leads two of the projects investigating new approaches to foot ulcers caused by leprosy. He and his team are looking at how community interventions can prevent ulcers, and how a new, revolutionary ulcer treatment could transform a patient’s outcome.
The SHERPA Project – Community intervention could prevent leprosy-related ulcers
Prevention is better than any treatment, so Dr Indra and his team are looking into how communities can be equipped and mobilised to prevent ulcers from occurring.
Through the SHERPA Project, the team are tracking the work of 18 self-help groups (SHGs) across three districts of Nepal. These SHGs are trained in how to prevent ulcers and are supported by our team so that they have different tools for self-help.
Our team wants to research which interventions work best, which will be done by periodically interviewing participants and measuring what did or did not help prevent ulcers.
One of the interventions they are particularly interested in is financial support. Each SHG has around 25 participants and each group will be given 20,000 rupees (or £125), which can be used as an investment fund and a savings scheme. The money could prove vital in preventing ulcers because it allows SHG members to invest in new livelihood activities. This is crucial in a country where two-thirds of the population are farmers.
When SHGs invest financial support in members, they are able to set up trades and develop their own work that is a better fit or not as physically demanding on their affected limbs, such as tailoring, raising chickens or goats, or running a small shop. This means there are fewer opportunities for them to pick up an injury that could develop into an ulcer.
Once they have completed this research, the team are looking to develop international guidelines on ulcer prevention and self-care. They hope that these guidelines will be submitted to the WHO and will become standard practice across the world. Such a step could prove transformative for hundreds of thousands of people affected by leprosy all over the world.
The TABLE Project – Finding revolutionary ways of treating ulcers
For as long as people can remember, leprosy ulcers have been treated with a daily saline (salt water) wash and fresh gauze wrap. Dr Indra and his team are trialling a new treatment called L-PRF (Leukocyte Platelet-Rich Fibrin).
This is a regenerative treatment that utilises concentrated white blood cells and regular stem cells that circulate in the blood.
Our blood contains lots of stem cells which our bodies use for regeneration – it’s what causes our hair and nails to grow.
For L-PRF treatment, blood is drawn from the leprosy patient, and then spun in a centrifuge so that the white blood cells, stem cells and other healing factors are concentrated.
Afterwards, the healing mixture is like a gel that is then pressed into strips and applied like a plaster directly to the same patient’s ulcer.
At Anandaban, these healing L-PRF strips have caused leprosy ulcers to heal more quickly, regenerating new tissue without much scarring.
One patient with a foot ulcer covering nearly the entire sole had not healed after a year in hospital with saline treatment and seemed destined for amputation. But, after switching to L-PRF treatment, the ulcer healed within 10 weeks.
As part of the study, Dr Indra is leading the TABLE Project in Nepal, which is a randomised control trial comparing L-PRF with the traditional saline method of treating ulcers. They expect the results from this trial will provide the evidence base that’s needed in order to change international treatment regimens.
The L-PRF method has already been proven to be an effective way of treating diabetic ulcers; and Dr Indra expects very similar results from this trial, with ulcer healing happening far faster than with the traditional saline method. Initial testing at Anandaban Hospital has been encouraging, with one patient even travelling for three days from New Delhi in order to access the treatment.
This research will have a worldwide impact
As well as developing new International Self-Care Guidelines, Dr Indra and his team will look to provide training for leprosy hospitals worldwide, starting with our team in Bangladesh in 2022.
For many people, ulcers are a persistent problem and they find themselves in and out of hospital; their jobs, homes, relationships and limbs are often the price they pay due to these constant hospital stays.
Through preventing ulcers and finding a faster, better treatment for ulcers, these projects will have an enormous legacy in these lives.
The 5 minute finger prick
test to prevent leprosy
The latest on this exciting research in Bangladesh
The Leprosy Mission’s team in Bangladesh are working on a research project that could dramatically reduce the rate of leprosy transmission within communities and prevent people from developing leprosy-related disabilities because of late treatment. By developing a new field-friendly diagnostic tool and testing preventative medicines, the team are hoping to take big strides towards our goal of zero leprosy.
This image and cover image:
© Tom Bradley
How to find the missing millions
Did you know that a person with leprosy can be asymptomatic, and that we have no lab test that can confirm whether they have leprosy or not?
Researchers estimate that there are “missing millions” of asymptomatic or undiagnosed leprosy cases, and that these untreated cases are the reason leprosy transmission continues to stably persist in populations.
Currently, only those with detectable symptoms can be conclusively diagnosed with leprosy and treated; and signs and symptoms are often delayed 2-5 years and up to 30 years. Late diagnosis can also lead to nerve damage and disability.
In order to impact transmission, we need a reliable diagnostic test that is capable of detecting asymptomatic and early leprosy cases. This is a key priority for TLM research.
At the moment, a household contact or close neighbour of a newly diagnosed person won’t be tested for leprosy because there is no effective diagnosis tool. They could have contracted the disease and be infectious, but no one will be able to tell because they don’t have any symptoms yet.
In partnership with Dr Annemieke Geluk and her team at Leiden University Medical Center, TLM Bangladesh is performing field trials of a finger-prick test, much like the one used to diagnose diabetes. The aim is to test 10 household or neighbouring contacts from 100 leprosy cases. This means, if you are diagnosed with leprosy, 10 of your household contacts and neighbours will receive a finger-prick blood test.
They will be initially tested four times over a period of six months to track crucial biomarkers. After six months, the contacts will be followed up annually over the next few years to see if any do develop leprosy symptoms or not. In this way, they can correlate which finger-prick results indicated asymptomatic or early leprosy.
Dr Annemieke Geluk and her team have been developing leprosy diagnostics over many years, across continents and countries – including both TLM Bangladesh and Nepal. But this is the first study that will simultaneously test for six different biomarkers in the blood.
Our researchers hope that it could prove an effective way to diagnose leprosy in a person and give them treatment long before they develop leprosy-related complications. Further to this, these tests could significantly impact and reduce the numbers of hidden cases of leprosy and persistent transmission, helping to bring about the eventual defeat of this horrible disease.
We are also testing drugs to prevent leprosy
The biomarkers that the team are testing show whether or not a person has asymptomatic leprosy; so, while they are testing for these biomarkers, they are also testing different forms of PEP (Post-Exposure Prophylaxis) treatment to see which is better at preventing a leprosy development in contacts.
PEP is a prophylaxis, or a treatment that reduces the risk of a person developing leprosy. With PEP, a person who is a close contact of a recently diagnosed person is given a dose of Rifampicin, one of the antibiotics used to treat leprosy.
In a previous TLM Bangladesh study, run in partnership with Dr Jan Hendrik Richards and Erasmus University, a single dose of Rifampicin as PEP was seen to reduce the risk of developing leprosy by an average of 57 percent; however, protection was highest for furthest away neighbours and lowest for household family.
In the current study, our team are looking at whether two doses of Rifampicin is more effective by tracking these crucial biomarkers for indications of growing leprosy infections after PEP treatment.
This research could push us towards zero leprosy
The new finger-prick test could go a long way to identifying leprosy patients earlier than ever before. As well as this, knowing the right dose of Rifampicin to give to a potential patient is crucial in our efforts to stop the disease spreading further.
The discoveries we might make through this research could enable us to achieve our goal of zero leprosy transmission by 2035.
Thank you for reading our first newsletter
Which feature did you find most interesting?
- Mental Health
- Ulcer care
- Diagnostic tests