An interview with Dr Deanna Hagge
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.
© Ruth Jones
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.
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 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.
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.
