This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.
Hansens disease or leprosy has been around for thousands of years, with references to the disease being found as far back as 1550 B.C. Treatment of leprosy was not understood for many years and so patients were excluded from conventional society for a long time due to the physical symptoms that are associated with condition. It wasn't until the 1940's when modern antibiotics became available that leprosy could be treated rather than just being managed that so called "leper colonies" began to fall out of favour.1
Leprosy has been the focus elimination programme backed by the World Health Organisation pledge since 1991 for the "elimination of leprosy as a public health problem by the year 2000"2 which has been defined in real terms as the reduction in the number of patients that will receive antibiotic treatment to less than 1 in 10000. 107 out of the 122 country's that were defined as being epidemic in 1985 have seen reductions in treatments rates down to 'elimination' standards.
Leprosy is caused by the acid fast bacilli Mycobacterium leprae, with its primary reserve being Humans. M. Leprae cannot be cultured in vitro however it can be cultured in nine-banded armadillo and in mouse footpads providing all the samples that are required for studies. This has allowed the analysis of the bacterium and now the full genome has been published. Analysis on the genome shows M. Leprae is related to the M. tuberculosis bacterium, however over half the functional genes of M. tuberculosis are lost in the M. Leprae bacterium, including some that are required for some metabolic pathways. This may explain why the bacterium is unable to survive in vitro and long doubling time of 14 days as it may require the hosts own metabolic pathway to gain the necessary nutrients it requires. The cell wall of M. Leprae is thought to be largely responsible to the resistance to the body's immune responses. The cell wall is similar to the rest of the Mycobaterium species and is part of the genome that was not lost. Mycolic acids make up around 60% of the cell wall and are attributed to the acid-fast stating. The external cell wall contains many exposed proteins that are unique to each species, and it is this complex mixture of polysaccharides and glycolipids that makes the bacterium impenetrable to many solutes without specific transport systems.
The route of transmission of M. Leprae has not been completely proven however the primary route is thought to be by aerosol spread and uptake with though the repertory system, much like Tuberculosis. Most people are actually resistant to M. leprae, however there are certain genotypes that are susceptible to infection including both Human and non-Human leukocyte antigens.
Like transmission the actual pathogenesis of Leprosy is not very well understood, but evidence suggests that the clinical manifestations within the patient are mainly due to the immune response and can be classified by either the Ridley-Jopling Scale or the World Health Organisation(WHO). Usually the WHO ranking is combined with the Ridley-Jopling scale to decide which drug treatment should be recommended. Since we are dealing with multibacillary leprosy we know that the response is mainly down to the Th2-type cellular immune responses which usually leads to multiple progressive skin lesions and may involve peripheral nerves.
Since the pathogenesis of Leprosy has a large scale of variation patients can present with heterogeneous clinical manifestations of the disease. It is not only the presentation of symptoms that can vary also the time from infection to clinical manifestation which can range from a few months to 30-40 years. Some of the common symptoms of leprosy are skin lesions, weakness or numbness caused by nerve damage and burn or ulcers in anaesthetic hands or feet.
Skin Damage - Normally the skin lesions are macules or plaques; however rarely papules and nodules can be seen. Since we are dealing with Multibacilliary leprosy there are large numbers of lesions and can vary in size, shape and location, lesions can be hypopigmented or erythematous. If patients are more mid-borderline form of leprosy then these lesions can be immulogically unstable.
Nerve Damage - Nerve damage can occur in two regions, peripherally at the nerve trunks and in the small dermal nerves. Peripherally the bacterium attacks the nerves near the surface of the skin, in areas like the neck, elbow, wrist, facial nerves. The posterior tibial nerve is the most commonly affected nerve followed by the ulnar, median and lateral popliteal and facial nerves. It is the damage to these nerves that cause some of the symptoms of leprosy such as motor and sensory loss. Attack of the small dermal nerves can lead to hypoaesthesia and anhydrosis in borderline-tuberculoid and tuberculoid lesions. Within lepromatous disease glove and stocking sensory loss occurs instead.
Eye Damage - Leprosy can cause damage to the eye by causing nerve damage and from the bacteria invading the eye. Studies have shown that 2.8% of patients with multibacillary leprosy were blind when diagnosed with leprosy and a further 11% had potentially blinding pathology. This can be potentially devastating if the patient has nerve damage that has caused anaesthia in the hands and feet.
There are two types of Immulogical reactions associated with leprosy, type 1 (reversal) or type 2 (erythema nodosum leprosum [ENL]). Around a third of patients that have borderline leprosy can have type 1 reactions while 50% of those who suffer from lepromatous form and 10% of borderline leprosy are affected by type 2 reactions. However these reactions can occur at any time and may be a reaction to the bacterium or the multidrug therapy (during or after treatment).
Our patient is suffering from type 2 reactions or ENL, which is typically associated with fever, malaise, painful inflammation of the nerves and the appearance of new nodules. These nodules are typically subcutaneous, erythematous and painful for the patient. They are typically found on the face and limbs, but can be found on any part of the body.
ENL is thought to be an immune complex disease which consequently activated the compliment immune response; there are also elevated levels on TNF-Î± and interferon-Î³ within the patients system. Widespread immune complex deposition can occur and this can lead to further complications to the patient including polyarthritis, lymphadenitis and iridocyclitis.
Treatment of Hansen's Disease
Early treatments of leprosy were mainly down to trial and error and many compounds were indicated for use that would not be considered today. These include anilin dyes, antimony, arsenic, baths, copper, electrical currents, potassium iodide, radium, sera, strychnine, thymol, vaccines and X-rays. However one of the major treatments throughout the late 19th and early 20th centuries was chaulmoogra oil, which was mixed with lard and was applied topically or taken orally. The product then became commercially in 1909 available from Bayer and Company and Winthrop Chemical Company under the trade names Antileprol and Chaulmestrol respectively. However these treatments have all been superseded by newer treatments which are listed below, most of the treatments used being antibiotics.
Part of the sulfones, Dapsone is usually considered one of the foundations of treatment of leprosy. Dapsone exerts in antibacterial action against M. Leprae by the indirect reduction in folic acid through the inhibition of dihydropteroate synthase. In one mouse foot-pad model oral therapy of dapsone saw a reduction in the number of viable organisms by 99.4% which was evident by the lag in growth curves between dapsone treated versus the control group. The dose of dapsone is usually 100mg once/day orally with no adjustment needed with patients with renal impairment, however for those with hepatic impairment; however no guidelines exist on dosage adjustment for hepatic impairment.
Dapsone was originally used in monotherapy of leprosy but resistance became problematic, estimated at 2-10%. It has been proposed that the mutation of the folP1 gene leading to a more resistant dihydopteroate synthase which is capable of synthesising folic acid in more extreme conditions. Due to resistance expected with monotherapy, multidrug therapy has now become the standard for care.
Dapsone has been associated with methemoglobinemia, haemolysis, lymphadenopathy, fever, hepatitis, leukopenia, anaemia, acute psychosis and rarely peripheral neuropathy. These adverse effects can be limiting to treatment however the most profound side effects being methemoglobinemia and haemolysis linked to a deficiency in glucose-6-phosphate dehydrogenase (G6PD). Dapsone can be used in pregnancy however caution should be used as it is potential harmful to the foetus, according to FDA classifications it is a class C drug. It is also excreted through breast milk and can be potentially harmful to babies that have a reduced level of G6PD who are breast fed.
Rifampicin is a bactericidal agent that acts by binding to the Î²-subunit of RNA polymerase and block transcription of RNA and its activity is seen in even slow dividing cells such as M. leprae. Bactericidal success can be seen within 3 weeks of therapy and even a single dose has been shown to be effective in reducing the bacterial load. Rifampicin can be taken monthly or daily depending if the patient is to be supervised or not, it is also available as I.V. infusion but this form of treatment is rarely used. Patients with hepatic dysfunction do not require a reduction in dose however for those who have renal impairment with creatinine clearance below 10ml/min should have a 50% reduction in dose. Rifampicin should only be used in multidrug therapy due to the rapid appearance of resistance; this is likely due to mutations in the Î²-subunit of RNA polymerase through point mutations in ropB gene.
Side effects of rifampicin include malaise, rash and hepatotoxity. Warning should be given about the fact urine, sweat and tears can have orange discolouration and this may cause distress to the patient and may make wearing contact lenses uncomfortable but it does not mean the drug should be withheld. However if the patient develops thrombocytopenia, a rare side effect, rifampicin should be discontinued immediately and another treatment should be initiated. There are many interactions with rifampicin and patient's medication should be checked before initiating treatment. Dapsone metabolism is increased by rifampicin but it is not considered important in the treatment of Leprosy, but prednisolone, used in the treatment of type 1 and 2 reactions, has a significant interaction. Due to this interaction if prednisolone needs to be introduced into therapy the rifampicin dose should be reduced from a maximum of 600mg/day to 600mg/month. Rifampicin is rated by the FDA as a class C drug in pregnancy and therefore should be used with some caution however it is not teterogenic, it also excreted through breast milk.
A phenazine dye that has a similar antibacterial activity as Dapsone, clofazine is useful in dapsone resistance as it is still active in strains resistant to dapsone treatment. Its method of action is not understood but its ability to bind to DNA of M. Leprae may be linked to its activity. There are some suggestions that cloafimine as the added benefit of being immunomodulatory and this may which can be useful if the patient is likely to suffer either a type 1 or type 2 reaction. The usual dose of clofazine is 300mg monthly under supervision, and 50mg daily supervised (or 100mg on alternate days). However in the case of an immune reaction clofazimine dose can be increased up to 300mg daily for a maximum of 3 months; however it may take up to 6 weeks before they have maximum therapeutic effect.
Side effects are relatively mild in comparison to the some of the other medications used to treat leprosy with the main ones being nausea and vomiting, abdominal pain and skin discolouration. Most of the discolouration manifests itself as increases pigmentation on the skin due to increased levels of melanin, this can persist after treatment but mainly the discolouration fades once treatment has been withheld. Since clofazimine can be excreted though tears patients should be warned that contact lenses may become stained when used during treatment. One issue with clofazime in the UK is down to its availability only on a named patient basis which may increase the time a patient has to wait before treatment can start.
Fluoroquinolones, such as moxifloxacin and ofloxacin, act by inhibiting DNA gyrase and DNA replication and transcription in M. Leprae. Antibacterial drugs like moxifloxacin have a similar bactericidal activity to rifampin with one dose producing a substantial reduction in bacterial load. In one study after three weeks of daily treatment there were no viable organisms remaining. Ofloxacin also has substainal activity and is used in the treatment for single lesions along with a combination of other drugs. However the other drugs in this class have little activity against the bacterium and should be avoided in treatment. Resistance to this class of drug occurs mainly due to mutations in the gyrA but not through gyrB.
Minocycline is a tetracycline antibiotic that exerts its effect on the 30S ribosomal subunit in M. Leprae. It is not as active as rifampin, however it is still considered a useful alternative in treatment of Leprosy due to resistance, intolerance or clinical failure. There are adverse effects in using long term treatment of minocycline, including skin pigmentation, g.i. irritation and central nervous system effects. It should be avoided in pregnancy due to its ability to stain enamel.
Clarithromycin is a semisynthetic macrolide that has better antibiotic activity than the rest of the macrolides but has reduced activity against minocycline. It is thought that it acts by the reduction of ATP and is useful as an alternative to therapy where there is intolerance or resistance.
Treatment of Immunological Reactions
These types of reactions are medical emergencies that must be treated as soon as possible to ensure that there are no long term effects on the patient. Antibacterial therapy should be continued throughout these reactions because the benefits of treatment outweigh the risk. There are several options for treatment that each has their own benefits and risks associated with them. Type 2 reactions or ENL is difficult to treat and so many options need to be considered
Corticosteroids are used to provide symptomatic relief from immune responses and work well for type 1 reactions. Initiation therapy of 40-60mg of prednisolone daily can be used to provide this relief. Treatment length should be kept as short as possible to reduce the risk of developing the long term effects associated with steroid use however these effects should be weighed against the patients risk if they do not receive steroids. When used to treat ENL it has been found that repeated courses of corticosteroids may be required due to the difficultly in providing sustained relief.
Thalidomide is a useful drug in the treatment of ENL and has been shown to be more effective at providing relief than corticosteroids and should be considered if the patient is corticosteroid treatment does not provide relief to ENL symptoms or if they are contraindicated. Its method of action is not fully understood, but it has been shown to reduce the levels of TNF-Î±. Through the ADF rating system thalidomide is a class X drug and therefore it should normally be avoided in female patients who are or who may become pregnant. Treatment of these patients with thalidomide should not be taken lightly and the patient needs to part of the decision making process before starting treatment.
Pentoxifylline has been shown to decrease levels of TNF-Î± in patients through an unknown mechanism when a dose of 400-800mg three times daily. However it does not perform as well as thalidomide in a randomized clinical trial. There is a use for it though when thalidomide is contraindicated or ineffective, as 62.5% of patients receiving treatment experienced relief in their symptoms. The major adverse effects with this drug include g.i. problems and CNS problems however by using controlled-release formulations there are reductions in side effects.
Working on the basis that many of the drugs listed above reduce levels of TNF-Î± systemically using biologic TNF inhibitors for the treatment of ENL reactions would be a logical step. It has been shown in studies that using biologics like etanercept and infliximab can be used to treat more serious and difficult to treat reactions, however they should be used with caution as the biologics are also known the aggravate infections and reports have also been published showing infliximab and adalimumab increase the bacterial load within patients. Therefore any decision on whether to commence treatment should be based upon the severity of the reaction.
Recommendation for treatment
Our patient is a 25 year old female with multibacillary Hansen's disease, with a severe type II reaction. Initially I'd recommend that the treatment of leprosy is continued due to the health risks associated by withholding treatment is too great. The combination I would recommend is Dapsone 100mg daily (unsupervised), Rifampicin 600mg monthly (supervised) and Clofazimine 300mg daily for 3 months to help reduce the severity of the ENL reactions, after 3 months this then needs to be reduced back down to 50mg daily plus 300mg monthly. To help with the severe ENL reactions I would also recommend adding on Prednisolone 60mg to help relieve symptoms, withdrawing treatment as soon as clinically possible, repeat courses may be required. If further treatment is required to provide relief then I would recommend adding in Pentoxifylline 400mg daily.