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The effects of Multibacillary Hansens Disease

Hansen's disease, also known as leprosy, is a chronic disease caused by Mycobacterium leprae (M. leprae). It is a slowly progressive infectious disease of the peripheral nerves and skin, but sometimes it can be spread to other tissues such as eye, mucosa of the upper respiratory tract, muscle, bone and testes.1 According to the recent report from World Heath Organisation (WHO) in year 2009, 213 036 cases of leprosy were detected. Most prevalent cases of leprosy were concentrated in poorer parts of the world, such as Africa, India, Brazil, Madagascar, Nepal and the United Republic of Tanzania. With over-crowded population and scant sanitation in these countries, this slow-growing bacillus is more easily spread via close and long-term contact with infected patients. The transmission of M. leprae is thought to be either through the inhalation of air-borne infectious droplets from respiratory secretion or through skin contact with wound exudate from the skin lesions. Even though leprosy is not highly contagious, if the patient is left untreated, progressive damage to the nerves, eyes and skin may occur, leading to permanent disabilities.2

The microorganism responsible for this disease, M. Leprae is an acid-fast aerobic rod. This slow-multiplying bacillus has a prologed incubation period of about 5 years due to a slower rate in synthesising DNA or RNA which limits the growth of the mycobacteria cell.3 The optimum temperature needed for this mycobacteria cell growth is at 23-30°C. Hence, it has the highest multiplication rate in cooler parts of the body which includes nerve, skin, upper respiratory tract and testis. These areas are therefore more susceptible to the invasion of this pathogen.4 M. Leprae enters the host cell by phagocytosis and multiply inside the macrophages in skin and Schwann cells.Host immune response is then elicited and it involves predominantly or entirely cell-mediated immunity. The humoral immune response which is mediated by the production of antibodies does not eliminate the mycobacterium from the system, but it does causes type 2 hypersensitivity reaction due to bacillus antigen. Leprosy is classified according to the degree at which cell-mediated immunity develops. The main classes of leprosy are paucibacillary(PB) leprosy also known as tuberculoid leprosy, and multibacillary leprosy (MB) or lepromatous leprosy.5

In immuno competent patient with PB, strong T-cell mediated immune reaction occurs when the mycobacterium invades the body system. In response to the M. leprae infection, macrophages secrete cytokines mediators to increase localised inflammatory response by recruitment of T-cells and natural killer cells into the infected area, resulting in the destruction and elimination of the pathogen. It is characterised by granulomas consisting of epitheloid cells, Langhan's giant cells and lymphocytes. This disease is localised to few parts of the skin and largely peripheral nerves. The entire nerve can be destroyed by typical infiltrations in the affected nerves trunk, causing tissue necrosis.5,6 On the other hand, a defect in cellular response to the antigen of bacillus is associated with MB. Consequently, the lack of host defence will cause the growth of M. leprae in the dermal macrophages and the Schwann cells of the peripheral nerves. This disease is usually dominated by foamy histiocytes full of bacilli. Damage of dermal appendages and nerve proceeds slowly and thus causing this disease to be detected only at a later stage of the disease. MB is not localised and is easily spread throughout to other body parts such as skin, nerves, mucosa layer of respiratory tract, eyes and testes. Thus, this is the most contagious form of leprosy.1

Due to slow onset of the disease, sign and symptoms of leprosy might take up to 20 years to appear. The clinical features of the disease depend on the host's immune response to the bacilli. In most cases, patients are presented mostly with skin lesions, limb numbness and muscle weakness. Type and number of skin lesion patches are used to catagorise the type of leprosy. If there are less than five skin lesions being detected, it can be classified as paucibacillary leprosy. In contrast, patient who has six or more lesions are diagnosed as multibacillary leprosy. 7 In this case, 25 years old female patient was diagnose with multibacillary Hansen's disease. Symmetrically and widely distributed erythematous macules or occasionally papules and nodules may be seen on her. The margin of these smooth and shinny macules are poorly defined. Unlike in PB, impairment of sweat gland and hair growth in MB patients only occurs at a later stage of the disease. Other manifestations of nerve damage are also slow to appear. Palpable nerve enlargement caused by inflammation of the peripheral nerves may be observed. There might not be pain as the loss of sensory and motor function contribute to lesion anaesthesia. Besides that, weakness of muscle in limbs will affect patient's motility hence restricting daily routine of the patient. In addition, signs and symptoms related to the upper respiratory tract, eyes and testes are also reported in patient with multibacillary leprosy.8

Complication is an important sequel of the mycobacterium infection. The most serious complication in this disease is neuropathy. In untreated patients, loss of sensitivity to touch, pain and heat may account for unintentional self-harm. Deformities in the hands and feet where clawing of the fourth and fifth fingers and foot drop could also seen in patient with leprosy. Meanwhile, repeated injury at the sole of the foot caused by lack of sensation may give rise to a platar ulcer, thus making walking difficult for the patients. Other parts of the body that might have potential short or long term problems include the eyes, nose, and kidney. Invasion of M. leprae into the eyes may result in iritis, which in turn may lead to glaucoma and cataracts. Moreover, scarring and blindness may also occur if the corneal becomes insensitive. Chronic nasal congestion and nosebleeds are often seen in patient with MB due to the damage of the nasal mucosa layer. If it is untreated, septum of the nose may erode and collapse. On the other hand, secondary amyloidosis complicates the disease by causing malfunction of the kidneys. In severe cases, renal failure may be observed. 9 As a result, early detection of the signs and symptoms early is crucial to prevent severe complications that arise from the untreated conditions.

Diagnosis of leprosy can be made by clinical examination and laboratory investigations based on the signs and symptoms of the disease. There are three important cardinal signs of leprosy that should be thoroughly checked, these are skin lesions with definite loss of sensation, enlarged or thickened peripheral nerves associated with loss of sensation and positive skin-smear test . According to the WHO operational guideline, patient having one or more of these cardinal signs is diagnosed with leprosy. Anaesthesia at erythematous or hypopigmented macular lesions may be detected by using a cotton wool or a pen to test the infected area for the level of sensitivity. If stimulation could not be felt, patient will be diagnosed with hypaesthesia, hence leprosy.7 On the other hand, if enlargement of ulnar nerve which is located at back of the elbow or peroneal nerve near the knee could be felt by physical examination, this could mean that the patient has leprosy. 10 In addition, skin smear test is performed in suspected cases of multibacillary leprosy. Positive result indicates the presence of the acid-fast bacilli at the site of skin lesions and this is suggestive of multibacillary disease.7 After a diagnosis is confirmed, management of the disease should be started immediately.

Management of leprosy can be approached by different ways, ranging from pharmacotherapy to psychological rehabilitation. The aim of pharmacotherapy is to prevent the spread of infection, resolve complications and reduce morbidity. Current WHO recommended multi-drug therapy (MDT) for multibacillary leprosy includes rifampicin, clofazimine and dapsone.7 Due to the bactericidal effect of rifampicin, once-monthly rifampicin is the main component of the MDT, where dapsone and clofazimine are included to prevent the emergence of rifampicin-resistant M. leprae. These first line drugs are to be completed within 12 months and therefore this increase chances of patient to be non-compliant. As a result, treatment supervision serves an important role to help recovery of the patient. According to WHO recommendations, MB patients with high bacterial index and with no signs of improvement after 12 months therapy should start a further 12-month regimen.11 MDT is provided in blister packs covering four weeks of treatment and it is supplied free of cost from WHO. This treatment is cost-effective where it has successfully been used to cure 8.4 million sufferers of all forms of the disease since 1981.12

Rifampicin is used as an anti-mycobacterial agent in MDT. It inhibits RNA synthesis by binding to the bacterial DNA-dependent RNA polymerase ß-subunit. This B-derivative antibiotic is most active against M. leprae which are undergoing cell division and therefore, it is a more potent bactericidal drug than any combination of the other drugs for the treatment of MB as proven by Ji B et al.13 Rifampicin is well absorbed from the gastrointestinal tract giving a peak concentration of 7µg/ml within 2-4 hours, after a 600mg dose in healthy fasting adult. It is metabolised by the liver and undergoes biliary excretion and enterohepatic recirculation. The suggested rifampicin dose to be given is 600mg once a month.11 In a single-blind trial conducted by Yawalkar et. al, it was concluded that in untreated MB patients, when combined with daily dapsone dose, single dose of 1200mg rifampicin given monthly was as effective as daily rifampicin dose of 450mg.14 As a result, monthly rifampicin regimen is satisfactory. With the use of this anti-leprosy drug, patient should be informed that slight red-coloured urine may be observed. Besides that, cytochrome P-450 enzymes induced by rifampicin may reduce the metabolism and therefore effectiveness of oral contraceptives. Hence, patient is to be advised to use alternative forms of contraception such as barrier contraception.15

Clofazimine is also one of the effective drug used in the pharmacotherapy of MB. This rhiminophenazine dye has a weakly bactericidal action against mycobacteria. The mechanism of action for this drug is unclear but it was suggested that clofazimine binds to the GC-rich DNA, increase phospolipase A2 activity and inhibit potassium transport of the mycobacteria. The anti-inflammatory effect of this drug is also useful in reducing the incidence of type 2 reaction, erythema nodosum leprosum (ENL).15 It is to be administered 300mg once a month and 50mg once daily. Once monthly dose is to ensure that the clofazimine plasma concentration is at the optimum level, even if the patient misses a daily dose once in a while.11 Clofazimine is a relatively safe drug and generally well tolerated when given at 50mg daily as being proven by Queiroz et al.16 It is absorbed from the gastrointestinal tract and peaks at 4-12 hours after dose administration. Incomplete absorption may occur due to presence of food in the GI tract.11 As shown by Nix et al., greatest bioavailability is observed when patient took in high fat meal while aluminium-magnesium antacid and orange juice reduce the bioavailability of this drug.17 Clofazimine is excreted in feces. The most distressing side effect of this drug is skin discolouration, hence patient counseling should be done.11

Dapsone is an orally available sulfone which is included in the MDT regimen of multibacillary leprosy. This bacteriostatic agent acts by competitively inhibiting the dihydropteroate synthase of M. leprae and preventing the normal bacterial ultilisation of para-amino-benzoic acid.15 Treatment with daily dapsone dose of 100mg of has been successful since high compliance of 81.6% was observed over 6 years in a monitoring programme conducted by Piscitelli et al.18 Plasma concentration of this protein-bound drug peaks at 2-8 hours following oral administration. It is being metabolised in the liver and excreted in urine. Metabolites of dapsone includes monoacetyldapsone and hydroxylamine dapsone. The latter metabolite causes significant side effects which are haemolysis and methemoglobinemia in patient with glucose-6-phosphodihydrogenase (G6PD) deficiency. A clinical trial conducted by Degowin et al. concluded that healthy men with G6PD deficiency were more susceptible to dapsone-induced haemolysis than did normal man.19 Besides that, oral administration of sulfones may also cause adverse effect of anorexia, nausea and vomiting. If severe side effects are observed, patient may discontinued from dapsone and the therapy will only contain rifampicin and clofazimine given at the dose recommended by WHO.11

The combination of these three drugs are shown to be advantageous and efficacious. In the past, cases of rifampicin and dapsone resistance were reported when these drugs were used alone to treat MB. However, co-administration of these three drugs prevents the emergence of rifampicin and dapsone resistance.11 According to the global statistical report of leprosy, there was a sharp decline in the global new case detection of this disease. 16% fall in new cases detection was observed in year 2008 compared to year 2007. This has proven that treatment of leprosy is effective in controlling the spread of the infectious disease.20 The downside of this treatment is that patient may relapse where re-occurrence of the disease might happen after the completion of MDT regimen. It is indicated by the appearance of new lesions and an increase in bacterial index of two or more unit in MB patient.7 In the study performed by Girdhar et al., MB patient treated till the point of skin-smear negativity was shown to have a lower relapse rate than those who are given a fixed 24 doses of WHO MB regimen.21 However, relapse are generally rare. Dasananjali et al. carried out a prospective study of effectiveness of MDT regimen in the northeast of Thailand. A low relapse rate of 0.2 per 100 person-years at risk after an average of 8 years of follow up concluded that pharmacological management of multibacillary leprosy is still effective and safe.22

There are a few complications associated with the multi-drug treatment of leprosy. One of the major disadvantages of this therapy is that erythema nodosum leprosum (ENL), a type 2 reaction of leprosy might develop in MB patients. During the chemotherapy, antigen-antibody reaction occurs with the immune complexes, mostly immunoglobulins and are deposited in the blood vessels wall. This gives rise to an acute inflammation in the tissues or organs infected by M. leprae. Clinical features of the reaction includes red painful nodules which may evolve to lesions discharging thick yellow pus. Other manifestations such as fever, enlargement of peripheral nerves, iritis and lymphadenitis may also observed in MB patient with type 2 reaction. Treatment of this reaction includes clofazimine, prednisolone and thalidomide. Clofazimine has been used in the management of ENL but it is not as effective as prednisolone and thalidomide. If neuritis or iritis is present, systemic corticosteroids are used.23 Smith et al. Demonstrated that low dose prednisolone was effective in lowering the occurrence of ENL in the first 4 months but the effect does not last for the complete 1 year of multi-drug therapy.24 Among these three drugs, thalidomide is the most effective anti-inflammatory therapy for ENL reaction. It acts by preventing the antigen presentation by Langerhans cells and selectively inhibiting the production of tumor necrosis factor-a (TNF-a). The recommended initial dose is 400mg daily and it is to be reduced to a maintenance dose of 50-100mg daily.25 According to Iyer et al., recovery rate of skin lesions on patients receiving thalidomide was better than those on acetylsalisylic acid.26 However, this drug induces teratogenicity, producing characteristic human birth defects. As a result, this female patient cannot take this drug if she plans to have a child.27

In patients who cannot tolerate clofazimine or dapsone, there are a few alternative drugs such as clarithromycin, ofloxacin and minocycline which can be use as second line therapy.8 Clarithromycin is a bacteriostatic agent that binds to 50S ribosomal subunit or to the site which is very near to the binding site of chloramphenicol.15 The anti-mycobacterial property of this macrolide is clinically proven by Chan et al. where all patients showed a bacterial index of zero within 3 weeks of clarithromycin treatment.28 Ofloxacin is a fluroquinolone which is active against M. Leprae. It targets the mycobacterial DNA gyrase, inhibiting its activity. On the other hand, minocycline is a semisynthetic tetracycline that inhibits protein synthesis of the mycobacteria. For treatment of MB in patients who cannot take rifampicin, they are treated with a combination of clofazimine 50mg daily, ofloxacin 400mg daily and minocycline 100mg daily for 6 months followed by 18 month of therapy of clofazimine plus ofloxacin or plus minocycline. Besides that, another combination of rifampicin, ofloxacin and minocycline is also recommended by WHO to patients who refuse to take clofazimine due to its side effects.29 An assessment was made by Villahermosa et al. comparing 24 months of this combination of drugs with 2 years of WHO recommended MDT in MB patients. The former multi-drug combination was shown to be safe and well tolerated and thus maybe used as an alternative to MDT.30 Pharmacotherapy managements of MB are summarised in Table 1.

Table 1 Summary of phamacological management of multibacillary leprosy.29

Type of treatment recommended by WHO

Drug treatment

Length of treatment

Monthly supervised

Daily self-administered

Multi-drug therapy

Rifampicin 600mg

Clofazimine 300mg

Clofazimine 50mg

Dapsone 100mg

12 months

Alternative combination of drug treatment

-

Clofazimine 50mg

Ofloxacin 400mg

Minocycline 100mg

Followed by

Clofazimine 50mg

plus either

Ofloxacin 400mg

or

Minocycline 100mg

6 months

18 months

Rifampicin 600mg

Ofloxacin 400mg

Minocycline 100mg

-

24 months

In conclusion, multibacillary leprosy is an infection of Mycobacterium leprae which causes major morbidity and mortality in infected patients. Early detection of signs and symptoms of nerve impairment is the most effective way in preventing disabilities in leprosy and further transmission of the disease. The management of this disease does not only rely on eliminating M leprae from the body with MDT, but it also requires the management of of type 2 reaction which may cause further damage to the peripheral nerves to reduce the risk of permanent disabilities. In return, this will significantly improve the physical, psychological and social well-being of the patient. The ultimate goal of the management of this disease is to obtain leprosy eradication. Several strategies has been implemented by the WHO to eliminate leprosy. These include providing free MDT to all the health facilities so that proper treatment can be given to newly diagnosed patients, monitoring patient's compliance to avoid relapse or drug resistance and organising campaigns to increase the awareness of the community.31 By taking these steps, global cases of leprosy may be decreased and eventually eradicated some time in the future.


References

  1. Bryceson A, Pfaltzgraff RE. Leprosy. Edinburgh: Churchill Livingstone; 1979.

  2. World Health Organisation. Leprosy fact sheet (revised in Febuary 2010). Weekly epidermiological record 2010; 85: 27-48.

  3. Weeler PR. Recent research into physiology of Mycobacterium leprae. In: Advances in microbial physiology. London: Academic Press Limited; 1990.

  4. Agrawal A, Pandit L, Dalal M, Shetty JP. Neurological manifestations of Hansen's disease and their management. Clinical Neurology and Neurosurgery 2005; 107; 445-454.

  5. Mycobacterium. Murray PR, Rosenthal KS, Pfaller MA. In: Medical Microbiology, 6th ed. Philadelphia: Mosby; 2009. 277-290.

  6. Meyers WM. Leprosy. In: Doerr W, Seifert G. In: Tropical pathology, 2nd ed. Berlin: Springer-Verlag; 1995. 294-333.

  7. World Health Organisation. Global Strategy for Further Reducing the Leprosy Burden and Sustaining Leprosy Control Activities 2006-2010 Operational Guidelines. Accessed on 25 Febuary 2010 from http://www.who.int/lep/resources/SEAGLP20062.pdf.

  8. Walker SL, Lockwood DNJ. Leprosy. Clinics in Dermatology 2007; 25: 165-172.

  9. Leprosy (Hansen's Disease). Merck's Manual Online Medical Library: The Merck Manual for Healthcare Professional. Assessed on 25 Febuary 2010 from http://www.merck.com/mmpe/sec14/ch179/ch179d.html?qt=leprosy&alt=sh.

  10. Learning Guideline One: How to diagnose and treat leprosy. Groenen G,Saunderson: The International Federation of Anti-leprosy Association (ILEP). Assessed on 25 Febuary 2010 from http://www.ilep.org.uk/fileadmin/uploads/Documents/Learning_Guides/lg1eng.pdf

  11. McEnvoy GK, editor. AHFS Drug Information. Maryland: American Society of Health-System Pharmacist; 2009.

  12. World Health Organisation. Reports on individual drugs. Simplified treatment for leprosy. WHO Drug Information. 1997; 11:131.

  13. Ji B, Jamet P, Perani EG et al. Bactericidal activity of single dose of clarithromycin plus minocycline, with or without ofloxacin, against Mycobacterium leprae in patients. Antimicrob Agents Chemother. 1996; 40:2137-41.

  14. Yawalkar SJ, McDougall AC, Languillon J. Once-monthly rifampicin plus daily dapsone in initial treatment of lepromatous leprosy. Lancet 1982; 1: 119-1202.

  15. Brunton LL, Lazo JS, Parker KL, editors. Chemotherapy of Tuberculosis, Mycobacterium avium Complexes disease, and Leprosy. Petri WA, p. 1203-1223. In, Goodman and Gilman's: The pharmacological basis of therapeutics, 7th ed. United States of America : The McGraw-Hill Companies; 2006.

  16. Queiroz RHC, de Souza AM, Sampaio SV, Melchior Jr . Biochemical and hematological side effects of clofazimine in leprosy patients. Pharmacological Research 2002; 46: 191-194.

  17. Nix DE, Adam RD, Auclair B, Krueger TS, Godo PG, Peloquin CA. Pharmacokinetics and relative bioavailability of clofazimine in relation to food, orange juice and antacid. Tuberculosis 2004; 84: 365-373.

  18. Piscitelli SC, Danzinger LH, Hill C, Slajchert AA, West DP, Fischer JH. Effectiveness of a dapson compliance program in leprosy. International Journal of Dermatology 2007; 32: 206-209.

  19. Degowin RL, Eppes RB, Powell RD, Carson PE. The haemolytic effects of diaphenylsulfone (DDS) in normal subjects and in those with glucose-6-phosphate-dehydrogenase deficiency. Bull World Health Organ 1966; 35: 165-179.

  20. World Heath Organisation. Leprosy today. Assessed on 25 Febuary 2010 from http://www.who.int/lep/en/

  21. Girdhar BK, Girdhar A, Kumar A. Relapses in multibacillary leprosy patients: effect of length of therapy. Lepr Rev. 2000; 71:144-53.

  22. Dasananjali K, Schreuder PA, Pirayavaraporn C. A study on the effectiveness and safety of the WHO/MDT regimen in the northeast of Thailand; a prospective study, 1984-1996. Int J Lepr Other Mycobact Dis. 1997; 65:28-36.

  23. Moschell SL. An update on the diagnosis and treatment of leprosy. Journal of the American Academy of Dermatology 2004; 51:417-426.

  24. Smith WCS, Anderson AM, Withington SG, van Brakel WH, Croft RP, Nicholls PG et al. Steroid prophylaxis for prevention of nerve function impairment in leprosy: randomised placebo controlled trial (TRIPOD 1). BMJ 2004; 328: 1459.

  25. Cuevas J, Rodríguez-Peralto JL, Carrillo R, Contreras F. Erythema Nodosum Leprosum: Reactional Leprosy. Seminars in Cutaneous Medicine and Surgery 2007; 26:126-130.

  26. Iyer CGS, Languillon J, Ramanujam K, Tarabini-Castellani G, de las Aguas JT, Bechelli LM et al. WHO co-ordinated short-term double-blind trial with thalidomide in the treatment of acute lepra reactions in male lepromatous patients. Bull World Health Organ 1971; 45: 719-732.

  27. Britton WJ, Lockwood DNJ. Leprosy. Lancet 2004; 363:1209-1219.

  28. Chan GP, Garcia-Ignacio BY, Chavez WE, Livelo JB, Jimenez CL, Parrilla ML et al. Clinical trial of clarithromycin for lepromatous leprosy. Antimicrob Agents Chemother. 1994; 38:515-517.

  29. World Health Organisation. Reports on individual drugs. Simplified treatment for leprosy. WHO Drug Information. 1997; 11:131.

  30. Villahermosa LG, Fajardo TT Jr, Abalos RM, Cellona RV, Balagon MV, Dela Cruz EC et al. Parallel assessment of 24 monthly doses of rifampin, ofloxacin, and minocycline versus two years of World Health Organization multi-drug therapy for multi-bacillary leprosy. Am J Trop Med Hyg. 2004; 70:197-200.

  31. World Health Organisation. The "Final Push" Strategy for elimination. Assessed on 25 Febuary 2010 from http://www.who.int/lep/strategy/en/
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