A chronic granulochromatous infection

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Disease Overview

Hansen's disease is a chronic granulochromatous infection caused by Mycobacterium leprae, a type of rod shaped acid fast bacillus.1,4 Hansen's disease is also commonly known as leprosy. Superficial tissues especially skin and peripheral nerves are mainly infected and cause cellular immune responses.1 As a result of the cellular immune responses, peripheral neuropathy with potentially lasting consequences may occur.1

According to WHO system, leprosy can be categorized into 2 types: paucibacillary leprosy which is defined by less than 5 lesions with the absence of bacteria were found in the infection area whereas multibacillary leprosy which is having more than 6 skin lesions with large amount of bacteria detected were found in the infection area.1,2,5 Paucibacillary leprosy usually occur in individual with strong cellular immune response to M. leprae and the skin lesion appears to be dry as well as hypoesthetic.1,2 Asymmetric nerve involvement is typically found in paucibacillery leprosy. This form of leprosy is milder, rare and less infectious.1,2

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On the other hand, individuals with weaker cellular immune response will tend to have multibacillary leprosy.1,2 This form of leprosy is usually characterized by widespread of skin involvement. Infiltrated nodules and plagues are frequently appeared on skin lesions and nerve involvement more likely to be symmetric. This form of leprosy is more common and contagious.1,2

In an immunological sense on the basis of skin and biopsy results, motor and sensory variations, leprosy can be further characterized into 5 types which are indeterminate (I), tuberculoid (TT), borderline tuberculoid (BT), mid-borderline (BB), borderline lepromatous (BL), and lepromatous (LL).4,5 This is the Ridley-Jopling classification but compared to WHO classification, it is more complicated under most situation.4 In general, BB, BL, and LL are equivalent to multibacillary leprosy while I, TT, and BT leprosy are corresponding to paucibacillary disease.1,2,4,5,18

WHO reported that the number of registered leprosy patients was 5 million (12 per 10000) in 1985 but it had reduced to 212,802 (below 1 per 10000) in early 2008.6,16 In 2009, Asia, Carribean, America, parts of Europe, parts of Australia and Africa are still present with leprosy patient.6 Although once an endemic disease worldwide, leprosy has no racial predilection and age preference.1 Thus, any race at any age can be infected by leprosy. However, male is more prone to leprosy than female with a ratio of 1.5 male to 1 female except in some areas of Africa, the incidence of female is equal or greater than male.1

Symptoms of leprosy usually will not appear until infected more than 1 year but once the symptoms appear, it will progress slowly.2 Skin and peripheral nerves are the main site that leprosy affect.4 Cutaneous symptoms are often the first to appear on leprosy patient and normally are hypopigmented or erythematous macules or plagues which are inadequately defined.1,4,7 In BT and TT, skin lesions are hypopigmented and infiltrated with a raised, well-defined edge.4,7 It is also mostly scaly, dry and hairless.4 No acid-fast bacilli are seen.4 Alternatively, diffuse infiltration of skin and poorly defined mild hypopigmentation and erythema skin lesion are more commonly seen in LL patient.4,7 Acid-fast bacilli are found in skin lesions of LL patient.4

Peripheral nerve trunks and small dermal nerves are the two settings where nerve damage may occurs.4,7 Fibro-osseous tunnels near the surface of skin are the place where peripheral nerves are affected and posterior tibial nerve is the most common site.7 As a result, numbness and weakness occur when sensory, motor and autonomic function of peripheral nerves involved in leprosy.2,4 The first and most commonly affected modality is sensory loss but motor loss can also occur for the most part.4 Hypoaesthesia and anhidrosis within BT and TT as well as glove and stocking sensory loss in LL will be observed if there is involvement of small dermal nerves. A dangerous worsening in sensory or motor function without signs or symptoms of inflammation known as silent neuropathy may also occur.4,7

In general, symptoms that appear in patient who suffer from leprosy are painless skin lesions accompanied by loss of sensation, muscle weakness, ulcerations on hands or feet, foot drop or clawed hands.1,2 Other symptoms of leprosy are like eye involvement which will results blindness and mucosal involvement which causes ulceration on the tongue and epistaxis.4,7

Leprosy reactions may also happen due to inflammatory response of the immune system. A spontaneous increase in cell-mediated immunity may produces type 1 reaction where most commonly occur in borderline leprosy patient or patient who started multidrug therapy (MDT).2,4 Type 1 reaction can cause hyperthermia and acute inflammation of pre-existing skin and peripheral nerve lesions, causing skin oedema, erythema as well as tenderness and worsening of nerve function.2 Significant nerve damage like permanent loss of nerve function may be the consequences if not treated early.4 This reaction is also called reversal reaction because of the increase of the immune response.2

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Another leprosy reaction is type 2 reaction which is also termed as erythema nodosum leprosum, or ENL.2,4 It is a type of systemic inflammatory reaction which the rate of occurring is proportional to the extent of infiltration of the skin and bacterial index.4 Erythematous and painful papules, postulated and ulcerated nodules, fever, neuritis, lymphadenitis, orchitis, knees arthritis and glomerulonephritis are usually the symptoms of type 2 reactions.2,4 Moreover, haemolysis or bone marrow suppression and hepatic inflammation may also occur, resulting in anaemia and mild abnormalities in liver function tests.2

Regarding the mortality of leprosy, it is rarely fatal. The primary consequence of this infection is nerve impairment and debilitating sequela. According to Utianowski and Lockwood, signs of nerve impairment can be observed on 33~56% of the newly diagnosed patient.3 Many leprosy patients who completed the multidrug therapy for leprosy have sustained disability due to nerve damage.2 As a result of nerve damage, frequent trauma and amputation often happens.2

Treatment Options

Since the incidence of resistance to dapsone had increased, multidrug therapy (MDT) has been suggested by a WHO study group and then introduced by WHO in 1982 to replace the single drug regimen for the treatment of leprosy.1,6 This multidrug therapy consist of three first-line drugs which are against leprosy.1,2,4,5,6,7 They are dapsone, rifampicin and clofazimine.1,2,4,5,6,7 However, in paucibacillary leprosy patient, dapsone and rifampicin are used more often. There are also second-line drugs such as minocycline, clarithromycin and ofloxacin against leprosy.4,6,18 They are highly active against M. Leprae but not as active as rifampicin.4,6,18

  1. Mechanism of Action
  2.                Dapsone is the most commonly used antibacterial in the treatment of leprosy.8 In a similar way as sulphonamides, it inhibits the synthesis of dihydrofolic acid by binding to the active site of dihydropteroate synthetase.8,9 It was the first effective antimicrobial against M. Leprae and used alone for the treatment of leprosy.7 However, due to high incidence of primary and secondary resistance towards dapsone, it is now used in combination with other antibiotics like rifampicin and clofazimine in MDT.1,6,7

                   Rifampicin is also an effective antibacterial against M. Leprae.4 It is bactericidal and inhibits bacterial RNA synthesis by restraining the activity of DNA-dependant RNA polymerase through binding its β subunit to prevent the transcription of mRNA and thus stopping the translation to protein.7,10

                   Clofazimine is a weak bactericidal antibacterial.4,7 Arbiser and Moschella suggested that the primary site of action of clofazimin are neutrophil and monocyte.11 It is thought to exert bactericidal action by catalysing the production of hypochlorous acid which is a powerful chlorinating agent that causes inactivation of multiple proteins including bacterial proteins.11 Moreover, clofazimine has been assumed to exert direct bactericidal action by increasing the activity of phospholipase A2 and release of lysophospholipids, a type of enzymatic hydrolysis product which is toxic to gram-positive organisms and Mycobacterium.11 Nevertheless, the exact mechanism of action of clofazimine is currently unknown.7,11

                   Tetracycline antibiotics like minocycline is also effective against leprosy.4,6 Minocycline exerts its antibacterial effect by inhibiting the synthesis of bacterial protein.12 As a result, the association of aminoacyl-tRNA with bacterial ribosome has been prevented.12 They are bacteristatic.

                   Clarithromycin is a type of macrolide which inhibits the growth of bacteria by binding to the subunit 50S of the bacterial ribosome to inhibit peptides from translocation.13,14 In the end, the synthesis of protein in bacteria will be inhibited.13 Thus, clarithromycin can be considered as bacteristatic.14

                   Ofloxacin is bactericidal in action.15 It acts by inhibiting DNA synthesis within bacteria.15 DNA gyrase and topoisomerase IV are the target of ofloxacin.15 By the inhibition of these enzymes, movement of the DNA replication fork will be blocked.15 Thus, DNA replication will be inhibited which then resulting in cell death.15

  3. MDT treatment for paucibacillary leprosy
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    In general, treatment for paucibacillary leprosy patient is according to WHO regimens guidelines.5,6,7 For paucibacillary leprosy patient who has only single lesion, the treatment will be slightly different. A single dose treatment consist of 600mg of rifampicin, 400mg of ofloxacin and 100mg of minocycline will be given.4,5,6,7 Child who age 10~14 year old will be given half of the adult dose.4,5,6,7 Long-term follow-up has been suggested to be carried out to reduce chance of relapse.6

    According to WHO recommendation, paucibacillary leprosy patient who has body weight of 50~70kgs and two or more lesions should receive treatment comprises dapsone 100mg and rifampicin 600mg.1,2,4,5,6,7 On the other hand, child patient's dose will be lesser than the adult's which are 50mg of dapsone and 450mg of rifampicin for children which are 10~14 year old.6 Rifampicin should be taken once a month under supervision while dapsone is self-administered by the patient once every day. The duration of this treatment is 6 months.1,2,4,5,6,7 Dose of child under 10 year old has to be adjusted according to body weight for both type of paucibacillary leprosy patient.6 Table 1 summarises the WHO recommendation of paucibacillary leprosy treatment.

    In US, the MDT treatment guidelines for paucibacillary leprosy is similar to WHO therapy guidelines which is also contains dapsone and rifampicin.6 The only difference is that the duration of the treatment is 12 months instead of 6 months, which is longer than the WHO recommendation.6

    MDT has been safe and successful in treating leprosy.5,6 In addition, MDT has advantages of preventing dapsone resistance, causing reduction in the rate of infectivity, and resulting in fewer chance of relapses and reactions, and therefore, lesser disabilitiest.16 The relapse rate of paucibacillary leprosy patient receiving MDT has been reported as varying from 0% to 2.5% which is quite low.4,7 However, in a small study in Mali, higher relapse rate has been reported.5 Since drug resistance is less likely to occur if the MDT was originally effective against the M. Leprae in patient, same regimen should be used.5 It is also often used due to its advantage of able to administer easily under field condition.5

    Nevertheless, there are some limitations for the MDT treatment. Firstly, the residual disease activity is an issue as there were cases where active lesions have been observe at the end of the treatment.19 The are also published clinical outcomes shown that the percentage of patient with active skin lesions after finished the 6 months treatment is ranging from 2 to 44% for patient treated with WHO recommended paucibacillary treatment.7,19 Secondly, complication during or after treatment is also a limitation.7,17 In 2.5% of patient, nerve impairment occurred starting from the beginning of the treatment while an increase from 4% to 7% in visible disabilities was found after 8~10 years of follow-up.7,17 In addition, long duration of the standard MDT treatment for paucibacillary leprosy has been a disadvantage because it may lead to increase in non-compliance, encouragement of default and incidence of operational problems.16 As a result, treatment failure could occur.

    In some literature, the single dose drug combination (ROM) for paucibacillary single lesion leprosy has been reported for not being persuasive to be more effective than the standard WHO paucibacillary leprosy regimen.5,6,7,17,19 It is because instead of increasing the rate of clinical improvement, the single dose MDT regimen was less effective.5,7

                   Severe side effects of the drugs are rarely occurred with these regimens.5 A mild haemolytic anaemia may cause by dapsone but it may be severe in patient with glucose-6-phosphate dehydrogenase deficiency.4,5 Rifampicin has a common side effect of body fluids discoloration into orange-red in colour.4,6 Other than that, rifampicin has no significant side effects. Ofloxacin and minocycline are seldom used in field condition, not because of their side effect but their relatively high in cost compared to other drugs used in leprosy patient.7

  5. Treatment option for leprosy reactions

               Treatment Type 1 reaction is normally aimed to control acute inflammation, pain relieve pain, as well as reversing eyes and nerve damage.4,7 Prednisolone 40~60mg daily for 3~6 months and then tapered down very slowly by 5mg every 2~4 weeks is often the first choice treatment to be commenced immediately.4,5,6,7 If prednisolone fails to control the reaction, cyclosporins or azathioprine can be used to replace prednisolone.6,19

In type 2/ENL reaction, thalidomide 300mg to 400mg daily has a significant effect in controlling it and preventing recurrence.4,5,6,7,16 However, thalidomide use requires highly precaution especially in women due to its teratogenicity and neurotoxicity side effect.4,5,6,7 Due to the side effects of thalidomide, prednisolone and clofazimine are also used in treating ENL reaction.4,5,6,7,16

Treatment Recommendation

               In this case, a 52 year old male patient has paucibacillary hansen's disease (leprosy). Since there is limited information about his leprosy like the amount of lesion, the treatment options will be according to WHO recommendation, either paucibacillary or paucibacillary single lesion.

               If the patient has only single lesion, the ROM treatment would be recommended according to WHO guidelines. The treatment will be a single dose treatment and consisting of rifampicin 600mg, ofloxacin 400mg and minocycline 100mg given orally to the patient. Single dose ROM treatment has been shown to have definite and good bactericidal activities against M. leprae in the footpad of normal mice in a study.20 A clinical trial which involves 20 untreated leprosy patients also shown that single dose ROM treatment gives significant clinical improvement with a reduction of 32.5% in morphological index (MI) and over 95% of viable M. leprae was killed in leprosy patients' post treatment biopsy samples.20 In a recent study involving 135 single lesion paucibacillary leprosy patient , no reactional episode was detected during the 3 years clinical follow-up in patients treated with single dose ROM treatment.21 Furthermore, typical steroid is adequate in the prevention of nerve damage in these patients.21 Shift from paucibacillary to multibacillary leprosy was also rare in patient treated with single dose ROM treatment.21 In a double-blind trial, single dose ROM treatemtn was used to treat 739 patients and the side effects were found to be very rare where only 0.5% of the patients experience it.25

On the other hand, if the patient is having more than one lesion paucibacillary leprosy, 600mg of rifampicin should be administered under supervision for once a month and 100mg of dapsone to be taken once daily for over 6 months. According to a uniform MDT trial which involves 1777 paucibacillary leprosy patients, the MDT treatment is effective as a better result of 59% instead of 31% (reported in previous studies) of the patients having inactive lesions was observed.22 Besides, in a retrospective study in Hong Kong, MDT treatment was shown to be effective and well tolerated.23 A study also showed that the combination of rifampicin and dapsone reduced the occurrence of dapsone resistance significantly.24

It can be noticed that there is rifampicin in both regimen. This is because rifampicin is effective in treating leprosy and there is a few evidences supporting this. Rifampicin's bactericidal activity was established in a series of pilot, uncontrolled and controlled trials.24 In the pilot trial and long term trial, rapid bactericidal effect was observed in untreated patients.24 Significant loss of viable M. Leprae also observed in the controlled clinical trial.24 In another pilot type chemotherapeutic trial consist of 6 cases, the basic bacteriological, clinical and histological assessments within 4.5 months of taking rifampicin have shown that rifampicin 600mg daily is therapeutically active against M. Leprae.25

After started the MDT treatment, the patient should be monitored for the signs and symptoms of having leprosy reaction. If the patient is found to have type 1 or type 2/ENL leprosy reaction, 40~60mg of prednisolone daily should be commenced. In a recent Indian study, long duration of prednisolone treatment was shown to have good clinical outcomes in leprosy reactions.7 In ENL reaction patient, prednisolone is normally used when thalidomide is not available or unable to be used due to its side effects.6 However, thalidomide can be given if the ENL reaction of the patient is not controlled by prednisolone. Daily dose of 300mg of thalidomide was proved to be effective in treating type 2 leprosy reaction because improvement rate of 95% of patients participated in a double blind trial in brazil was observed.26 Since the patient is a male, teratogenicity will not be a problem. However, other side effects of thalidomide may be dangerous. Thus, monitoring of the patient on thalidomide side effect is necessary.

Conclusion

               In conclusion, treatment of this patient basically follows the recommendation of WHO. In view of the fact that relapse of leprosy is an issue after the patient completed the MDT treatment, follow-up is very important and recommend to be carried out every 6 months over 5 years.6 Nevertheless, treatment of leprosy contains not only chemotherapy but also other aspects such as nerve damage monitoring and care, concern of disability, patient education, social support, as well as rehabilitation.

Reference:

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  15. Ofloxacin D5W IV. Medscape. Accessed 31 january 2009. Available from: URL: http://www.medscape.com/druginfo/monograph?cid=med&drugid=10120&drugname=Ofloxacin+in+D5W+IV&monotype=monograph&secid=8
  16. Samuel L. Moschella. An update on the diagnosis and treatment of leprosy. J Am Acad Dermatol 2004;51:417-426.
  17. Bernard Naafs. Treatment of Leprosy: science or politics? Tropical Medicine and International Health. March 2006. Volume 11 no 3 pp 268-278.
  18. BNF 57. March 2009
  19. Vishwa M. Katoch. Advances in the diagnosis and treatment of leprosy. Expert Reviews in molecular medicine. Cambridge University Press. 22 July 2002.
  20. Ji, B., S. Sow, E. Perani, C. Lienhardt, V. Diderot, and J. Grosset. 1998. Bactericidal activity of a single-dose combination of ofloxacin plus minocycline, with or without rifampin, against Mycobacterium leprae in mice and in lepromatous patients. Antimicrob. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol. 42, No. 5, May 1998, p. 1115-1120
  21. Ana Lucia O. M. Sousa, Mariane M. A. Stefani, Gisner A. S. Pereira, Mauricio B. Costa, Paula F. Rebello, Maria Katia Gomes, Kazue Narahashi, Thomas P. Gillis, James L. Krahenbuhl, and Celina M. T. Martelli. Mycobacterium leprae DNA Associated with Type 1 Reactions in Single Lesion Paucibacillary Leprosy Treated with Single Dose Rifampin, Ofloxacin, and Minocycline. Am. J. Trop. Med. Hyg. The American Society of Tropical Medicine and Hygiene, 77(5), 2007, pp. 829- 833
  22. Axel Kroger, V. Pannikar, M. T. Htoon, A. Jamesh, K. Katoch, P. Krishnamurthy, K. Ramalingam, Shen Jianping, Vitthal Jadhav, M. D. Gupte and P. Manickam. International open trial of uniform multi-drug therapy regimen for 6 months for all types of leprosy patients: rationale, design and preliminary results. Tropical Medicine and International Health. volume 13 no 5 pp 594-602 may 2008.
  23. CK Ho and KK Lo. Epidemiology of leprosy and response to treatment in Hong Kong. Hong Kong Med J. Vol 12 No 3 June 2006.
  24. M F R Waters, R J W Rees, J M H Pearson, A B G Laing, H S Helmy, R H Gelber. Rifampicin for lepromatous leprosy: nine years' experience. British Medical Journal, 1978, 1, 133-136
  25. Single-Lesion Multicentre Trial Group. 1997. Efficacy of single dose multidrug therapy for the treatment of single-lesion paucibacillary leprosy. Indian J. Lepr. 69:121-129.
  26. A.M. Sales, H.J. de Matos, J.A.C. Nery, N.C. Duppre, E.P. Sampaio and E.N. Sarno. Double-blind trial of the efficacy of pentoxifylline vs thalidomide for the treatment of type II reaction in leprosy. Braz J Med Biol Res, February 2007, Volume 40(2) 243-248