Leprosy, besides known as Hansen ‘s disease, is a chronic morbific disease caused by acid-fast, Gram-positive Mycobacterium leprae ( M.leprae ) . Several manners of transmittal are suggested such as skin contact and sexual activities but the primary mechanism is via air by oral cavity and rhinal discharge of untreated septic people. Leprosy can be considered in two parts in which the first milder signifier involves infection of superficial tissues such as tegument. This undetermined province is normally surmounted by the human organic structure arousing sufficient immune response, with about 95 % of people being non susceptible. However, if the organic structure produces excessively high or excessively low a response, the 2nd more terrible signifier of leprosy develops and progresses go forthing malformations in countries such as tegument, nervous system, mucous membrane, limbs and eyes.
Therefore, depending on the patient ‘s immune response, Hansen’s disease is classified by the World Health Organization ( WHO ) into multibacillary Hansen’s disease in which the organic structure ‘s defence system is uneffective, and paucibacillary Hansen’s disease ( PB ) which produces aggressive response.1 In footings of tegument vilification trials, MB which has big figure of bacteriums in skin lesion would bring forth positive consequences while PB produces negative consequences. Another type of categorization known as Ridley-Jopling categorization divides leprosy into 5 phases ; tuberculoid ( TT ) , marginal tuberculoid ( BT ) , midborderline/borderline ( BB ) , borderline lepromatous ( BL ) and lepromatous ( LL ) Hansen’s disease in which the latter three are the equivalent of MB.
Figure 1: Phases in leprosy infection.4
In 2009, leprosy instances were reported in 121 countries.2 Based on WHO figures, the figure of new instances detected in 2008 was 249007 while the registered prevalence of leprosy worldwide at the beginning of 2009 was 213036. Although there has been a steady autumn in the figure of new instances detected yearly, leprosy remains a planetary menace.
In MB, the first marks and symptoms perchance encountered are numbness, rhinal discharge every bit good as assorted sorts of lesions, maculas, nodules and papules. More terrible symptoms may be spread skin thickener, oculus lesions taking to cataract, secondary infection and nervus lesions.
Although leprosy can impact all people, assorted specific factors predispose to leprosy. First, leprosy typically affects people populating in tropical and semitropical clime such as Africa and South East Asia. Peoples in endemic countries every bit good as the hapless and marginalized community are at greater hazard of undertaking Hansen’s disease. In footings of age, leprosy demonstrates an age-related form with peak incidence in kids below 10 old ages old and mid mid-thirtiess while seldom acquired by infants.3 Besides that, work forces are by and large more susceptible than adult females and familial factors may play a function excessively.
Despite old ages of incubation period, the differential diagnosing of Hansen’s disease is critical because the intervention continuance is prolonged. Besides, an accurate diagnosing helps in finding the appropriate and effectual intervention. In vitro civilization of M.leprae is non executable given the highly slow growing rate. Methods that can be used include skin lesion biopsy and rhinal vilifications done utilizing Fite ‘s acid fast tissue staining which stains the B red in a bluish background or utilizing Hematoxylin and eosin discoloration ( H & A ; E ) for histological confirmation.3,4 The figure of B visible will denote the type of Hansen’s disease. Besides, phenolic glycopilid-1 ( PGL-1 ) feature of M.leprae can be distinguished utilizing serology techniques.
Given its low mortality rate, leprosy confers enfeebling reverberations however on patients both physiologically and psychologically. Leprosy causes hypoesthesia due to impaired peripheral nervus map, musculus failing every bit good as glaucoma, iridocyclitis and redness of the oculus. As a consequence, patients are prone to hurts due to decrease vision, and inability to experience and command the organic structure. The incidence of optic jobs is markedly elevated and intervention has proved to cut down prevalence of these complications as described by Gupta et Al, whereby 66.3 % active leprosy patients manifested optic jobs compared to bring around patient at 14.3 % .5 If blindness occurs, the comparative decease hazard in blind patients compared to non-blind patients augments by 4.8fold.6 Additionally, leprosy causes clawed fingers and toes, hypopigmented skin lesions with terrible ulcerations particularly on pess and custodies, and facial distortions.
Figure 2: Nerve harm taking to malformation and attendant ulcers and bone resorption.1
Figure 3: A patient with active, untreated MB.1
These disablements occurs more often in MB patients than in PB patients,5,7 and it was suggested that MB patients have higher hazard of decease compared to PB patients ; the mean decease age being 5 old ages younger.8 Contrasting prevalence of malformations was concluded in different surveies which includes 56.97 % ,7 82.4 % ,9 84.4 % ,10 67 % 11 and these differences may be the consequence of improper scrutiny technique or dissimilar scaling standards. However, the point to observe here is that all surveies acknowledge the badness of this disease.
Besides, besides enforcing limitations on physical mobility, such vastly conspicuous infirmities have led to a stigma linked to leprosy. Leprosy patients are frequently subjected to public bias and favoritism, go forthing them significantly affected both socially and economically. Therefore, accurate diagnosing and aggressive beginning of leprosy intervention is indispensable to better patients ‘ quality of life every bit good as diminishing mortality rate.
2.1 First line therapy
The current pharmacotherapy options include dapsone, rifampicin and clofazimine as the first line therapy. Dapsone is a bacteriostatic antibacterial active against M.leprae. Its good unwritten bioavailability allows its disposal in the tablet signifier. However, dapsone monotherapy is no longer used as several surveies have established profound drug resistance.12,13,14 Following this, WHO recommends the usage of three drugs ; dapsone, rifampicin and clofazimine, administered as multiple drug therapy ( MDT ) for MB.1 Supporting this is a systemic rating by Kundu et Al. which compared dapsone monotherapy to MDT and proved that MDT was significantly superior with capacity to forestall dapsone resistance.15
Figure 4: Multi-drug therapy consisting dapson, rifampicin and clofazimine.2
The current MDT dosing is dapsone 100mg and clofazimine 50mg day-to-day self-administered, and rifampicin 600mg and clofazimine 300mg one time monthly supervised. Several surveies have shown that MDT is effectual in riddance Hansen’s disease with low backsliding rates.16,17,18,19 For illustration, Georges et Al. demonstrated patients treated on MDT until bacterial clearance showed no validated backslidings in the follow up period between 4 months to 5 old ages and 10 months.16
If inauspicious effects or contraindication occurs ensuing in MDT expiration, WHO recommends alternate regimen.20 Nevertheless, it is critical to determine once and for all that the negative effects are due to MDT. Dapsone should be terminated instantly if patient develops inauspicious effects such as Dapsone Hypersensitivity Syndrome ( DHS ) . Rifampicin and clofazimine should be continued at usual dose. The usage of lone rifampicin and clofazimine was proven effectual for dapsone intolerant patients as described by Sapkota et al.21 These patients treated for a average continuance of 15 months post-dapsone surcease showed steady lessening in average bacteriological index ( BI ) . Following, if rifampicin is ill-tolerated, alternate therapy comprises clofazimine 50mg, ofloxacin 400mg and minocycline 100mg day-to-day for six months, followed by clofazimine 50mg combined with either ofloxacin 400mg or minocycline 100mg for at least 18 months ; given under supervising. Ji et Al showed that ofloxacin was capable of extinguishing rifampicin-resistant cells.22 Finally if clofazimine has hapless acceptableness, MDT can be replaced with ROM consisting rifampicin 600mg, ofloxacin 400mg and minocycline 100mg given monthly for 24 months. In a field test in Senegal, patients on ROM showed satisfactory advancement with exceeding conformity perchance attributed to the simpler monthly dosage.23 This combination was farther advocated by S. Ura24 and Villahermosa et al25 who compared 2 old ages ROM intervention with MDT. The surveies concluded that both therapy depicted similar advantages sing their consequence on BI, their safety and tolerability. The latter survey besides showed no backsliding after follow ups 5 old ages subsequently or more.
2.2 Second line therapy
Ofloxacin ( a racemic mixture of levofloxacin and dextrofloxacin ) and pefloxacin are broad-spectrum flouroquinolones used as 2nd line therapy for MB. They are disinfectant moving via suppressing enzyme DNA gyrase required in DNA reproduction thereby interfering with bacterial cell division. Patented in 1982, ofloxacin has been reported to hold profound effects on Hansen’s disease. A clinical test executed by Ji et Al showed killing of more than 99.99 % of feasible M.leprae in skin vilifications inoculated into mouse pes tablet, with important clinical betterments by twenty-four hours 56 of therapy using 400mg ofloxacin daily.26 Besides, its consequence was non enhanced when used in combination with clofazimine and dapsone. A similar survey by Jianping et Al which besides utilized mice footpad inoculated with leprosy patients ‘ tegument biopsies had correspondent findings, with no M.leprae growing detected.27 These surveies supports the impression that ofloxacin possesses strong disinfectant activity. In another survey, Tranquiolino et al reported greater bactericidal activity by pefloxacin and ofloxacin compared to dapsone and clofazimine but non rifampicin.28 This consequence was subsequently confirmed by Grosset et Al which besides utilized the fluoroquinolones for intervention during the first two months followed by criterion WHO MDT.29 Comparing pefloxacin to ofloxacin, it was found that pefloxacin was less active, necessitating 150mg/kg to exercise disinfectant consequence compared to 50mg/kg for ofloxacin.22 Although minimum side effects were encountered in these surveies, the short continuance of therapy will non vouch for this as terrible inauspicious reactions have been reported including tendon harm, peripheral neuropathy, cardiovascular toxicity and hepatotoxicity.
Traveling on, the wide spectrum Minocin is a Achromycin bactericide which can be used in patients intolerant to dapsone or clofazimine.30 In a clinical test by Fajardo et Al, patients treated with 100mg day-to-day Minocin for 6 months followed by WHO MDT manifested distinguishable clinical betterment within the first month with negative PGL-1 antigen at the terminal of 6 months treatment.31 However, it has been reported that Minocin induce hyperpigmentation which resulted in expiration of therapy.32 This side consequence ought to be considered peculiarly when Minocin is used to replace clofazimine. In footings of bactericidal activity, Minocin is considered more effectual than clarithromycin, but significantly diminished activity compared to rifampicin.
Clarithromycin is a bactericidal macrolide which suppresses bacterial growing by forestalling its protein synthesis. A few clinical tests have shown the advantages of clarithromycin including its capableness to kill M.leprae, considerable clinical betterment, patient acceptableness and minor inauspicious effects.33,34 Daily dose of 500mg revealed violent death of 99 % B within 28 yearss and 99.9 % by twenty-four hours 56.34 However, limited surveies with clarithromycin for leprosy usage have been done. Until farther researches are carried out, clarithromycin remains the 2nd line intervention for multibacillary Hansen’s disease.
Since the past two decennaries, concerns over established dapsone opposition and progressively emerging rifampicin opposition have set involvement on usage of either thioamide or clofazimine at the same time with rifampicin. However, clofazimine was chosen by WHO due to studies of hepatotoxicity when thioamides were used with rifampicin.35,36 Nevertheless, ethionamide and prothionamide are two thioamide drugs being investigated presently as monotherapy for leprosy intervention. Although chiefly used for TB therapy, both drugs have been shown to exhibit important anti-leprotic activity based on a clinical test by Fajardo et al.37 Treatment was good tolerated for both drugs with a clinical advancement of 74 % and 83 % severally. Prothionamide was found to be superior to ethionamide and the overall efficaciousness of both drugs was similar to that of dapsone and clofazimine. However, they were less efficacious compared to rifampicin, ofloxacin, pefloxacin, Minocin and clarithromycin. They are besides more expensive than dapsone. Consequently, thioamides are by and large non recommended.
Finally, rifampicin and Isoprodian consisting dapsone, prothionamide and INH were used in Malta Leprosy Eradication Project ( MLEP ) .38 During the 30-year undertaking, the leprosy prevalence steadily declined with exceptionally low grade of backsliding and toxicity. It was suggested that intervention with two Isoprodian tablets daily and 600mg rifampicin tablet wholly eradicated leprosy from Malta. This may good put the baseline for leprosy intervention. However, Isoprodian being non readily available became a drawback in continuing with this therapy. Besides, the MLEP posed several restrictions including the parturiency of the undertaking to a comparatively little country which hinders its feasibleness in larger countries. Additionally, the fact that Hansen’s disease was already worsening in Malta before the undertaking commenced in 1971 raised inquiries over the true consequence of the therapy on leprosy riddance.
Figure 5: Fall in incidence of Hansen’s disease in Malta between 1953 and 2002.38
3.0 Treatment recommendation and back uping grounds
After discoursing the intervention options available, 24 months MDT is recommended for the 32 twelvemonth old female patient in this instance survey. This determination is made based on the groundss presented antecedently on efficaciousness of MDT and besides the fact that non many dependable surveies have been conducted on other options. The clinical pharmacological rules of each MDT drug and more groundss will be presented in this subdivision to warrant the recommendation.
First, dapsone Acts of the Apostless via forestalling dihyrofolic acerb formation therefore suppressing nucleic acerb synthesis crucial for M.leprae development. In footings of inauspicious effects, dapsone has been associated with side effects such as methaemoglobinamia, hemolysis, allergic coryza, neurophaty, aganulocytosis and DHS dwelling Type 1 reversal reaction and Type 2 erythema nodosum leprosum ( ENL ) reaction. However, at doses used for leprosy intervention, these side effects are uncommon.39 Besides, DHS can be ameliorated with corticosteroid therapy. In order to control opposition against dapsone, it should be used concomitantly with rifampicin and clofazimine as MDT due to its established anti-leprotic consequence. Besides, there has been grounds of important diminution in frequence and earnestness of Type 1 and 2 reactions in patients on MDT, perchance due to rapid apprehension on leprosy patterned advance and clofazimine ‘s anti-inflammatory action.20
Following, rifampicin is an antibacterial which plays a major function in bring oning rapid M.leprae cell decease by suppressing RNA polymerase involved in protein synthesis. Rifampicin has good unwritten bioavailability as it is readily absorbed from the GI piece of land. A monthly 600mg dosage is extremely disinfectant and is about every bit effectual as rifampicin given daily as subsequent doses do non augment killing rate proportionally. Thus although rifampicin is expensive, a monthly dosage contributes to its cost-effectiveness, feasibleness and compliance.20 The downside of rifampicin is that inauspicious effects such as hepatotoxicity have been reported necessitating frequent liver map trials and blood trials to observe liver damage. Other common side effects of rifampicin include GI perturbations, febrility, concern and roseolas. Besides, being a liver enzyme inducer, rifampicin upregulates cytochrome P450 ensuing in enhanced metamorphosis of many concomitantly administered hepatic cleared drugs. However, this consequence is comparatively minimum due to its one time monthly dosing. Besides, although rifampicin additions dapsone clearance rate, no alterations in dosage have been necessary as concluded by Pieters et al.40 Interaction with clofazimine is besides non likely as rifampicin deficiency inclination to roll up in tissues due to its comparatively short half life ( 2-3 hours ) compared to clofazimine ( 70 yearss ) .
The 3rd drug used in MDT is clofazimine which based on the MDT dose is the most well-tolerated amongst the three drugs and is practically non-toxic.41 Clofazimine is a bacteriostatic bactericide which has preference towards mycobacterial DNA and inhibits bacterial growing. A 300mg lading dosage one time monthly service as a depository to keep sufficient drug in the body.20 The most common side consequence of clofazimine looking in some 75-100 % instances is pink color of the tegument which are reversible months after halting therapy.42 Its usage is evident as assorted surveies and clinical tests have proved its efficaciousness as an anti-leprosy agent without serious inauspicious effects.43,44,45
In footings of continuance of MDT, the recommended continuance of MDT has been invariably altering over the old ages. WHO ‘s old recommendation of 24 months therapy showed high efficaciousness with vey low backsliding rate. However, in the Seventh Expert Committee ( 1997 ) , the continuance of MDT was shortened to 12 months.1 A survey conducted by Gross saless et al. showed that the diminution in bacillary index and happening of inauspicious reactions was correspondent for both 12 and 24 months MDT.46 However, this was opposed by US National Hansen Disease Program ( NHDP ) which stands house with 24 months MDT with the position that more vigorous and longer intervention continuance generates higher efficaciousness with lower backsliding rate.30 It besides mentioned that the 12 months MDT recommended by WHO was due to be consideration in developing states. Based on the BNF, intervention for at least 2 old ages is necessary for MB.39
The cardinal aim of leprosy therapy is determined by the backsliding rate and grade of disablement. Having said so, many surveies have showed that the backsliding rate after completion of MDT for 2 old ages yielded either zero or really low backsliding rate.47,48,49,50,51,52 This is supported by a long term followup by Shaw et al47 which proved zero backsliding utilizing this regimen and besides by a retrospective analysis conducted in China by Shen et al49 which showed that out of 2374 patients followed up for a mean of 8.27 old ages, five patients had relapse ensuing in a backsliding rate of 0.21/1000 person-years. Another footing for the 24 months MDT was the reappraisal by WHO which revealed a really low backsliding rate of 0.9/10 000 person-years in analysis of more than 20,000 MB patients.51 Furthermore, Katoch et al reported that follow up conducted between 12-44 months after MDT intervention revealed impairment in patients who received merely 12-18 months intervention and uninterrupted betterment in those given 24 months therapy.53
Bearing in head that this patient is a 32 twelvemonth old female who is at her kid bearing age, it is overriding to determine is she is pregnant or breastfeeding. Extreme cautiousness should be undertaken if patients are pregnant or lactating, taking into account risks-benefits of leprosy intervention. Several surveies have demonstrated inauspicious effects encountered by pregnant and breastfeeding females such as backsliding, type 1 and 2 dapsone reactions and peripheral neuropathy following therapy and are thought to be due to suppression of unsusceptibility during gestation and breast-feeding.54,55,56 However, some surveies have showed that these drugs can be used safely during pregnancy.20,57 Thus, although MDT may incur hazards to gestation and exacerbate Hansen’s disease, a well-organized wellness program, frequent and regular supervising may good outweigh the hazard with its possible benefits.4,56 Besides, effects of MDT on lactating is really minor. Although important sum of dapsone is found in chest milk, its hazards to babies are really minimum. In contrast, the measure of rifampicin in milk is excessively little to be harmful to the babe. Likewise, merely infinitesimal sums of clofazimine are excreted through chest milk and therefore far there have non been studies on terrible negative effects on breast-feeding except minor skin stain of baby.
All in all, intervention utilizing 24 months MDT has proven extremely successful with rapid transition of disease province from infective to being non-infectious even after the first dosage. MDT remain the ultimate option due to its evident benefits of bring arounding and halting transmittal of leprosy, its virtually zero backsliding rate, minimum side effects, easiness of disposal and storage, cost-effectiveness and huge clinical groundss. Additionally, patient and public instruction is critical to help patient conformity and better apprehension on leprosy. In this context, wellness professionals carry enormous duties in giving societal support and psychological rehabilitation to assist patients get by with the physical and mental hurt caused by the disease every bit good as bring arounding the stigma of Hansen’s disease.
Figure 6: A patient with Hansen’s disease who was cured utilizing MDT.1