The Multibacillary Hansens Disease Biology Essay

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Leprosy i.e. Hansens disease is a chronic infectious disease known to be caused by the acid-fast, rod-shaped bacillus Mycobacterium leprae M leprae. With references of the disease dating as far back as 1550B.C., leprosy has always been believed to be a fearful disfiguring disease for which no treatment would ever be able to cure. (2) Often times, individuals affected with leprosy are subjected to ostracism and abandonment, and are forced to live in segregated 'leper colonies' for which unfortunately still do exist today in countries such as India, China and Romania. It wasn't only until 1873, when Dr. Amauer Hansen of Norway first characterised the causative pathogen, Mycobacterium leprae, interests in the disease and treatment for the disease began pouring in. (2, 3)

Epidemiology

Globally, leprosy remains as a prevalent issue in regions of South East Asia, South America, Africa, Western Pacific and the East Mediterranean.(4) Leprosy for a fact is known to generally manifests in both subtropical and tropical temperate climates and this may be exemplified by countries such as India, Brazil and Indonesia being the top three countries with most number of reported leprosy cases in 2010.(2,4) Nonetheless, since the introduction of a multidrug therapy (MDT) by the World Health Organisation (WHO) in 1985, approximately 11.5 million individuals affected with leprosy have already been cured of the disease.

In 2009, 244 796 cases of leprosy have been newly detected globally, and the registered prevalence at the start of 2010 totalled to 211 903 cases, resulting in a global prevalence of registered leprosy cases of just 1.77 per 10 000. (4)

Humans unfortunately however represent the main carriers for M Leprae. Besides man, only the wild nine-banded armadillos are also known to be hosts of the microorganism. Hitherto, no other living organisms are known to be natural hosts of M Leprae. (2, 3) In a study conducted by Truman et al, a distinct M Leprae genotype '3I-2-v1' was found in three afflicted patients and in nine-banded armadillos captured randomly from the wild in the southern states of the United States (i.e. Arkansas, Alabama, Louisiana, Mississippi and Texas). Evidently, Truman et al suggested the possibility of a zoonotic factor in the transmission of M. Leprae. (5)

Nevertheless, most individuals are physically resistant to an infection with M Leprae and the disease is rarely ever fatal. (2,3) Primary consequence of an infection crucially involves nerve impairment and debilitating sequelae. (6)

[Insert Image of Mycobacterium M Leprae]

Microbiology

Over the last two decades, progression into the understanding of the microbiology of M Leprae has helped bridged the gaps of knowledge associated with leprosy. The capability to infect and reproduce M Leprae on mouse footpads has not only overcome the challenge of cultivating M Leprae in cell culture, but it has also provided opportunities for detailed microbiological investigations and clinical studies.(7)

For the most, M Leprae, a gram-positive and obligate intracellular parasite, is known to exhibit tropism for macrophages and Schwann cells, and is figured to thrive predominantly in regions of lower body temperature (e.g. skin, upper respiratory tract, eyes and peripheral nerves). Predilection for Schwann cells are due vitally to the affinity to the G domain of the 2 chain of laminin-2, which are found in abundance in the basal lamina of Schawnn cells. Evidently, consequences of an infection are cutaneous in nature and at times may involve permanent disability caused by severely impaired nerve function.

Additionally, clinical manifestations of leprosy vary depending upon host immune responses towards M Leprae. The complex mixture of polysaccharides and glycolipids which forms the cytoplasmic membrane of M Leprae represents important targets of host immune responses. Phenolic glycolipid I (PGL-I) for example, a component of the membrane is known to stimulate both a specific and potent Immunoglublin M (IgM) response that is proportionate to the bacterial load in patient. Accordingly, treatment management will vary depending upon the different clinical manifestations of the disease.

Moreover, with leprosy epidemiological linkage between exposure and manifestation of the disease is complex. The period between infection and onset of the disease varies significantly between just a few months to 30 to 40 years. Correspondingly, due to the lack of particular regulatory genes and a sole dependency of on host metabolic products, M Leprae is known to require a prolonged doubling period of 14 days, the longest amongst all known pathogens. This may in turn explain the insidious incubation period of leprosy.

Clinical Manifestations

As aforementioned, variability in host immune responses corresponds to diverse clinical manifestations of the disease. Accordingly, based on a classification system designed by the WHO, leprosy may be categorised based on the number of skin lesions present and the presence of bacilli determined via a slit-skin smear examination. Paucibacillary Hansen's disease on one hand is defined as lesser than six skin lesions without the presence of bacilli on slit-skin smear testing. Multibacillary Hansen's disease on the other hand, is characterized by six or more lesions with or without positive skin smear results. Notably, paucibacillary patients with positive skin-slit smears are automatically reclassified as multibacillary afflicted to ensure the effectiveness of treatment management.

Nonetheless, classical features of leprosy include skin lesions, weakness or numbness, and even eye pain or visual impairment. If left untreated, the disease may result in permanent damage to the skin, nerve, limbs or eyes. In this case of a 25 year old female diagnosed with multibacillary Hansen's disease, the patient may firstly present with numerous anaesthetic skin lesions (≥6) with symmetrical distributions. The skin lesions may additionally exhibit hypopigmentation or erythema, and may be easily confused for other dermatological conditions (e.g. dermatitis, tinea corporis and psoriasis).

Appreciably, the enlargement of certain peripheral nerves (e.g. ulnar, median and posterior tibial nerve) is a hallmark sign of leprosy. Due to the tropism and subsequent multiplication of M Leprae within Schwann cells, enlargement of particular peripheral nerves ensues. Thus, resultant enlargement of these nerves may further indicate leprosy as the diagnosis.

Damage afflicted from the accumulation of M Leprae within Schwann cells may also result in other distinct signs of leprosy. For example "clawing" of the hands or foot is commonly reported cases distinct of leprosy.

In cases of the multibacillary form of the disease, leonine facies (i.e. lion-like appearance) may also be manifested.

[Image of Multibacillary Skin Lesions]

[Image of Peripheral Nerve Enlargement]

[Image of Leonine Facies]

Type II (Cytotoxic) Hypersensitivity Reaction

Under normal circumstances, immune responses are in place to combat infections and to subsequently promote healing and restoration in the events of injuries. In certain instances however, immune responses in certain selective individuals may react abnormally or exaggeratedly to certain substances (e.g. pollens, food stuffs or drugs) others wouldn't normally do. These hypersensitivity reactions may result in serious damage to the host and at times may even lead to death. (9, 10, 11)

Depending on the mechanism involved and time taken for a hypersensitive reaction to occur, hypersensitivity reactions may be classified according to 4 different categories based on the Gels and Coombs classification scheme (i.e. type I, type II, type III and type IV). In a type II hypersensitivity reaction specifically, immunoglobulin G (IgG) or IgM antibodies are involved in the destruction of blood cells (e.g. erythrocytes, leukocytes and thrombocytes) by complement-induced lysis or by antibody-dependent-cellular-toxicity (ADCC).

More importantly in type II hypersensitivity reactions, certain drugs (e.g. penicillin, chloramphenical, sulphonamides) or haptens may result in haemolytic anaemia, thrombocytopenia or neutropenia. As a result, this may consequently affect any treatment options available to a patient. In this particular case for example, the prospects of a 25 year old female with multibacillary Hansen's disease is further complicated by a severe type II hypersensitive reaction. Accordingly, treatment options for this patient are further limited down to a handful of choices, thus placing a risk for treatment failure. Crucially, a positive direct or indirect Coomb's test may be used as a confirmatory test to determine the potential immunogenicity of particular drugs prior to the initiation of therapy.

Treatment

Before the introduction of the MDT, dapsone (diamino-diphenylsulphone) was initially thought of to be the long awaited cure for leprosy. Dapsone was first used as a monotherapy but it required patients to be on long term, often lifelong treatment due its slow bactericidal activity. Years after its introduction however, over and uncontrolled use of dapsone led the emergence of resistant M Leprae strains. Globally, primary and secondary resistance rates soared to as high as 50% and 19% respectively. In response to the alarming threat to leprosy control, in 1982 treatment for leprosy was revolutionised with the advent of MDT. The concept of combining several drugs was ideally aimed at limiting the development of antibiotic resistant pathogens. Since then, approximately 11.5 million individuals have been treated with MDT.

Therapeutic effectiveness in the context of treating leprosy however is determined by measuring rate of relapses following successful completion of a scheduled course of treatment. Rate of relapses since the introduction of MDT was discovered to be only 0.06% among multibacillary afflicted patients globally, thus proving the therapeutic efficacy of MDT. Since then, MDT has been the mainstay first-line regimen for the treatment of leprosy.

Table 1: Recommended MDT according to the WHO and National Hansen's Disease Program (NHDP) for treatment of multibacillary Hansen's disease.

WHO

NHDP

Dapsone 100mg/day

Rifampicin 600mg/mo

Clofazimine 100mg/mo

for 12 months

Dapsone 100mg/day

Rifampicin 600mg/day

Clofazimine 50mg/day

For 24 months

Dapsone

Dapsone, which represents a component of the MDT, exhibits structural similarities to sulphonamides. It is known to target dihydropteorate synthase, a key enzyme involved in the folate biosynthesis pathway in M Leprae.

In a study conducted in 1975 utilizing mouse footpad models, Louis Levy detected a pertinent interval between the growth curves attained from passages from control and dapsone-treated mice. A 99.4% elimination rate of viable M leprae with the use of dapsone as a singular therapy was observed and the growth curves comparing treated and control mice exhibited an average 78 day delay between both groups, with the bacilli from the treated mice lagging behind. Appositely, dapsone was concluded to have exhibited both bacteriostatic and bactericide effect. Despite the fact however, in comparison to the efficacy of rifampicin, dapsone was only considered to be weakly bactericidal against M leprae. For the most, it is used in combination with rifampicin and clofazimine crucially to prevent the emergence of resistant strains.

Missense mutation within codons 53 and 55 of the folP1 gene encoding dihyropteorate synthase has been implicated in the emergence of dapsone resistant strains. Patients whom are likely to relapse after either dapsone monotherapy or MDT would most likely display mutant folP1 genes rather than rpoB genes (i.e. rifampicin resistant genes).

In certain cases, patients lacking glucose-6-phosphate-dehydrogenase (G6PD) started on dapsone therapy may exhibit methaemoglobinemia and hemolysis. Adverse events as such limits the use of dapsone and thus requires patients to be screened for G6PD deficiency prior to starting therapy.

Rifampicin

Rifampicin on the other hand, which represents the key component of MDT, is known to be the most bactericidal antileprotic agent available. Numerous studies at most have highlighted its potent and rapid activity against M Leprae () . A study conducted by Levy et al for example demonstrated no viable bacilli via mouse footpad tests just after 4 days of a single 600mg dose of rifampicin. Additionally, a study by Ji et al established that rifampicin was more bactericidal when compared to any combination of new antileprotic agents (e.g. clarithromycin-minocyclin-ofloxacin, clarithromycin-minocyclin and dapsone-clofazimine).

Rifampicin essentially acts on the β-subunit of the DNA dependent RNA polymerase encoded by rpoβ. It is never used as monotherapy due to the risk of rapid development of resistant strains. Depending on the treatment algorithm by WHO or NHDP, rifampicin may be taken on a monthly basis or even a daily basis. Crucially however, it was noted that patients are less likely to relapse if prescribed rifampicin on a daily basis.

Due to the risk of a hypersensitive reaction towards rifampicin, it is most advisable for the patient in this case to partake in a Coomb's allergological test. If unfortunately tested positive, an alternative regimen to MDT may need to be considered instead. Considering the fact that rifampicin represents the main component of MDT, therapy for leprosy without rifampicin would inevitably reduce the prospects of the patient and also increase the risks of relapse.

Adverse effects with the use of rifampicin commonly include hepatoxicity, malaise and rash. Patients may at times also experience a reddish discolouration of the urine but it is nevertheless harmless. In a case of a hypersensitive reaction, the patient may exhibit haemolysis, thrombocytopenia or even neutrocytopenia.

Clofazimine

Clofazimine crucially represents the third and last component of the MDT. Despite an unestablished mechanism of action to date, the antibacterial activity of clofazimine has been attributed to both its lipophilic and anti-inflammatory properties. For the most, the highly lipophilic property of clofazimine enables it to accumulate in the skin and nerves, the similar sites whereby M Leprae resides. Additionally, the anti-inflammatory properties of clofazimine has been hypothesised to reduce the occurrences of harmful erythrosum nodum leprosum(ENL) reactions.

Clofazimine, if used singularly, even at 600mg monthly as demonstrated by Jamet et al, was only partially effective in eliminating M Leprae. Thus, similarly to dapsone, it is to be used a combination therapy to prevent the emergence of resistant M Leprae strains. A commonly noted side effect with the use of clofazimine includes a reddish-brown discolouration of the skin and conjunctiva, both of which are reversible upon discontinuation of therapy.

Multidrug Therapy

Over the last 3 decades, overall responses towards MDT have been relatively satisfactory. The use of dapsone, rifampicin and clofazimine in combination was considerably tolerable and were devoid of major interactions. The bactericidal activity of MDT crucially became the benchmark in determining the effectiveness of newer combination regimens. Relapse rates, as previously mentioned were relatively low.

Recommended treatment durations however vary between regimen algorithms. As per WHO, a 12 dose regimen was thought to be sufficient. Conversely, as per the NHDP, a 24 month duration treatment was considered appropriately intensive. Sales et al described no significant differences in decline of bacillary levels between the 12 and 24 dose multidrug regimens. Katoch however associated increased rates of relapses due to an insufficient reduction in bacilli index (BI) after 12 months of therapy. Controversially, various sources have even recommended treatment durations till smear-negatives are achieved; however this depends very much on the initial BI count prior to initiation of therapy. In some cases patients may require up to 5-6 years to achieve smear negatives. (Ref 65 from Advances in Treatment 21113)

As such, depending on the severity of the disease, an intensive 24 months therapy of MDT or till smear negatives are achieved may be most suitable as a first line treatment option for this patient. As per the NHDP, 100mg of dapsone, 600mg of rifampicin and 50mg of clofazimine is to be each taken daily for 24 months. Prior to the initiation of therapy, is required of the patient to undergo an indirect or direct Coomb's test. Owing to her severe type 2 hypersensitivity reaction, this places the patient at an immunologic risk to the use of both dapsone and rifampicin. Appropriately, an alternative regimen to MDT must be considered.

Alternative Regimens

If the patient however has established conclusively that she exhibits hypersensitive reactions towards any of the standard MDT drugs (i.e. rifampicin or dapsone), other antileprotic agents must be considered. Alternative treatment options include combinations of ofloxacin, moxifloxacin minocyline and clarithromycin. At the very most, each agent has exhibited bactericidal activity against M Leprae, but these effects despite being used in combination are nonetheless incomparable to that displayed by rifampicin. (advances in treatment) These regimens include;

rifampicin + ofloxacin + minocycline (ROM)

Clarithromycin + ofloxacin + minocycline (COM)

moxifloxacin

In short, minocycline is the only member of tetracycline class active against mycobacteriaceae. It functions by binding to the 30s and 50s ribosomal subunits and consequently inhibiting protein synthesis. Clarithromycin alternatively, is an erythromycin derivative also known to inhibit protein synthesis by binding into to the 50s ribosomal subunits. Ofloxacin on the other hand is the recommended alternative to rifampicin by WHO. It functions by inhibiting DNA gyrase, thus interfering with cell replication. Similarly, moxifloxacin belongs to the same class of drug as ofloxacin but is known to be more bactericidal than ofloxacin.

Rifampicin + Ofloxacin + Minocycline

ROM primarily consists of rifampicin, ofloxacin and minocycline. ROM may be represented as an alternative regimen for patients whom are contraindicated to the dapsone component of MDT. In various studies utilizing mouse footpad tests and clinical trials, the use of ofloxacin and minocycline in combination exhibited greater bactericidal activity than dapsone and clofazimine. (Time to Test ROM 1, 2, 3)

Additionally, in a study by Villahermosa et al assessing the effectiveness of ROM (n=10) against the effectiveness of the WHO-MDT (n=11) amongst multibacillary afflicted patients, both groups exhibited similar reductions in mean BI levels. ROM of which was given for 24 consecutive monthly observed doses of rifampicin(600mg), ofloxacin(400mg) and minocycline(100mg) were generally well tolerated and were devoid of treatment failures, although all MDT treated patients developed clofazimine induced skin discolouration. Additionally, histological improvements were similar in both groups and no evidence of relapse was shown during follow up. Crucially however, despite displaying promising outcomes, the treatment size in this study (Villahermosa) was small and may not warrant for similar outcomes in a larger population size. Moreover, the cost of a ROM regimen quadruples the cost of a standard WHO-MDT regimen.

Pertinently, in a recent systemic review (Setia MS) assessing several studies (n=6) utilizing ROM against MDT, it was made known overall that ROM was as effective as MDT in reducing BI levels in patients (proportion change: -4%, 95% CI -31% to 23%). Similarly, no major interactions were identified and that ROM was generally well accepted.

Patients whom are however hypersensitive towards rifampicin may face a higher risk of treatment failure and eventual relapsing. To date, only a couple of regimens are available, however only with limited evidence to support its use.

Clarithromycin + Ofloxacin + Minocycline

In a study by Xiong et al assessing the combination of clarithromycin, ofloxacin and minocycline (COM) via mouse footpad test, administration of a single dose of the three drug combination eliminated 98.4% of viable M. Leprae, approximately similar to that produced by a single dose of rifampicin (99.4%).

XIONG, J., J1, B., PERANI, E. G. PETINON, C. andGROSSET, J. Further study of the effectiveness ofsingle doses of clarithromycin and minocyclineagainst Mvcobacterium /eprae in mice. Int. J.Lepr. 62 (1994) 37-42

Ji, B., PERANI, E. G., PI:TINON, C. and GROSSET, J.Bactericidal activities of combinations of newdrugs against Mvcobacterium /eprae in nude mice.Antimicrob. Agents Chemother. 40 (1996) 393-399.

Likewise, in a study by Ji et al assessing the administration of a single monthly dose of COM (i.e. 2000 mg of clarithromycin, 200mg of minocycline and 800mg of ofloxacin) in MB afflicted patients (n=10), a similar degree of bactericidal activity as to that of the mouse model was observed. In the same study, patients treated with COM demonstrated improvements in morphological indices similar to those treated with ROM (n=10) but most however also suffered from mild to moderate gastrointestinal disturbances due to the use of clarithromycin. Gastrointestinal disturbances however subsided within a few hours after administration. The fact that the patients have only received a single dose of COM may not even be sufficient to suggest the need for the discontinuation of therapy due to clarithromycin. More importantly, because most studies have only experimented with a single dose in 1 month, appropriate treatment duration with COM for the treatment of MB has yet to be suggested. Thus, assumingly if the patient is started on COM, it would be most advisable that she should be on a prolonged treatment (≥ 2 years) or till smear negatives are obtained, although as aforementioned, there is no evidence to support this suggestion.

Bactericidal Activity of Single Dose of Clarithromycin plus Minocycline, with or without Ofloxacin, against Mycobacterium leprae in Patients

Moxifloxacin

Unlike ciprofloxacin, moxifloxacin along with ofloxacin have proven bactericidal activity against M Leprea. Studies however have proven that moxifloxacin is more bactericidal than ofloxacin and interestingly, equally as potent as rifampicin.1 Moxifloxacin may potentially be used as replacement of ofloxacin, but monotherapy or combination therapy involving moxifloxacin is yet to be extensively studied.

Studies currently available at most analysed small groups of patients with an initial dose of 400mg of moxifloxacin, followed by 7 days of non-therapy, and subsequently daily supervised 400mg doses from day 8 to day 56. At the end of each trial, patients are then started on a standard WHO-MDT, thus making it unlikely to determine the true efficacy or determining rates of relapse with the use of moxifloxacin.

In a recent study conducted in the Philippines by Eleanor et al for example, moxifloxacin was demonstrated in eight MB to have eliminated a mean of 91% of viable M Leprae. Skin lesions were described to have improved regularly throughout the 56-day trial period and patients only suffered from relatively mild symptoms (e.g. diarrhoea, dizziness and epigastric pain). The study as previously mentioned, was really small and no detailed follow up post treatment was attained.

As with the history of the use of dapsone however, it is very much unacceptable to permit the use of moxifloxacin as a monotherapy for the treatment of leprosy. Crucially, combination therapy with other agents such as clarithromycin and minocycline, thus replacing ofloxacin, may be practical to prevent the emergence of resistant M Leprae strains. Likewise with COM, there are no evidences to support this suggestion.

Gillespie, S. H., and O. Billington. 1999. Activity of moxifloxacin against mycobacteria. J. Antimicrob. Chemother. 44:393-395.

Powerful Bactericidal Activity of Moxifloxacin in Human Leprosy Fe Eleanor 2008.

Treatment Plan

NHDP-MDT

Dapsone 100mg/daily

Rifampicin 600mg/daily

Clofazimine 50mg/daily

for 2 years

1st Line

contraindicated to dapsone

contraindicated to rifampicin

COM

Clarithromycin 2000mg/monthly

Ofloxacin 800mg/monthly

Minocylcline 200mg/monthly

≥ 2 years or till smear negatives are achieved

ROM

Rifampicin 600mg/monthly

Ofloxacin 400mg/monthly

Minocycline 100mg/monthly

supervised for 2 years

2nd Line

Moxifloxacin 400mg/daily

Clarithromycin 2000mg/monthly

Minocycline 200mg/monthly

3rd Line

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