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Expert Reviews in Molecular Medicine: http://www.expertreviews.org/
Accession information: (02)00476-3h.htm (shortcode: txt001vka); 22 July 2002
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Advances in the diagnosis and treatment of leprosy
Vishwa M. Katoch
Leprosy is a chronic infectious disease caused by Mycobacterium leprae that mainly affects the skin and peripheral nerves. Over recent years, many important advances have been made in developing molecular diagnostics, in identifying highly effective drugs and designing multidrug regimens for treatment, and in unravelling the genomic structure and functions of the leprosy bacillus. Using the new information about specific sequences of M. leprae, several gene probes and gene amplification systems for confirming diagnosis and monitoring treatment have been developed. Among these, polymerase chain reaction (PCR)-based methods have been useful in confirming the diagnosis in paucibacillary leprosy (where few bacilli are present). RNA-targeting systems for monitoring the progress of treatment, in situ hybridisation techniques for analysing specimens with nonspecific histological features, and molecular methods for direct detection of rifampicin/dapsone resistance are other major technological advances with immense applied value. Several effective regimens for the treatment of leprosy have been developed, which include rifampicin, clofazimine and dapsone as core drugs. Although these regimens are generally satisfactory, limitations in terms of persisting activity and late reactions/relapses in paucibacillary leprosy, and persistence of dead and/or live organisms in multibacillary forms of the disease, have been observed.
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The demonstration of the bacterial aetiology of leprosy in 1873 by the Norwegian Armauer Hansen (yielding the alternative names for leprosy of Hansen’s disease and Hanseniasis) is considered one of the important landmarks in the arena of infectious diseases. However, because it has not been possible to cultivate Mycobacterium leprae in vitro, progress in understanding the biology of leprosy bacillus has been very slow. The success achieved in growing leprosy bacillus in the mouse foot (Ref. 1) galvanised leprosy research, leading to extensive work in different animal models, development of new chemotherapeutic agents, and the analysis of the biochemical, antigenic and molecular structure of leprosy bacillus. These advances have culminated in important developments in terms of both molecular diagnostics for early diagnosis and effective regimens for the treatment of leprosy. This article briefly reviews the aetiopathology of leprosy before focusing on recent advances in the diagnosis and treatment of leprosy.
Aetiopathology
of leprosy: an introduction
M. leprae
M. leprae, a member of the family Mycobacteriacae, is
a straight or slightly curved rod-shaped organism, 1–8 mm
long and 0.3 mm in diameter. It divides by binary
fission, is Gram-positive, and strongly ‘acid fast’ following staining
with basic fuchsin, which stains the bacteria pink. (In contrast, staining of
M. tuberculosis is both acid fast and alcohol fast.) M. leprae
is an obligate intracellular parasite, found predominantly in macrophages, where
the organism commonly occurs in clumps or ‘globi’. The optimal growth
of M. leprae is observed at 27–30 ºC, which is also reflected
clinically, as the cooler areas of the body such as the skin, nasal mucosa,
and superficial peripheral nerves (particularly Schwann cells) are the predominant
sites of infection.
Epidemiology
The current geographical distribution of leprosy is shown in Figure
1. The global burden of the disease has decreased tremendously since the
introduction of multidrug treatment (MDT) in 1982. Nearly half a million cases
are estimated to remain worldwide, mainly in the Asian and African subcontinents
(Table 1). Countries where leprosy continues to
be a major problem include Brazil and India. Although no non-human sources of
infection have been established, naturally occurring infection in monkeys and
armadillos has been reported. M. leprae-like organisms have also been
reported to be present in soil. The mode of transmission of leprosy has not
been fully established, but nose and skin are considered as the main portals
of exit as well as entry (Ref. 2).
Clinical features and
classification
The incubation period of the disease is long and highly variable (usually
2–10 years). Most individuals exposed to infection are naturally protected,
are able to mount an efficient immune response, and do not suffer from the disease.
In those who suffer from the disease, the main clinical features in paucibacillary
(PB) disease (see below) result from damage due to immune responses mounted
by the host, whereas in the lepromatous (LL) forms bacillary load and to some
extent immune response are responsible for the clinical presentation. Symptoms
and signs pertaining to involvement of the skin and nerves are most commonly
encountered, including hypopigmented macules and sensory loss (Ref. 3).
At least two of the following findings have to be present for a clinical diagnosis
of leprosy: (1) a characteristic patch or skin lesion with impaired sensations;
(2) a thickened and/or tender cutaneous or peripheral nerve with impairment
of sensations in the area supplied by it; and (3) acid-fast bacteria in the
skin smear.
The disease is formally classified into a range of subtypes that include, in approximate order of extent of disease, ‘suspicious’, early indeterminate (I), tuberculoid (TT), borderline tuberculoid (BT), mid borderline (BB), borderline lepromatous (BL) and LL disease (Ref. 4). Other forms, such as pure neurotic leprosy (without skin lesions), are also recognised (Ref. 5). The degree and type of immune response and also probably the route of infection determine the clinical forms of the disease. Individuals with strong cell-mediated immunity (CMI) or delayed-type hypersensitivity (DTH) show a localised TT disease, whereas individuals lacking CMI progress from I to LL disease. The immune defect is specific to M. leprae; other immune responses remain intact. The disease is characterised by the formation of granulomas; these vary from epithelioid type in TT leprosy to foamy cell (macrophage) type in LL disease (Ref. 6).
The lepromin skin test, which measures DTH to M. leprae antigens, is used to assist diagnosis and classification of leprosy (Ref. 7). The response is biphasic, with an early response at 24–48 h, and a late response at 3–4 weeks. Bacterial load in the disease can be estimated from a smear, taken from skin lesions, stained for acid-fast bacteria. Density of bacteria (both viable and nonviable) is expressed using the logarithmic Ridley Scale [bacterial index (BI) 0–6] (Ref. 8). For treatment purposes, smear-positive BT, BB, BL and LL cases are referred to as multibacillary (MB) leprosy, whereas smear-negative I, TT and BT cases are termed PB leprosy (Ref. 9).
Reactions and relapses
Episodes of acute inflammation in the leprosy lesions and/or in nerves and
other body parts have been popularly referred to as ‘reactions’. It
is hypothesised that these are brought about by disturbances in immunological
balance as a result of immune reactivity to M. leprae antigens. Identical
antigenic determinants of the host might also contribute to the autoimmune phenomenon.
Three types of reactions are recognised. (1) Type I (reversal) reactions are
associated with changes in CMI; BT, BB and BL patients usually suffer from these
reactions, and if not promptly treated the reactions can result in nerve damage
and deformities. (2) Type II reactions [erythema nodosum leprosum (ENL) reactions]
affect patients with MB disease (BL and LL, and sometimes BB) and are thought
to arise from deposition of immune complexes in target organs and skin. (3)
The Lucio phenomenon, which is less well understood, is associated with extensive
skin necrosis due to acute vasculitis and occlusion of arterioles whose endothelium
is massively invaded by M. leprae. In addition to these classifications,
episodes of inflammation or reactions occurring during treatment are known as
‘early reactions’, whereas when the same occur after stoppage of treatment
they are known as ‘late reactions’. It is thought that late reactions
are caused by dead bacteria or antigens.
Relapse in leprosy is defined as recrudescence of the disease activity after successful completion of a prescribed course of therapy. This is considered to result from multiplication of the few remaining live organisms. As there is an element of inflammation in the re-activation and appearance of new lesions, relapses are often confused with late reactions (presumed to be due to dead organisms). Clinically these two conditions overlap, and histology is also not always helpful in distinguishing the two. Currently available methods for determination of viability of M. leprae (including the mouse foot-pad assay, and bacillary ATP and substrate uptake assays) are reliable only in MB disease (Ref. 10).
Molecular
techniques for diagnosis and monitoring of treatment for leprosy
Standard immunological
and histological approaches for assessing leprosy have limited value for diagnosing
new cases at the ‘suspicious’ and early I stages and for monitoring
treatment. Immunological techniques for eliciting DTH and serological responses
in leprosy are useful only for determining exposure, as the antigens and resultant
response persist for a long time after subsidence of clinical or subclinical
disease. Demonstration of acid-fast bacteria in skin smears is also often not
sufficiently sensitive, and in histology assessments, some granuloma characteristics
can suggest nonspecific dermatitis. Extensive information about the molecular
structure and function of leprosy bacillus is now available (Refs 11,
12, 13), and this has helped in developing
molecular techniques for early diagnosis, monitoring of treatment and detection
of drug resistance (Refs 10, 14).
Molecular methods for
diagnosis
Probes targeting stretches of DNA (Ref. 15) and ribosomal
(r)RNA or rRNA genes of M. leprae (Refs 16, 17,
18, 19) have been developed by various investigators.
The probes targeting DNA need the presence of at least 104
copies of target DNA for a positive result (Ref. 15), whereas
rRNA-targeting systems can be 10–100-fold more sensitive (Ref. 19);
however, because of the small number of organisms present in specimens from
PB cases, these probes serve only a limited purpose. During the past 10 years
or so, several polymerase chain reaction (PCR) methods have been developed to
amplify different gene stretches of M. leprae. These include the genes
encoding various M. leprae proteins [18 kDa (Ref. 15),
36 kDa (Ref. 20), 65 kDa (Refs 21, 22),
leprosy serum reactive (LSR) (Ref. 23)] and rRNA (Refs 24,
25), and repetitive sequences (Ref. 26).
These assays have been reported to be sensitive to 1–10 organisms and to
be positive in 95–100% of BL/LL and 50–70% of TT, BL and
I specimens (Refs 10, 14). rRNA-targeting
probes have been developed into in situ hybridisation protocols and have been
found to be of value in confirmation of diagnosis in cases with nonspecific
histological features (Mohan Natrajan, Central JALMA Institute for Leprosy,
Agra, India, pers. commun.). Therefore, in situ hybridisation and immunohistological
approaches (Ref. 27) provide good diagnostic strategies to
enhance the sensitivity and specificity of histological diagnosis. Forty to
fifty per cent of cases missed by standard histology can be confirmed by the
use of molecular methods. Absence of positivity in the remaining cases could
reflect the need to further optimise these methods, and/or the possibility that
many cases with nonspecific histological features might not be leprosy. These
probes and gene amplification assays can be of immense help for the diagnosis
of early atypical PB leprosy and also in mass confirmation of diagnosis for
epidemiological and research purposes (Refs 10, 14).
Molecular methods for
monitoring treatment
As M. leprae has not been cultivated in any acceptable in vitro medium
system, time-consuming and relatively insensitive animal models have to be used
to assess M. leprae viability (Ref. 10). Molecular
biology has provided an alternative effective technology route for this purpose.
When the PCR technology for detecting M. leprae gene sequences was introduced, it was reported that this might be useful both for diagnosis and for assessment of viable load, as a reduction in signals was found to correlate with loss of viability (Ref. 26). These trends were confirmed in subsequent studies (Ref. 28). However, because of the persistence of weak signals in some cases a long time after effective treatment (Refs 10, 29), DNA-based PCR assays appear to have limited application in monitoring treatment, particularly in distinguishing late reactions and relapses.
During recent years, molecular techniques for viability estimation of M. leprae have been developed that are based on a quantitative estimation of RNA levels by direct hybridisation with specific probes (Refs 10, 14, 30), or by amplification by PCR (Ref. 31) or isothermal reactions (Ref. 32). The method of grading the positivity levels of M. leprae-specific rRNA in the tissues has been useful for monitoring therapeutic responses (Ref. 30). Techniques such as reverse transcription (RT)–PCR targeting 16S rRNA (Refs 10, 31), and nucleic acid sequence-based amplification (NASBA) targeting 16S rRNA (Ref. 32), have been reported to be useful for the determination of viability of M. leprae. Cases with positive results indicate the presence of viable organisms and should be considered for anti-leprosy chemotherapy. Such approaches could also be helpful in differentiating conditions such as late reactions and relapses for patient care.
Molecular methods for
monitoring drug resistance
The lack of a suitable in vitro cultivation system for M. leprae
has also hindered assessment of drug resistance. Molecular biology has provided
important tools to investigate the molecular mechanisms of drug susceptibility
and resistance in leprosy. The use of dapsone and rifampicin as monotherapies
to treat leprosy in the 1970s resulted in the rapid emergence of drug resistance.
With the introduction of MDT the trend has been apparently reversed and at present
drug resistance is not considered a major problem. However, as active surveillance
studies have not been carried out, the exact magnitude of drug resistance currently
is not known. As in M. tuberculosis, mutations in the M. leprae
rpoB locus are associated with rifampicin resistance (Refs 33,
34). The basis of dapsone resistance appears complex, but
mutations in the M. leprae folPI locus have been found to be associated
with a high degree of dapsone resistance (Ref. 35). PCR is
used to directly amplify the target loci (rpoB for rifampicin and folPI
for dapsone) and mutations are confirmed by techniques such as hybridisation
with appropriate probes or sequencing. Little is known about the basis of resistance
for drugs such as clofazimine. With the use of new techniques for the detection
of mutations directly from clinical specimens, surveillance programmes to determine
the exact magnitude of drug-resistant mutants to rifampicin, and possibly other
drugs, can be undertaken from the biopsies.
Sequencing of the genome of M. leprae has been completed (Ref. 36). The information generated opens new opportunities in functional genomics and proteomics. Such studies will undoubtedly provide scope to develop improved molecular methods for confirmation of diagnosis, for assessing prognosis and for detection of drug resistance.
Current
therapy for leprosy
There have been
rapid changes in the treatment of leprosy in the past few decades. The therapeutic
scenario has moved from dapsone monotherapy in the 1970s to MDT using drugs
such as dapsone, rifampicin and clofazimine. MDT was expected to shorten the
length of treatment, leading to better patient compliance, and reduce the problem
of drug resistance because of the combined use of multiple drugs with differing
modes of action. MDT has indeed revolutionised the treatment of the disease
and has been greatly welcomed by patients and doctors alike. More recently,
several newer, more-potent drugs and immunomodulators have been introduced in
the treatment of leprosy. This has increased the scope for further improvement
in the treatment of the disease.
Evolution and current
status of WHO MDT regimens
The World Health Organization (WHO) introduced MDT in 1982, and advocated
short-course treatment regimens (Ref. 37). According to WHO
guidelines, PB patients were to be treated with two drugs [rifampicin (600 mg,
once a month, supervised) and dapsone (100 mg, daily, unsupervised, for 6 months)].
As most of these patients are lepromin-positive, it was thought that any residual
organisms remaining after stoppage of therapy would be taken care of by the
immunity of the host. Treatment for MB patients comprised three drugs [rifampicin
(600 mg, once a month, supervised), clofazimine (300 mg, once a month, supervised;
along with 50 mg, daily, unsupervised) and dapsone (100 mg, daily, unsupervised)].
The treatment was to be given for 2 years or until the attainment of smear negativity
– whichever was earlier.
In the early 1990s, the concept of fixed-duration treatment (FDT) was introduced for control programmes. It was advocated that treatment in PB cases should be stopped after completion of six supervised doses taken in a maximum of 9 months, and treatment in MB cases be stopped after completion of 24 supervised doses in 36 months, irrespective of whether the smears were positive or negative (Ref. 38). This duration has been further reduced to 12 months for MB cases, and a single-dose regimen comprising rifampicin (600 mg), ofloxacin (400 mg) and minocycline (100mg) (ROM) has been recommended for mono-lesion cases (Refs 39, 40). These regimens have already been implemented by control programmes in some countries, such as India (Ref. 41).
Although ROM and 12-month FDT regimens have been introduced only recently, considerable experience has accumulated on the application of various earlier recommended MDT regimens. The overall response has been good. With MDT, there is rapid killing of M. leprae and also faster negativity has been observed from the main portal of exit and dissemination – the nose. Confidence in the results has led to the declaration of ‘cured’ patients, and thus the prevalence of recorded leprosy cases has declined significantly worldwide. Problems of drug resistance using these regimens also appear to be under control. However, some limitations have been consistently observed, and in order to achieve more-effective patient care and control of the disease it is important to discuss these.
Limitations in PB leprosy
therapy
On the whole, treatment in this group of patients appears satisfactory (Ref.
42). There are four issues that require debate, as follows.
First, residual disease activity in the lesions at the end of six months of treatment has been observed in the skin lesions in 10–67% of patients by various workers (Refs 42, 43, 44, 45, 46, 47). This persisting activity is lower in fresh leprosy cases reporting for treatment recently (Ref. 48). Follow-up studies have shown that this persisting activity does subside in some patients, but in others this worsens and requires further therapy (Refs 43, 44).
Second, there is the issue of late reactions. Late reactions usually occur after 6–18 months, but have also been reported up to 5 years after stoppage of therapy. After discontinuation of therapy, 5–21% of patients have been reported to suffer from late reactions (Refs 43, 45, 49). It needs to be emphasised that it is very difficult to distinguish reactions from relapses (Ref. 46). These conditions overlap not only clinically but also histologically. Using the mouse foot-pad assay (Ref. 50) and molecular probes targeting rRNA (Ref. 10), evidence for the presence of live organisms in specimens from cases clinically diagnosed as ‘late reaction’ has been reported. It is therefore at present too risky to treat these patients with steroids alone for long periods after stoppage of the MDT; additional MDT along with steroids would be more appropriate.
Third is the issue of relapse. The relapses can be defined as the gradual appearance of new lesions with increased reactivity in some or all old lesions, with or without nerve involvement or skin smear positivity. Relapse rates have varied from 0.1–1% in some studies (Ref. 47) to 6–13% in others (Refs 43, 44, 49). Some of this variation could be due to the different definition of relapses being used in different studies, and to the difficulty in the diagnosis because of the overlap between relapses and reactions. It has been observed that all the ongoing problems of persisting activity and reactions/relapses can be significantly reduced by extension of MDT (Ref. 45), additional dapsone therapy (Refs 43, 49), addition of clofazimine to the drug regimen (Ref. 48) and use of drugs such as prothionamide (Ref. 51). Of these, clofazimine appears to be the most attractive option, as the same regimen, with a different duration, can be administered to PB and MB patients. Experience with the use of other drugs such as minocycline in PB leprosy is very limited (Ref. 52). At present, these will perhaps be considered in cases with hypersensitivity and intolerability to conventional drugs.
Fourth, it is unclear how mono-lesion cases should be treated. After the widespread use of MDT, there has been a change in the profile of the disease, and a substantial proportion of fresh cases are presenting with single lesions as they are being diagnosed early. Such lesions are considered innocuous and capable of self healing. The 7th WHO Expert Committee (Ref. 39) has recommended a single dose of ROM for the treatment of these cases. These recommendations have been accepted by the national programmes in countries such as India (Ref. 41). In a study reported from India, nearly half of the cases treated with ROM and standard treatment with 6 months of PB MDT were inactive after 18 months of follow-up (Ref. 53). Promising results of ROM treatment in cases with two lesions have been subsequently reported (Ref. 54). These are at variance with earlier studies of responses in single-lesion cases from India (Ref. 55), and Malawi (Ref. 46). Such variance in observations indicates that it might be premature to conclude ROM is efficacious for single-lesion cases, which are likely to be heterogeneous and evolving cases. Published follow-up of these cases is inadequate (Ref. 56). Furthermore, there are several theoretical risks from the use of a single-dose treatment (Ref. 57). For example, some bacteria might not be multiplying at the time of administration of the drug and will therefore not be targeted; also, some cases will be MB or progressing towards MB disease, for which this single-dose regimen is absolutely inadequate.
Limitations in MB leprosy
therapy
MB patients have a higher bacterial load and, to prevent the emergence of
drug-resistant strains, treatment for 2 years or until smear negativity (Ref.
37) was recommended with at least three drugs: rifampicin,
clofazimine and dapsone. This regimen has been found to be highly bactericidal
and well tolerated, and is widely accepted. With this regimen, the incidence
and severity of reactions decreased and the compliance of the patients has improved.
Most of the MB patients become smear negative with 24 doses, although the highly
bacillated cases require 5–6 years to become smear negative. Various modifications
to the WHO regimen have been proposed. No additional benefits of an initial
intensive course of rifampicin or monthly loading dose of clofazimine have been
observed (Ref. 58). The response to the operationally easier
FDT of 24 doses in 36 months has been good (Ref. 38). This
regimen has been used worldwide during the past 5–6 years and overall relapses
of less than 1% have been reported (Ref. 59).
Three important issues have emerged from these trials. First, even after 2 years of therapy, viable persisters have been reported in 9–16% of the initially highly bacillated (BI 3–6+) patients (Refs 60, 61). Relapse rates of 2.9% after a follow-up of 3–5 years, increasing to 20% after a follow-up of 7.5 years, have been recorded (Ref. 62). Such high relapse rates have also been reported by others (Ref. 63). Second, an important problem in FDT-treated cases is the occurrence of repeated reactions and therefore continuing morbidity after stoppage of treatment. These patients require treatment with steroids, which is given without the cover of MDT. Chemotherapy along with steroids is desirable as a section of these cases are known to harbour live bacilli. Third, on the basis of theoretical considerations and limited published work (Refs 40, 64), the WHO and some programmes have recommended stoppage of treatment in MB patients after 12 doses (over 1 year) using the standard WHO regimen. It has been reported that rates of decline in BI in leprosy in cases treated for 12 months or 24 months were similar (Ref. 64). However, in another study, high relapse rates in patients with high BI defaulting after 12–16 months of therapy have been reported (Ref. 65). Considering the problems of persisters/relapses even with the 24-month regimen (Refs 62, 63), caution is required with the 12-month duration regimen. Intensive surveillance at least in selected areas for a period of 8–10 years is required for detection of relapses.
Treatment of MB leprosy
with newer or alternative drugs
Several newer drugs active against M. leprae have emerged that are
being evaluated to improve the treatment and reduce the duration of treatment
in MB leprosy. Prominent among these are: quinolones (pefloxacin, ofloxacin
and sparfloxacin, moxifloxacin); ansamycins (rifabutin, KRM-1648); macrolides
(clarithromycin); tetracyclines (minocycline), fuscidic acid and other sulphones
(brodimoprim). Of these, quinolones, minocyline and clarithromycin appear to
be the front runners in providing alternative drug treatment for MB leprosy
(Refs 66, 67). However, experience of clinical
application and the establishment of appropriate regimens of these newer drugs
are limited. Trials have been conducted in MB patients with an intensive short-course
regimen consisting of daily treatment with 600 mg rifampicin plus 400 mg of
ofloxacin for 1 month. The treatment was then stopped and patients followed-up
on placebo (Refs 64, 68). The initial results
suggest that the regimen is well tolerated, but high relapse rates have been
observed (Refs 68, 69). Trials have also
been conducted using the addition of supervised monthly doses of 100 mg minocycline
plus 400 mg ofloxacin to the standard MB MDT regimen, with the treatment stopped
after 1 year (Ref. 70). The response to the therapy was satisfactory
during the treatment and early follow-up period (Ref. 70);
however, conclusions can be drawn only after a longer and adequate follow-up.
Role of immunotherapy
in the treatment of leprosy
Besides the presence of a small population of viable organisms (‘persisters’)
after therapy, the problem of persistence of a large pool of dead bacilli is
often encountered. Immunomodulators that can stimulate CMI have been applied
to reduce this pool. These agents can be divided into three broad groups: drugs,
antigenically related mycobacteria, and other immunomodulators (Ref. 71).
In the drug category, levamisole (Ref. 72) and zinc (Ref. 73), when used as an adjunct to dapsone therapy, have been reported to be useful, as seen by clinical improvement in the lesions and a decrease in the incidence and severity of reactions. Although both are considered to be immunopotentiators of CMI, their exact mechanisms of action are not completely understood. Furthermore, these compounds have not been adequately investigated along with MDT.
Antigens of various mycobacteria have been observed to cross-sensitise the immune response to M. leprae and this might help in augmenting CMI in leprosy (Ref. 71). Prominent among these are Bacille-Calmette Guerin (BCG) (Ref. 74), BCG plus killed M. leprae (Ref. 75), Mycobacterium w (Mw) (Refs 74, 76, 77, 78, 79, 80), and Indian Cancer Research Centre (ICRC) bacillus (Ref. 81). BCG, when administered to patients once in 6 monthly repeated injections along with MDT, resulted in a faster killing of bacilli, a more rapid fall in BI, a reduced incidence of reactions and a faster attainment of smear negativity as compared with the control group, who received placebo with the same MDT (Ref. 74). The combination of BCG plus killed M. leprae has been reported to have an immunomodulatory role in I and LL patients, and in lepromin-negative contacts of leprosy patients (Ref. 75). Mw, a cultivable mycobacteria that has antigenic similarities with M. leprae, has been investigated in different trials in humans and has been found to be safe and well tolerated. Compared with MDT, MDT plus Mw has been observed to enhance bacterial killing (Ref. 74), clearance of bacilli (Refs 74, 76, 80) and clearance of granuloma (Refs 78, 79, 80). As the granuloma and bacilli are cleared faster, a reduced severity and frequency of reactions has been observed (Ref. 77). Combined chemotherapy and immunotherapy with ICRC has been shown to significantly accelerate bacterial clearance (Ref. 81). M. vaccae also shares some antigens with M. leprae and has been proposed as an immunotherapeutic agent (Ref. 82).
Several other mediators of immune responses, such as transfer factor (Ref. 83) and various cytokines such as recombinant interferon g (IFN-g) (Refs 84, 85, 86, 87) and interleukin 2 (IL-2) (Ref. 88) have been used to treat leprosy. Transfer factor induced transient effects such as lepromin conversion (from negative to positive), granuloma formation and increased influx of lymphocytes locally (Ref. 83). Intralesional administration of IFN-g in leprosy patients induced accumulation of lymphocytes and monocytes at the local site of injection (Refs 84, 85, 86). There was a distinct fall in the BI at the local site, with formation of epithelioid granuloma and occurrence of a reversal reaction in some cases, and enhanced bacterial clearance with IFN-g has also been reported. However, repeated doses of IFN-g have to be given intralesionally to induce systemic effects and have been associated with ENL reactions in LL patients (Ref. 87). The administration of IL-2 also accelerated bacterial clearance (Ref. 88); however, these effects were seen only at the local site.
Therapy of reactions
Efficient management of reactions to prevent nerve damage requires good
clinical judgment in making an appropriate early diagnosis and assessing the
extent of severity in terms of nerve deficit and multi-organ involvement. The
treatment of reactions is based on suppression of inflammation and its consequences.
The frequency and severity of ENL reactions in BL/LL cases have been greatly
reduced by administration of clofazimine. Many drugs, such as salicylates, non-steroidal
anti-inflammatory drugs (NSAIDs), chloroquin, antimonials, steroids, pentoxyphylline,
thalidomide and others, are used in the management of ENL (Refs 89,
90). Steroids continue to provide the mainstay of management
of type I reactions in borderline and tuberculoid patients. Standard steroid
regimens have been described to control reactions (Ref. 89);
however, the standard WHO regimen is considered too short (Ref. 90).
The efficacy of drugs such as cyclosporin has been reported to vary from modest
to highly effective for the treatment of type I reactions (Ref. 90).
The application of molecular tools for quantitative estimation of cytokines
by mRNA-based methods and quantitative PCR (Refs 91, 92),
is leading to a better understanding of mechanisms and also of the effects of
treatment. Earlier compartmentalised concepts of type 1 and type 2 immunity
in tuberculoid versus lepromatous cases, respectively, and immune complexes
as solely responsible for ENL and DTH for reversal reactions, are now changing
with the new evidence. These studies have shown upregulation of T helper 1 (Th1)
responses in ENL (Refs 91, 92). A subgroup
of patients showing a slower response to steroids that correlates with cytokine
profiles (Ref. 92) needs to be followed up to identify patient
groups and markers that might help in deciding upon appropriate treatment. Steroid
dependence is a serious problem and thalidomide analogues might provide a possible
option, although these are still under development (Ref. 93).
Future
challenges
The treatment
of leprosy has improved significantly over recent years and this has helped
to tackle the disease at the public health level. However, optimal regimens
are still evolving. Some of the recently recommended regimens such as single-dose
ROM and 12-month FDT need to be kept under close scrutiny for some time, and
various modified regimens that have shown promising results need to be considered
for improving the therapy. The idea of developing a common regimen for PB and
MB leprosy is also gaining momentum (Refs 42, 48,
67) and needs to be pursued. The addition of newer effective
drugs such as ofloxacin and minocycline to treatment regimens is increasing,
and their potential in effectively reducing the duration of treatment and the
management of special situations such as resistance or intolerance is apparent.
Many patients require individual attention and tailor-made treatment. Indications
for such improvisations could be a poor response to standard treatment and hypersensitivity
to some of the drugs. For such patients, replacement of the drug(s) might be
required (Refs 94, 95). Currently, several
WHO- and ILEP-sponsored trials to monitor various regimens, including some new
alternatives, are progressing (Ref. 95).
As the total patient load has been considerably reduced, easy diagnositc methods such as skin smears for acid-fast bacilli should be re-introduced for monitoring of cases at field-level clinics. Molecular methods should be available at reference laboratories and be more extensively used in research and epidemiological studies.
Leprosy has been a feared disease mainly because of the deformities associated with it. After widespread use of MDT, there has been a sea change in the profile of the disease. Early and appropriate treatment undoubtedly helps in reducing the severity and frequency of deformities. Nevertheless, disabilities continue to be a major problem (Ref. 96). Different preventive (management of reactions, nerve decompression) and corrective (tendon transfers, management of plantar ulcers) procedures to manage deformities are available. Besides the availability of surgery, timely physiotherapy and health education are very important in the prevention, management and rehabilitation resulting from the disabilities. As leprosy patients continue to have disabilities for a long time or even life, these services will be required for a much longer time.
Genuine concerns have been raised about the continued high-incidence rates of leprosy even in areas with intensive MDT campaigns for 10–15 years. The issues of inadequate coverage, non-human sources, extraordinarily long incubation periods and effectiveness of regimens being used need to be analysed for these unexpected results. The rich experience of the past of treating leprosy patients with different regimens, together with lessons from careful follow-up of new regimens and the appropriate use of molecular tools for early diagnosis and surveillance of drug resistance, provide an excellent base from which to progress towards the goals of sensitive and specific diagnostics as well as optimal regimens for all leprosy patients. The knowledge emanating from analysis of the human genome and the M. leprae and M. tuberculosis genomes (Ref. 97) will undoubtedly strengthen the development of relevant technologies for more-effective management of leprosy at patient and public health levels.
Acknowledgements
and funding
I thank the various
scientific and technical colleagues who participated in the different studies
cited in this article. I also gratefully acknowledge the financial support of
the Indian Council of Medical Research, the Department of Science and Technology,
the Department of Biotechnology, the World Health Organization (WHO) and LEPRA.
My thanks to Prof. Ben Naafs (Gracht 15, 8485 KN Munnekeburen, The Netherlands)
and Prof. Bhushan Kumar (PGI, Chandigarh, India) for peer review of this manuscript,
and Sh. S. K. Kulshrestha, for secretarial assistance in its preparation.
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Further reading, resources and contacts The WHO’s Action Programme for the Elimination of Leprosy provides current information on therapy, endemic countries, research and publications. LEPRA is a UK-based medical development charity whose prime objective is to eradicate leprosy. The Novartis Foundation for Sustainable Development ‘has been actively involved in leprosy programs in Asia, Africa and Latin America in partnership with local health authorities, the WHO and non-governmental agencies’. The efforts of the foundation focus primarily on eliminating leprosy, and their website is a useful source of information on the diagnosis, treatment and elimination of the disease. Leproma is a powerful web-based tool for extracting information on gene structure and function from a Mycobacterium leprae genome database, using programmes such as BLAST and FASTA. |
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Features associated with this article Figure Figure 1. Global leprosy situation in 2000 Web, Reprint/PDF version Table Table 1. Leprosy situation in 2000 by WHO regions Web, Reprint/PDF version |
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Citation details for this article Vishwa M. Katoch (2002) Advances in the diagnosis and treatment of leprosy. Exp. Rev. Mol. Med. 22 July http://www.expertreviews.org/02004763h.htm |