Review Relapse in leprosy

Article

Sowmya Kaimal, Devinder Mohan Thappa

ABSTRACT

Department of Dermatology Leprosy is unique in terms of the nature of the causative organism (Mycobacterium
and STD, Jawaharlal Institute leprae), the chronicity of the disease, its prolonged treatment and the definitions of “cure”
of Postgraduate Medical
Education and Research and “relapse.” The principal mode of assessing the efficacy of therapeutic regimens in
(JIPMER), Pondicherry - 605 leprosy is the “relapse rate.” There are wide variations in estimates of relapse rates after
006, India the World Health Organization (WHO) multidrug therapy in different regions. The important
predisposing factors for relapse include the presence of “persister” bacilli, monotherapy,
Address for correspondence: inadequate/irregular therapy, presence of multiple skin lesions/thickened nerves and lepromin
Dr. Devinder Mohan Thappa, negativity. The conventional methods of confirming activity or relapse in an infectious disease
Department of Dermatology
and STD, JIPMER,
(demonstration and/or culture of the etiologic agent) have limited utility in leprosy because of
Pondicherry - 605 006, India. the difficulty in demonstrating bacilli in paucibacillary (PB) cases and absence of a method
E-mail: dmthappa@gmail.com of in vitro cultivation of M. leprae. Bacteriological parameters are useful in multibacillary
(MB) leprosy, whereas in PB leprosy, the criteria for relapse depend primarily on clinical
features. Although there are no widely available serologic tests for leprosy other than in
a research setting, various immunological tests may be useful for monitoring patients on
chemotherapy as well as for confirming suspected cases of relapse. The main differential
diagnoses for relapse are reversal reactions, erythema nodosum leprosum and reactivation/
resistance/reinfection. The most reliable criteria for making an accurate diagnosis of relapse
include clinical, bacteriological and therapeutic criteria. Additional ones that may be used,
depending on the setting, are histopathological and serologic criteria. Relapsed cases of
leprosy should be identified and put back on chemotherapy as soon as possible to prevent
further disability and transmission of infection. Factors that should be considered in choosing
an appropriate regimen are the type of leprosy (PB or MB), previous treatment and drug
resistance. Occasionally, clinicians may need to use their judgement to modify the standard
WHO treatment regimens according to the scenario in each patient.
DOI: 10.4103/0378-6323.48656
PMID: 19293498 Key words: Leprosy, reactivation, reinfection, relapse, resistance

INTRODUCTION Thus, the principal mode of assessing the efficacy of

the therapeutic regimens in leprosy is the “relapse
Relapse of diseases, acute or chronic, caused by rate.” A very low relapse rate over an adequate period
bacterial infections is quite common. Usually, relapse of observation indicates that the regimen used has
indicates a failure to treat the infection thoroughly, been effective and this is why prolonged periods of
which is compounded by irregular treatment, surveillance are recommended by the World Health
particularly in chronic disease. Organization (WHO) for all patients who have been
declared “cured” after receiving multidrug regimens.
The treatment of leprosy, compared with other
infectious diseases, is unique in terms of the fixed DEFINITION
dose and duration of regimens and also in terms of the
definition of “cure.” Often, termination of treatment is The definition of “relapse” can be understood only in
based on completion of the recommended duration of the context of the definition of “cure.” In the era of
treatment rather than disappearance of clinical signs Dapsone monotherapy, a patient with multibacillary
and symptoms, which led to initiation of treatment in (MB) disease was declared “disease arrested” when
the first place. skin lesions resolved and when 3 monthly consecutive
How to cite this article: Kaimal S, Thappa DM. Relapse in leprosy. Indian J Dermatol Venereol Leprol
2009;75:126-35.
Received: June, 2008. Accepted: September, 2008. Source of Support: Nil. Conflict of Interest: None declared.

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Kaimal and Thappa Relapse in leprosy

skin smears were negative for acid-fast bacilli (AFB), new paralysis of muscles and bacteriological
after which antileprosy treatment was continued for positivity.”
another 5–10 years or even a life time. A paucibacillary
(PB) patient was declared “disease free” when all skin Regardless of the definition used for a case of relapse,
lesions resolved, with no infiltration and no erythema it is important to remember that relapse in MB cases is
and the nerves were no longer painful or tender, after relatively easy to recognize clinically while relapse in
which antileprosy treatment was continued for 3–5 PB cases may be difficult to distinguish clinically from
years.[1] With the advent of multidrug therapy (MDT), reversal reaction occurring some time after therapy is
such rigid clinical criteria for cure have lost their completed.
importance. A leprosy patient is defined by the WHO
as one who is found to have signs and symptoms of the RELAPSE RATE
disease and who requires chemotherapy. As of 1995,
WHO recommends 1 year of MDT for MB patients (12 There are wide variations in estimates of relapse rates
pulses in 18 months) and 6 months (six pulses in 9 in different regions. This is probably due to variations
months) for PB patients. At any point in time during in the definition of relapse, proportions of previously
therapy, the patient should have ingested two-third dapsone-treated and untreated patients, range of skin
of the pulses till that time. For operational purposes, smear positivity in MB cases and differing durations
once a patient receives adequate chemotherapy, he is of follow-up. The risk of relapse is very low, both
considered “cured.” Histopathological resolution of for PB and for MB patients after completion of MDT,
the lesions and clinical subsidence of the disease take and this is at least 10 times lower than with dapsone
place months to years after antileprosy treatment is monotherapy.[1]
stopped.
The WHO has estimated a risk of relapse of 0.77% for
Several definitions have been proposed for relapse in MB and 1.07% for PB patients 9 years after stopping
leprosy.[1] MDT. Various other studies using person–years of
1. Guide to Leprosy Control (WHO 1988): observation estimate relapse rates varying from 0.65 to
“A patient who successfully completes an adequate 3.0% for PB and 0.02 to 0.8% for MB leprosy.[1]
course of MDT, but who subsequently develops
new signs and symptoms of the disease either A retrospective study of data from the Central Leprosy
during the surveillance period (2 years for PB and Teaching and Research Institute, Chengalpattu, Tamil
5 years for MB leprosy) or thereafter.” Nadu, included 3248 leprosy patients who completed
2. Becx-Bleumink lists several criteria for relapse,[2] the WHO MDT during the period 1987–2003.[5] The
which include: overall relapse rates for MB and PB leprosy were
a) new skin lesions 0.84 and 1.9%, respectively, whereas the rates for
b) new activity in previously existing skin lesions person–years of follow-up were 0.86 and 1.92/1000,
c) bacteriological index (BI) 2+ or more in two respectively. The majority of relapses occurred in
sets of skin smears the first 3 years after release from treatment. If an
d) new nerve function loss individual does not relapse within the first 5–6 years,
e) histological evidence of relapse in skin or nerve his/her risk of relapsing is negligible.
biopsy
f) lepromatous activity in the eye(s) In a recent retrospective analysis of the relapse rate in
3. Relapse in PB patients: China after 24 months of WHO MB-MDT for 2374 MB
a) Beorrigter et al,[3] – “appearance of a new skin patients who were followed-up for a mean duration
lesion or increase in size of pre-existing skin of 8.27 years per patient, five patients with relapse
lesion, provided there is either strong clinical were identified with an accumulated relapse rate of
or definite histopathological evidence (or both) 0.21/1000 person–years, which is quite low.[6]
of leprosy in such a lesion.”
b) Pandian et al,[4] proposed seven criteria for Surprisingly, there were no confirmed relapses in
defining relapse in PB – “extension of the 502 patients who completed fixed-duration MDT in
lesion, infiltration, erythema, occurrence of the AMFES (ALERT MDT Field Evaluation Study)
fresh lesions, pain and tenderness of nerve, cohort, a descriptive study of leprosy in Ethiopia,[7] in

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Kaimal and Thappa Relapse in leprosy

a follow-up period of up to 8 years after completion of biopsies from patients who completed 24 months of
treatment, even in the 57 cases with an initial average MDT showed any growth whereas a small percentage
BI >4.0, 20 of whom have been followed-up for more (3.3%) of patients with a high BI were found to harbor
than 5 years after ceasing MDT. This again indicates viable bacteria in the skin after 12 doses of MDT. These
that the relapse rate after MDT is low. patients need to be followed-up for a longer period to
ascertain whether or not they will relapse.
MICROBIOLOGICAL ASPECTS
IMMUNOLOGIC TESTS FOR RELAPSE
The conventional method of confirming activity or
relapse in an infectious disease is demonstration Although, there are no widely available serologic tests
and/or culture of the etiologic agent. These methods for leprosy other than in a research setting, various
unfortunately have limited utility in leprosy because immunological tests may be useful for monitoring
of the difficulty in demonstrating bacilli in PB cases patients on chemotherapy as well as for confirming
and absence of a method of in vitro cultivation of M. suspected cases of relapse. Lepromatous patients
leprae. Unlike PB leprosy, where the criteria for relapse show a significant rise in titer of phenolic glycolipid
depend heavily on clinical features, bacteriological (PGL) immunoglobulin (Ig) M antibodies during
parameters are useful in MB leprosy. the time of relapse. Tuberculoid (TT)/borderline
tuberculoid (BT) cases who relapse to borderline
Reappearance of positivity for AFB after the case has lepromatous (BL)/lepromatous lesion (LL) types may
become negative has been considered as a feature of be detected by measuring anti-PGL-1 and anti-35 kD
relapse in both PB and MB cases. Persisting high BI antibodies.[10] The dipstick assay for detection of anti-
or increase in BI are also important parameters for PGL-1 antibodies has been used as a simple tool for
diagnosing relapse in MB leprosy. BI persisting at the classification of patients and for identification of those
same level, an increase in BI of 2+, appearance of patients who have an increased risk of relapse.[11] The
active lesions with high BI or BI becoming greater than natural disaccharide ND-O-Bovine serum antigen
what it originally was in the pre-existing lesion are (BSA) enzyme-linked immunosorbent assay (ELISA)
some of the criteria for diagnosing relapse. However, (ELISA using the ND of the phenolic glycolipid antigen
an increase in BI of even 1+ should be considered as of M. leprae linked to BSA as antigen) is another
adequate supporting evidence for diagnosing relapse useful test both for screening for early infection with
in patients who had earlier become negative or were M. leprae and for predicting a relapse, particularly in
showing a downward trend in BI after MDT.[8] cured MB patients.[12]

A number of in vivo and in vitro techniques are The Th1 and Th2 type of interleukin (IL) profile may
available for monitoring the progress of treatment in be a useful method of identifying the type of relapsed
leprosy, which can also be used as additional objective leprosy. For example, when BL/LL patients relapse
criteria for confirming relapse. In vivo techniques as TT/BT type, an upgradation of cell-mediated
that measure viability include the use of mouse foot- immunity is expected, in the form of a Th1 type of
pads for cultivation of M. leprae. In vitro measures immune response, which consists of a rise in the levels
of viability include morphological index, fluorescent of interferon (IFN)-gamma, IL-2 and IgG2 antibodies,
diacetate ethidium bromide (FDA-EB) staining, laser in addition to a positive lepromin test. On the other
microprobe mass analysis (LAMMA), adenosine hand, when TT/BT patients relapse to BL/LL types,
triphosphate measurements and macrophage-based a Th2 type of immune response is initiated, which
assays. Molecular techniques include DNA and RNA should lead to a rise in IL-4, IL-5, IL-6, IL-10 and IgG1
targeting probes and gene amplification by polymerase production, a concomitant fall in IL-2 and IFN-gamma
chain reaction (PCR).[8] and lepromin negativity.[10]

A study conducted at the Schieffelin Leprosy Research It may be possible to differentiate reinfection from
and Training Center, Karigiri, India, tested biopsy relapse by molecular typing of M. leprae, based on
samples of lepromatous patients who completed 12 amino acid sequencing as well as to identify relapse
and 24 months of MB-MDT for viable M. leprae by at a very early stage using nucleic acid amplification
mouse foot-pad inoculation.[9] None of the skin or nerve techniques such as PCR.[10]

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Kaimal and Thappa Relapse in leprosy

HISTOPATHOLOGY Histopathology of relapsed lesions in PB leprosy[13]

Lesions in BT and TT leprosy are the result of a
Regular skin biopsies and skin smears, at least once hypersensitive granulomatous response to the antigens
in 6 months, from representative lesions should of M. leprae and are not directly due to the presence of
be studied during the period of treatment and the M. leprae. With treatment, there is reduction in the size
following 5 years after achieving negativity. of the granuloma without any fibrous replacement of
the skin adnexa. Dermal collagen is destroyed during
Histopathology of relapsed lesions in MB leprosy[13] the inflammatory process, leading to an atrophied
As LL resolve under treatment, increasing number and wrinkled appearance of the healed skin lesions.
of macrophages become foamy, Schwann cells show Nerves undergo perineurial and intraneural fibrosis.
foamy change, there is reactive proliferation of the M. leprae get buried alive in these nerves and also
perineurium and increasing fragmentation and in the arrector pili muscle cells, thereby serving as a
granularity of the AFB in the granuloma are seen. focus for relapse.
The granuloma gradually resolves, without any
residual fibrosis or scar formation, and there is fibrous The difficulty that arises in PB cases is the
replacement of the perineurium and hyalinization differentiation of relapse from reaction. Features
of the nerve parenchyma. Foam cell collections are that suggest a reaction include edema around the
known to persist for long periods in the tissues, many granuloma, dilated lymphatics and proliferating
years after the skin smears have become negative. A fibroblasts throughout the dermis. A true relapse can
mild non-specific chronic inflammation characterized be detected histopathologically only after recording
by small focal collections of lymphocytes around skin complete histological resolution of the lesion, which
adnexa can also persist in resolved LL lesions for may take years. Relapse indicates that the bacilli
several years. have survived despite antileprosy therapy and have
multiplied and released antigens to produce fresh
granulomas. This manifests as the appearance of
In the early phase of relapse, small and large foci of
solid-staining organisms inside the fibrosed nerve
newly arrived spindle-shaped macrophages with a
bundles (where there were none earlier) and the
pink granular cytoplasm are identified along with a
reappearance of a granuloma at the site of the original
few small clumps of persisting foamy macrophages.
lesion. This granuloma usually begins as a small focus
Solid staining AFBs reappear in skin smears and
of lymphocytes and epithelioid cells, which often
biopsy specimens in patients who may or may not have
starts in fibrosed nerve bundles or arrector pili muscle
become completely smear negative. Once the lesion is
cells. Once the granuloma becomes well established,
well established, the foamy change becomes obscured
it grows and involves large portions of the dermis,
by collections of spindle-shaped and immature
becoming indistinguishable from the original lesion.
macrophages. Skin adnexa are markedly atrophic and
Therefore, in PB patients, regular 6-monthly biopsies
scanty, and dermal nerve bundles are few and show
showing disappearance of the granuloma will confirm
perineurial thickening and fibrosis. Macrophages, “cure” and reappearance of the granuloma will identify
Schwann cells and endothelial cells are packed with “relapse.” Rarely, PB cases will relapse as MB, and
solid-staining AFBs. this is usually due to misdiagnosis of the spectrum of
disease and the resultant inadequate treatment in the
Occasionally, there is infiltration by polymorphs and first place.
it is also not uncommon to see LL patients relapsing
with upgrading reactions in the form of BL or, rarely, RELAPSE INTERVAL
BT lesions.
Relapse interval is otherwise known as incubation
Lesions of BL resolve much faster than polar LL cases period of relapse.[14] It is different with monotherapy
and become bacteriologically negative much earlier. and MDT.
Histopathologically, BL lesions leave behind a few
focal collections of mononuclear cells around the skin Dapsone monotherapy:[14]
adnexa and foam cells are not usually seen. Relapses Fifty-five to 57% of relapses occurred within
in BL manifest as LL, BL or, rarely, as BT. 1. 3 years in non-lepromatous

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Kaimal and Thappa Relapse in leprosy

2. 5 years in borderline three or more areas of the body, correlate with a higher
3. 6 years in lepromatous MDT.[14] relapse rate. Mycobacterial antibodies have been found
1. PB, same as with monotherapy in TT leprosy with a large number of lesions and in
2. MB, 9 years (median) BT leprosy with more than 10 lesions. Because this is
evidence of a fairly large number of organisms, these
The implication of these figures is that PB patients patients may not be truly PB and treatment with two
should be under surveillance for at least 3 years and drugs for 6 months might be considered inadequate
MB patients for 9 years so that a majority of the relapses for these patients.
can be detected.[14]
Lepromin negativity
PREDISPOSING FACTORS FOR RELAPSE[14] Borderline patients with a positive lepromin test have
been observed to have a lower relapse rate than those
Persisters with a negative response.
Persisting organisms or “persisters” consist of
permanently or partially dormant organisms that Human immunodeficiency virus (HIV) infection
have the capacity to survive in the host despite Although leprosy has now been reported presenting
adequate chemotherapy. They have been identified in as an immune reconstitution disease among patients
immunologically favorable sites such as dermal nerves, commencing highly active antiretroviral treatment,
smooth muscle, lymph nodes, iris, bone marrow and there is no evidence as yet to suggest an increased risk
liver. These organisms, which are responsible for of relapse in patients with HIV coinfection.
relapse, are present in about 10% of the MB patients,
and their proportion may be higher in cases with CLINICAL FEATURES[14,15]
higher BI.
Age: In MB cases, relapse is more common in the older
Inadequate therapy age groups. PB leprosy with single skin lesions is more
This is usually the result of clinical miscategorization common in younger age groups and relapse is less
of MB leprosy with few skin lesions as PB cases, common in this group.
who receive 6 months of MDT instead of 12 months,
initially respond to treatment and eventually relapse. Sex: Relapses are more common in males, possibly
because of the higher prevalence of leprosy in males.
Irregular therapy Relapses are seen in females in the setting of pregnancy
Irregularity in ingesting self-administered clofazimine and lactation.
and dapsone either due to an irregular supply of drugs
or non-compliance on the part of the patient, effectively Relapse in PB leprosy
resulting in a scenario of rifampicin monotherapy. a) Skin lesions: Previously subsided skin lesions
This will lead to rifampicin resistance and subsequent show signs of renewed activity, such as infiltration,
relapse. erythema, increase in extent and appearance of
satellite lesions. Often, there is an increase in the
Monotherapy number of lesions as well.
The relapse rate is high among patients who have b) Nerves: New nerves may become thickened and
received dapsone monotherapy and did not later tender, accompanied by an extension of the area of
receive MDT. This is also due to the development of sensory loss and an insidious onset of motor deficit.
resistant organisms. Patients may complain of aches and pains along the
peripheral nerves with or without evidence of nerve
High initial BI damage. Relapse may occur only in nerves without
Patients who have a high BI initially are at greater risk skin involvement (neural relapse) and there may be
of relapse after fixed duration MDT compared with a change in the spectrum of disease on relapsing.
patients who are smear negative or have a low BI.
Relapse in MB leprosy
Number of skin lesions and nerves a) Skin lesions: Relapse may present as localized areas
The number and extent of lesions including nerve of infiltration over the forehead, lower back, dorsa
lesions, when multiple, i.e. more than five and covering of hands and feet and the upper part of the buttocks.

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Kaimal and Thappa Relapse in leprosy

Soft, pink and shiny papules and nodules may be Relapse vs. resistance
found at these sites, with or without a background Drug resistance is an emerging problem in leprosy
of infiltration. Papules may enlarge to form plaques. worldwide, owing primarily to the chronicity of the
Subcutaneous nodules may appear on the posterior disease and the long duration of treatment required. [14,15]
arms and anterolateral thighs. They feel like peas in Drug resistance may be primary, wherein lepra bacilli
a pod and increase in size with time. Skin smears are resistant to the concerned drug from the onset
from the overlying skin may be negative; hence, the itself, or secondary, wherein resistance develops as
scalpel should be plunged deep into the core of the a result of mutant bacilli surviving in the setting of
nodule while taking smears. irregular therapy or monotherapy. Dapsone resistance
b) Nerves: Nodular swellings may occur along the is the most common, owing to the earlier concept of
course of cutaneous nerves and peripheral nerve dapsone monotherapy. Rifampicin resistance occurs in
trunks in addition to fresh nerve thickening and/or the setting of irregular therapy. Clofazimine resistance
tenderness, with insidious loss of function. is very uncommon. Although mouse foot-pad studies
c) Ocular lesions: Cases with pre-existing eye are recommended for confirmation of drug resistance
involvement may relapse with iris pearls or, rarely, in leprosy, these facilities are not available freely,
lepromata. forcing clinicians to rely on clinical features alone.
d) Mucosal lesions: Papular or nodular lesions may Drug resistance may itself be a reason for relapse and
be seen on the hard palate, inner lips and glans it is important to differentiate the two, as outlined in
penis. the Table 3.

DIFFERENTIAL DIAGNOSIS Relapse vs. reactivation

Reactivation of lesions occurs due to treatment failure,
Differences between erythema nodosum leprosum i.e. premature termination of treatment or gross
(ENL) and relapsed fresh papules and nodules[14] irregularity in treatment either due to non-compliance
Papules and nodules that occur as part of relapse in or irregular supply of drugs. [14,16] Reactivation occurs
the MB spectrum should be differentiated from ENL soon after subsidence of the disease while relapses occur
nodules. The most important point of difference is after complete and sustained subsidence of the disease.
that ENL nodules are tender and evanescent, unlike
lepromatous nodules. Additional differences are listed Relapse vs. reinfection
in Table 1. Recurrence of disease in a cured case may be due to
reinfection. [14,16] Reinfection is an extremely difficult
Differences between reversal reaction and relapse condition to prove, especially in an endemic area.
It is often a diagnostic dilemma to differentiate true When cured, leprosy patients continue to live in and
relapse from a late reversal reaction in a PB case.[14,15] around the leprosy sanatoria. In hyperendemic areas,
Many studies on PB leprosy show falsely high relapse they may develop the disease again due to exogenous
rates, possibly because of the inclusion of cases that infection. Also, patients get cured not only by the
are probably reactions and not really relapses. Some of killing of germs by bactericidal drugs but also by the
the features that will help in differentiating these two added immunity the patients develop subsequent to
conditions are given in the Table 2. the treatment. This is supported by the fact that even

Table 1: Differences between erythema nodosum and relapsed papules and nodules
Feature ENL Relapsed papules and nodules
History of therapy Episodes during therapy in LL, LLs and, rarely, BL After completion of therapy, during surveillance
in borderline borderline leprosy (BB), BL, LLs,
LL and, rarely, BT
Onset Sudden Insidious
Constitutional symptoms Present Absent
Physical signs Nodules are tender, warm, erythematous, blanchable Non-tender, not warm, pink, do not blanch,
on pressure and superÞcially located involve full thickness of skin
Skin smears Fragmented AFB, polymorphs BI > 2+, long solid staining AFB, globi +
Course Change from red to bluish and dusky, evanescent – Pink changes to skin colored, consistency
subside within 48–72 h changes from soft to Þrm, in months

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Kaimal and Thappa Relapse in leprosy

Table 2: Differences between reversal reaction and relapse

Feature Reversal reaction Relapse
Time course Usually within 6 months of release from treatment; 1 year or more after release from treatment
in recurrent reactions, up to 2 years
Type of disease BT, BB, BL All types
Skin lesions Increased erythema, swelling, tenderness on pressure, Increase in extent and number of lesions, no
succulent consistency; upward or downward change in tenderness, rubbery consistency; edema of
the spectrum may occur; edema of hands/feet hands and feet rare
Ulceration Seen in severe reactions Not seen
New lesions Few, same morphology Many
Nerves Acute painful neuritis; nerves exquisitely tender; New nerves involved; no spontaneous pain;
nerve abscess; sudden paralysis of muscles and tenderness on pressure; sensory and motor
increase in extent of sensory loss deÞcits slow and creeping
Skin smears Continued decrease in BI. Granularity of bacilli AFB positivity may occur in skin smear-negative
increases in reactions patients
Lepromin test Progressively positive Fernandez reaction in BL and Corresponds to the type of relapsed leprosy
BB upgrading to BB and BT, respectively
Response to systemic steroid Complete subsidence of lesions in 2–4 weeks; remain No response or partial response
subsided with 2-month therapy

Table 3: Drug resistant leprosy versus relapse

patients with a positive BI, if BI increases by 2+ over
previous smears at any two sites and continues to be
Drug-resistant leprosy Relapse
so at two examinations, it is diagnosed as relapse,
Because of primary or Mainly due to persisters
secondary drug resistance provided the patient has ingested 75% of the drugs.
Initial amelioration followed by halt Recurrence after release
or worsening from MDT Therapeutic criteria
Appearance of new lesions Reappearance of lesions This is useful when reversal reaction is suspected. The
over old lesions patient may be treated with prednisolone (reaction
Patient downgrades Patient rarely downgrades dose being around 1 mg/kg/day), after which a reversal
reaction should subside completely in 2 months. If
an LL patient is able to actively dispose off the dead symptoms do not subside or only partially subside or
bacilli. Hence, a treated lepromatous case is not truly lesions persist or increase under the cover of steroid,
immunoincompetent and the risk of reinfection is not relapse should be suspected.
high. When reinfection does occur, the incubation
period is bizarre and fresh skin and nerve lesions do Histopathological criteria
not correspond to the original lesions. This includes the reappearance of granuloma in PB
cases and increased macrophage infiltration with
DIAGNOSIS solid-staining bacilli and increasing BI in MB cases.

The diagnostic criteria for relapse are:[10,14] Serologic criteria

In LL cases, the measurement of PGL-1 IgM antibodies
Clinical criteria is a good indicator of relapse.
a) increase in size and extent of existing lesion(s)
b) appearance of new lesion(s) The first three criteria are sufficient to make a diagnosis
c) infiltration and erythema in lesions that had of relapse; criteria 4 and 5 are additional and may be
completely subsided used wherever facilities are available.
d) nerve involvement (thickening or tenderness)
TREATMENT
Bacteriological criteria
Positivity (in a smear-negative patient) at any site in Relapsed cases of leprosy should be identified and put
skin smears for AFB at two examinations during the back on chemotherapy as soon as possible to prevent
period of surveillance is diagnostic of relapse. In further disability and transmission of infection.[17]

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Kaimal and Thappa Relapse in leprosy

Factors that should be considered in choosing an the mouse foot-pad or other techniques, relatively few
appropriate regimen are: leprosy centers have such a facility available. Thus,
1. Type of leprosy (PB or MB) the decision on drug resistance most often is based on
2. Previous treatment clinical information alone. Recommended treatment
3. Drug resistance regimens are given in Table 4.

Type of leprosy Failure to respond to therapy

PB cases usually relapse as PB, and MB cases as MB. This group includes patients who do not respond as
However, PB cases occasionally relapse as MB and expected in terms of clearance of skin lesions and
such cases should receive MB-MDT. bacilli after therapy is discontinued or patients who
actually show disease progression during therapy.
Previous therapy The former group contains potential relapse cases, but
a) Patient previously treated with dapsone great care must be taken to rule out reaction and/or
monotherapy – standard WHO MDT is sufficient. slow clearance of lesions and bacilli as a cause of poor
response.
b) Patient previously treated with clofazimine
monotherapy – standard WHO MDT is sufficient
The WHO defines a “satisfactory result from MDT”
(clofazimine resistance is extremely rare).
in a patient who complies with treatment as – one
Drug resistance in which, after the start of therapy, bacilli begin to
Patients with known or suspected drug resistance pose clear in MB cases and lesions generally, although not
a treatment problem only in the case of rifampicin necessarily, rapidly improve in both PB and MB cases.
resistance, which is rare. MB patients who have Clearance of lesions is related more to the patient’s
received rifampicin as part of MDT are not at any immune response than to antileprosy treatment; all
significant risk of rifampicin resistance, unless they lesions and bacilli should eventually clear even though
were infected with fully dapsone-resistant bacilli clearance may be incomplete at the time treatment is
and either did not take their clofazimine or were discontinued.[17]
not given another effective drug. Dapsone resistance
occurs in the setting of prior dapsone monotherapy MDT regimens being used in the United States
and such cases respond well to standard WHO MDT. [Table 5] are more robust than the ones being
Clofazimine resistance is extremely rare, if at all it recommended in developing countries by the WHO.
occurs, and these cases also respond to the other two Although studies show that relapse rates are very
drugs in the standard WHO MDT. low after WHO MDT, the fact remains that relapses
do occur. There is a possibility that more relapses
Although drug resistance ideally is determined using in leprosy may develop if the WHO accepts uniform

Table 4: Recommended treatment regimens

Resistance Scenario Treatment
Relapse with M. leprae sensitive to Relapse after a course of MB-MDT Retreatment with WHO MDT depending on
all standard drugs the type of disease (PB or MB-MDT)
Relapse with dapsone-resistant M. leprae Relapse after previous “cure” with Standard WHO MDT
dapsone monotherapy
Relapse with rifampicin-resistant or Primary or secondary dapsone-resistant Clofazimine 50 mg daily for 24 months
rifampicin- and dapsone-resistant M. leprae MB cases who received standard WHO plus two of the following drugs for
MB-MDT but did not take their clofazimine 6 months: oßoxacin 400 mg daily or
(situation equivalent to rifampicin minocycline 100 mg daily or clarithromycin
monotherapy) 500 mg daily, followed by: oßoxacin 400
mg daily or minocycline 100 mg daily for
the remaining 18 months

Table 5: Multidrug therapy regimens in the United States of America[18]

Type of leprosy Dosage of drugs *CLF may be added Dapsone 100 mg after MDT for
Paucibacillary (I, TT, BT) Dapsone 100 mg daily + rifampin 600 mg daily for 6 months 3 years (I, TT) 5 years (BT)
Multibacillary (BB, BL, LL) Dapsone 100 mg daily + rifampin 600 mg daily for 3 years 10 years (BB) Lifelong (BL, LL)

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Kaimal and Thappa Relapse in leprosy

MDT. Unfortunately, it is not practical to introduce 2000;71:325-31.

8. Katoch VM. Microbiological aspects of relapse in leprosy.
regimens like those in the United States on a large Indian J Lepr 1995;67:85-98.
scale in a resource-poor setting like India. However, 9. Ebenezer GJ, Daniel S, Norman G, Daniel E, Job CK. Are
clinicians may use their judgement and tailor viable Mycobacterium leprae present in lepromatous patients
after completion of 12 months’ and 24 months’ multi-drug
treatment regimens for individual patients wherever therapy? Indian J Lepr 2004;76:199-206.
practicable. In selected cases, longer regimens similar 10. Sengupta U. Immunological aspects of relapse in leprosy.
to those used in the United States may be useful. Indian J Lepr 1995;67:81-3.
11. Bührer-Sékula S, Cunha MG, Foss NT, Oskam L, Faber WR,
Klatser PR. Dipstick assay to identify leprosy patients who
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Lepr 1995;67:13-26. on a possibility of predicting early relapse in leprosy using
2. Becx-Bleumink M. Relapses among leprosy patients treated a ND-O-BSA based ELISA. Int J Lepr Other Mycobact Dis
with multidrug therapy: Experience in the leprosy control 2002;70:1-8.
programme of the All Africa Leprosy and Rehabilitation and 13. Job CK. Histopathological features of relapsed leprosy. Indian
Training Centre (ALERT) in Ethiopia; Practical difficulties J Lepr 1995;67:69-80.
with diagnosing relapses, operational procedures and criteria 14. Ramu G. Clinical features and diagnosis of relapses in leprosy.
for diagnosing relapses. Int J Lepr 1992;60:421-35. Indian J Lepr 1995;67:45-59.
3. Boerrigter G, Ponnighaus JM, Fine PE, Wilson RJ. Four-year 15. Pfaltzgraff RE, Ramu G. Clinical leprosy. In: Hastings RC,
follow up results of a WHO-recommended multiple-drug Opromolla DV, editors. Leprosy. 2nd ed. Edinburgh: Churchill
regimen in paucibacillary leprosy patients in Malawi. Int J Livingstone; 1994. p. 237-87.
Lepr 1991;59:255-61. 16. Desikan KV. Relapse, reactivation or reinfection. Indian J Lepr
4. Pandian TD, Sithambaram M, Bharathi R, Ramu G. A study 1995;67:3-11.
of relapse in non-lepromatous and intermediate groups of 17. Jacobson RR. Treatment of relapsed leprosy. Indian J Lepr
leprosy. Indian J Lepr 1985;57:149-58. 1995;67:99-102.
5. Ali MK, Thorat DM, Subramanian M, Parthasarathy G, Selvaraj 18. Jacobson RR. Treatment of leprosy. In: Hastings RC,
U, Prabhakar V. A study on trend of relapse in leprosy and Opromolla DVA, editors. Leprosy. 2nd ed. Edinburgh:
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6. Shen J, Liu M, Zhang J, Su W, Ding G. Relapse in MB leprosy
patients treated with 24 months of MDT in south west China: Note: This article is modiÞed version of chapter submitted to
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multiple drug therapy: The AMFES cohort. Lepr Rev

Multiple choice questions

1. The WHO has estimated a risk of relapse of:
a) 1.07% for PB and 0.77% for MB leprosy. b) 0.65% for PB and 0.02% for MB leprosy.
c) 3.0% for PB and 0.8% for MB leprosy. d) 0.84% for PB and 1.9% for MB leprosy.

2. The correct statement regarding relapse among the following is:

a) Bacteriologic parameters are more useful in PB leprosy.
b) The diagnosis of MB leprosy relies on clinical features.
c) Both bacteriological and clinical features are useful in the diagnosis of relapse in PB cases.
d) The diagnosis of relapse in PB leprosy relies primarily on clinical features.
3. In vitro measures of viability of M. leprae include all except:
a) Morphological index. b) FDA-EB staining.
c) LAMMA. d) Titer of PGL-IgM antibodies.
4. Immunologic tests for leprosy include all except:
a) Macrophage-based assays. b) PGL-IgM antibodies.
c) ND-O-BSA ELISA. d) Lepromin test.
5. All of the following statements regarding histopathology of relapsing PB lesions are true except:
a) M. leprae in nerves and arrector pili muscle cells serve as a focus for relapse.
b) Reappearance of solid-staining organisms inside fibrosed nerve bundles.
c) Reappearance of a granuloma at the site of the original lesion.
d) There is edema around the granuloma.

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Kaimal and Thappa Relapse in leprosy

6. Relapse interval after MDT is:

a) 8 years in MB cases. b) 6 years in borderline cases.
c) 3 years in PB cases. d) 2 years in BT cases.
7. The ideal period of surveillance (based on relapse interval) so that a majority of relapses can be detected is:
a) At least 6 years for PB patients. b) At least 9 years for MB patients.
c) At least 2 years for PB patients. d) At least 5 years for MB patients.
8. All the following statements regarding “persisters” in leprosy are true except:
a) Dormant organisms that have the capacity to survive in the host despite adequate chemotherapy.
b) Present in immunologically favorable sites such as dermal nerves, smooth muscle, lymph nodes, iris, bone
marrow and liver.
c) Responsible for resistance to treatment.
d) Present in about 10% of MB patients.
9. The incorrect statement regarding clinical features of relapse in PB leprosy is:
a) Occurs within 6 months of release from treatment.
b) Previously subsided skin lesions show signs of renewed activity.
c) New nerves may become thickened and tender.
d) Relapse may occur only in nerves without skin involvement.
10. The recommended treatment for relapse cases with rifampicin resistance is:
a) Dapsone monotherapy.
b) Standard WHO MDT.
c) Standard WHO MDT without rifampicin.
d) A regimen of clofazimine combined with ofloxacin/minocycline/clarithromycin.

1-a, 2-d, 3-d, 4-a, 5-d, 6-c, 7-b, 8-c, 9-a, 10-d
Answers

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