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**Bombay Leprosy Project, 11 VN Purav Marg, Sion, Mumbai ...... Financial support for this study was from Leprosy Mission India and Tata Education Trust,.
Lepr Rev (2005) 76, 241– 252

Clinical, histopathological and bacteriological study of 52 referral MB cases relapsing after MDT V. P. SHETTY*, A. V. WAKADE*, S. D. GHATE*, V. V. PAI**, R. R. GANAPATI** & N. H. ANTIA* *The Foundation for Medical Research, 84-A, R.G. Thadani Marg, Worli, Mumbai 400 018, India **Bombay Leprosy Project, 11 VN Purav Marg, Sion, Mumbai 400 022, India Accepted for publication 14 June 2005 Summary Fifty-two BB-LL relapse cases referred to our cenre during 1997– 2003 were investigated in detail. Twenty-four cases had been treated with extended MBMDT [until smear negativity (NON-FDT)]. The remaining 28 cases (54%) had received one of the fixed duration regimens (FDT), of whom 11 had 24 months and 6 had 12 months of WHO MB-MDT. Eleven cases had received rifampicin/ofloxacin (RO) treatment. Follow-up slit skin smear reports were available for 41 cases, all but three cases had been smear negative at some point after release from treatment. None of the cases showed any clinical or bacteriological evidence of upgrading, i.e. LL to BT where as downgrading BB to BL occurred in five cases. The duration between cessation of treatment and reappearance of lesions (DCTR) varied from 2 to 15 years. The mean DCTR was longest (9.4 years) for the NON-FDT and 24 months MB-MDT cases. The mean DCTR was significantly lower in the 12 months MB-MDT and RO treated cases (6.8 and 6.2 years, respectively). Four of RO treated cases and four cases with multiple episodes of reaction had DCTR less than 5 years. Inadequate treatment/poor killing of Mycobacterium leprae results in early onset relapse, whereas ‘persisting’ or ‘drug resistant mutants’ contribute to late onset relapse.

Introduction The reappearance of lesions or relapse after the release from treatment (RFT) has profound implications for case management, compliance, disease transmission and control. Relapse may occur due to poor killing, persisting Mycobacterium leprae, drug resistant mutants or reinfection while recurrence of lesion could also be due to late reversal reaction. Rate of relapse is the single most important measure of efficacy of multidrug therapy (MDT) in leprosy.1 However estimation of relapse rate is difficult under field conditions as it may take up to 7 –15 years of careful follow-up after the cessation of treatment2 and also there is the problem of Correspondence to: V. P. Shetty (Tel/Fax: þ 91-22-24934989/24932876; e-mail: [email protected]; frchbom@bom2. vsnl.net.in) 0305-7518/05/064053+12 $1.00

q Lepra

241

242

V. P. Shetty et al.

differentiating relapse from late reversal reaction. Some of the cohort studies show that patients with high initial bacterial index (BI), receiving fixed duration MB-MDT (FDT) are at a higher risk of relapse.3 – 5 Some other similar studies,6 – 8 however, fail to support these findings, probably reflecting variability in study site, treatment compliance, follow-up rigor/ length, definition of relapse9 or for some reasons as yet unknown. The importance of documentation and studying the characteristics of cases presenting with post-MDT recurrence of lesions cannot be underestimated. On average, 20 –25 referral cases, with recurrence of lesions (of which , 50% were smear positive MB cases) are received annually at this centre, from within and around the city of Mumbai. All these cases are investigated in detail. The findings on a select group of borderline (BB) to lepromatous (LL) cases relapsing after the MB-MDT are presented and discussed in this paper.

Materials and methods A total of 52, BB-LL confirmed relapse cases, received during the period 1997 – 2003 are included in this study. Relapse was defined as: reappearance of skin and/or nerve lesions that are clinically and histopathologically consistent with active BB, BL or LL leprosy using Ridley –Jopling scale.10 All the cases included in this study had more than five skin/nerve lesions, were treated with one of the multibacillary regimens, had stopped treatment on advice and later presented with reactivation of old skin/nerve lesions and/or development of new lesions. Multiplication of M. leprae in the mouse footpad is used as an additional test for confirming relapse. Cases who had received extended MB-MDT, i.e. until smear negativity are called the NON-FDT group and those who had received one of the fixed duration regimens are the FDT group. The details of all the patients were obtained including clinical presentation, bacteriological status at registration, type and duration of anti-leprosy treatment or any other treatment taken, episodes of reaction or neuritis and its management and any other concurrent infection. Body charting was done to record the new and old skin/ nerve lesions, their nature and distribution. Late reversal reaction was ruled out in doubtful cases, using a therapeutic course of corticosteroids. Slit skin smears were done in all the cases and one of the newly developed skin lesions was biopsied in all but three cases. Additional nerve biopsy each was done in a total of nine cases and only nerve biopsy was done in one case, after obtaining informed consent. Two cases did not give consent for biopsy. The lesional biopsy thus obtained on relapse was divided into three parts. One part was fixed in formal Zenker and embedded in paraffin. Sections were cut, stained with Trichrome modified Fite Farracco (TRIFF), and were used for determining the nature of cellular infiltrate, presence of acid fast bacilli and for classifying as per the Ridley – Jopling scale.10 The second piece of the tissue collected in a sterile vial was homogenized and bacterial load per g wt. was determined using the standardized procedure.11 [It should be noted that the detection sensitivity of this method is . 1 £ 104 M. leprae/ml.] Homogenate thus obtained was also used for viability and drug sensitivity tests in the mouse footpad. The results of the drug sensitivity study have been published.12 The third piece collected in a sterile vial, was stored at 2 708C and kept as reserve.

Study of 52 referral MB cases relapsing after MDT

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Results TREATMENT DETAILS

The cases studied were from different cohorts, thus they had received various types of multidrug therapy (MDT) that were being tried during that period. Twenty-four of them were treated till smear negativity, had received either diaminodiphenyl sulphone (DDS) monotherapy prior to MDT (14 cases) or 30– 60 doses of MB-MDT (10 cases), (NON-FDT group). The clinical and bacteriological details are summarized in Table 1. The remaining 28 cases (54%) had received one of the fixed duration multibacillary regimens, i.e. 11 had 24 doses and six had 12 doses of WHO MB-MDT, while 11 cases had received rifampicin, ofloxacin daily (RO) for 28 days (FDT group). The clinical and bacteriological details are summarized in Table 2. Unless specified, the MB-MDT regimen refers to the use of three drugs i.e. rifampicin (RFP) 600 mg, clofazimine (CLF) 300 mg and DDS 100 mg once monthly; with CLF 50 mg and DDS 100 mg daily.13 RO is rifampicin 600 mg and ofloxacin 400 mg daily for 28 days. Twenty-one cases (21/52 ¼ 40.4%), i.e. 14 from the NON-FDT and seven from the FDT group, had received therapeutic course of corticosteroids for reaction or neuritis. The majority 13/21 (62%) had type 1 (T1R) reactions, seven cases had type 2 (T2R) reaction and one case had recurrent neuritis. Six cases (two T1R and four T2R) had single episode of reaction. Ten (10/21 ¼ 48%) cases (seven T1R, two T2R and one neuritis) had multiple (two to eight) episodes of reaction during and after treatment and were treated with steroids each time. Four cases (3, 9, 11 and 24) were empirically treated for late reversal reaction (see Table 1). CLINICAL MANIFESTATIONS

Details of clinical manifestations at onset were available in a total of 45 cases. It was noted that clinical presentation at registration and relapse were similar in most cases (31/45 ¼ 69%), i.e. predominantly erythematous lesions were seen in 11, hypo-pigmented patches (HPPs) in 10 and nodular lesions in 10 cases in both instances. Eleven cases had HPPs at onset, of which six presented with erythematous and five with nodular lesions on relapse, suggesting downgrading. The remaining three cases had nodular lesions at onset and presented with neuritis at relapse. SLIT SKIN SMEAR

Slit skin smear reports at onset were available in a total of 40 cases. In most cases (32/40), the highest (average) BI at onset and on relapse was comparable suggesting that there was no major shift in bacteriological status and therefore leprosy class. Twenty-nine cases who had pre-treatment BI of $ 3 þ , nine NON-FDT cases and two 24 months MB-MDT cases had relapsed after 10 years (see Table 3). Follow-up slit skin smear reports were available in 41 cases, all but three cases had turned smear negative at some point in time. OTHER ILLNESS

Three cases (12, 26, 42) had concurrent pulmonary tuberculosis and received 6 months of treatment with combinations of rifampicin, isoniazid, ethambutol and pyrazinamide.

BL

BL BL

BL

BL

1982– 1988b

1976– 1978a, 1983–1986b 1984– 1986a, 1991–1993b

1983– 1987b

1982– 1983a, 1984–1986b

12*; T1R 13 14; T2R 15; T2R 16

1969– 1981 , 1981–1983 1981– 1984b 1953– 1961a, 1982–1984b 1982– 1984b

a

LL LL LL BL

BB BL

1978– 83a, 1983–1985b 1984– 1987b

b

BB LL

1953– 1982a, 1982–1990b 1981– 1984a, 1983–1986b

9; T1R 10; T1R* 11; T1R

BL BL BL

1980– 1984a, 1987–1988b

2**; T2R* 3**; T1R 4 5**; T2R* 6; N* 7**; T1R 8

1979– 82a, 1982–1984b

BL

1979– 82a, 1982–1986b

Class

1: T1R*

Case no. Year

At diagnosis

Nod Nod Nod/Inf NA

Hpp/Inf

Hpp

Ery Hpp

Nod

Ery Inf/ Ery

Hpp Hpp

NA NA NA

Hpp

Clin. Fea.

5þ 3.5þ 3þ 3þ

3.3þ

NA

5þ 3þ

NA

1þ 4þ

3þ NA

4þ NA 2.7þ

NA

SSS BI

1983 1984 1984 1984

1986

1987

1986 1993

1988

1985 1987

1990 1986

1984 1988 1984

1986

Yearc

2ve 2ve 2ve 2ve

2ve

2ve

2ve 2ve

2ve

2ve 2ve

2ve 2ve

2ve 2ve 2ve

2ve

SSS BI

Follow up

14 13 13 14

11

9

11 4

9

12 10

6 10

11

7

7

DCTR years

d

Table 1. Summary of clinical and bacteriological findings in 24 NON-FDT, BB-LL relapse cases

Class

Ery

Ery

Ery

Clinical features

1997 1997 1998 1998

LL LL LL BL

1997 BL 1997 BL þ T1R 1997 BB þ T1R 1997 BLþ T1R

1997 BL

1997 BB 1997 BL

Nod Nod Nod/Inf Nod

Inf/Nod

Hpp

Ery Ery

Nod

Ery Ery

1996 LL Nod 1996 LL þ T2R Ery

1996 LL

1994 BL þ T1R 1996 BL

Year

At relapse

4þ 4þ 2.7þ 6þ



2ve

3þ 1þ



1þ 4þ

4þ 4þ







SSS BI

10 108 109 ND

9

108

,104

107 105

109, 108n

105 107

ND 109, 108n

109

109, 108n

106, 106n

M. leprae /g wt

þ ve þ ve þ ve ND

þ ve

þ ve

þ ve, þ ve þ ve þ ve

ND þ ve, þ ve þ ve þ ve

þ ve, þ ve 2ve, þ ve þ ve

MFP

244 V. P. Shetty et al.

BB LL LL BL LL

1986– 1990a, 1995–1996b 1983– 1988b 1987– 1991b 1986– 1988b 1965– 1985a, 1990–1992b

Hpp Ery Nod Ery Ery

Hpp

Hpp Ery

Clin. Fea.

1.2þ 4þ 6þ 3þ NA



4þ 1.3þ

SSS BI

1996 1988 1991 1988 1992

1995

1985 1988

Yearc

2ve 2ve 2ve 2ve 2ve

2ve

2ve 2ve

SSS BI

Follow up

3 12 9 12 9

4

13 11

DCTRd years Class Hpp Ery

Clinical features

2000 2000 2000 2000 2001

BB LL LL BBþ T1R LLþ T1R

Hpp EryA Neu Ery Ery

1999 BLþ T1R Hpp

1998 LL 1999 BL

Year

At relapse

1þ 3þ 5þ 2ve 3þ

2ve

4þ 4þ

SSS BI

105 108 109 ,104 107

,104, 106n

10 108, 106n

8

M. leprae /g wt þ ve þ ve, þ ve 2ve, þ ve þ ve þ ve 2ve þ ve þ ve

MFP

b

Duration of DDS monotherapy. Duration of MB-MDT. c Year of last available smear report. d Duration between cessation of treatment to actual detection of relapse. n M. leprae/g wt. in the nerve biopsy. * Multiple episodes of reaction. ** Drug resistant mutant. T1 ¼ type 1 reaction, T2R ¼ type 2 reaction, NA ¼ not available, ND ¼ not done, N ¼ neuritis, Hpp ¼ hypopigmented, Ery ¼ erythematous, Nod ¼ nodules, Neu ¼ neuritis, Inf ¼ infiltration. MFP ¼ mouse foot pad test results ( þ ve $1 £ 105 M. leprae/foot pad; 2ve 2 , 1 £ 104 M. leprae/foot pad).

a

BL

1978– 1981a, 1994–1995b

19; T1R* 20 21 22 23 24; T1R

LL BB

1980– 1985 1985– 1988b

b

Class

At diagnosis

17 18

Case no. Year

Table 1. continued

Study of 52 referral MB cases relapsing after MDT 245

24 months MB-MDT 25 1987 26, T2R 1982 27 1987, 1991 28 1987 29 1987 30 1983 31 1989 32, T2R* 1985 33 1991 34 1986 35** 1984 12 months MB-MDT 36, T1R* 1988 37 1993 38 1991 39, T1R 1991 40, T1R* 1994 41 1987 RO Rx 42, T1R* 1993 43 1991 44 1993 45 1989 46, T2R 1992

Case No. Year

Nod Hpp Hpp Ery NA Hpp Eyr Ery NA Hpp NA

Hpp Hpp Hpp Hpp Nod Hpp

Hpp Nod NA Ery Hpp

BL BL BL BL BL BL

BL LL LL BL BB

Clinical features

BL BB BL BB BL BB BL LL BB LL LL

Class

At diagnosis

NA 5þ 6þ 4.5þ 3þ

NA 4þ 2þ 1.3þ 3þ NA

4þ 1.5 þ 2þ 1þ NA 1.5 þ 4þ 3þ NA NA 5þ

SSS BI

1997 1992

1995

1992 1992

1985 1991 1987 1993

1984 1989, 1992 1989

Yeara

NA 2ve NA 0.6 2.8þ

NA NA 2ve 2ve NA NA

NA 2ve 2ve 2ve NA 2ve 2ve 2ve 2ve NA NA

2 6 4 10 7

8 3 6 6 4 14

6 13 4 8 9 13 8 12 6 13 15 BLþ T2R BL BB BL BB BL

BL BL þ T2R BB BB þ T1R BL BB þ T1R BL LL þ T2R BB LL LL

Class

1995 BL 1997 LL 1997 LL 1999 BL 1999 BBþ T1R

1997 1997 1998 1998 1999 2002

1995 1997 1997 1997 1998 1998 1999 1999 1999 2001 2001

SSS BI DCTRb years Year

Follow-up

Table 2. Summary of clinical and bacteriological findings in 28 FDT, BB-LL relapse cases.

Ery Nod Hpp Ery Hpp

Hpp Hpp Hpp Hpp Neu Nod

Neu Ery Ery Ery Ery Hpp Ery Ery Ery Nod Ery

Clinical features

At relapse

þ ve, þ ve 2ve þ ve 2ve, þ ve þ ve þ ve þ ve þ ve, þ ve 2ve þ ve 2ve

,104, ,104n 106 106 105 107n ,104 109 106n 108, 108n 1010 106 107

2ve 2þ 2þ 2ve 1þ 4þ 2þ 3þ 5þ 2þ 3þ

þ ve þ ve þ ve þ ve ND þ ve ND 2ve þ ve þ ve þ ve

MFP

107 108 105 106 ND ,104 ND 107 105 109 109

M. leprae/ g wt

1þ 3þ 1þ 3þ 4þ 2ve 5þ 3þ 2ve 4þ 4þ

SSS BI

246 V. P. Shetty et al.

Nod Nod Nod Inf/Nod Nod Hpp

Clinical features

NA 4þ 4þ 4þ 4þ 4þ

SSS BI

1999 1996 1999 1997 1994

Yeara NA 2ve 2ve 0.3þ 3þ 4þ

4 7 7 5 6 10

2000 2001 2001 2001 2002 2003

SSS BI DCTRb years Year

Follow-up

LL BL BL BL LL BL

Class Nod Nod Nod Nod Nod Nod

Clinical features

At relapse

4þ 5þ 4þ 4þ 5þ 5þ

SSS BI

MFP þ ve þ ve þ ve þ ve þ ve þ ve

M. leprae/ g wt 108 109 10 9 109 109 1010

n

b

Year of last smear record. Duration between cessation of treatment to actual detection of relapse. M. leprae load in the nerve biopsy. * Multiple episodes of reaction. ** Drug resistant mutant. T1R ¼ type 1 reaction, T2R ¼ type 2 reaction, NA ¼ not available, ND ¼ not done, N ¼ neuritis, RO ¼ rifampicin and olfloxacin regimen, Hpp ¼ hypopigmented, Ery ¼ erythematous, Nod ¼ nodules, Neu ¼ neuritis, Inf ¼ infiltration. MFP ¼ mouse foot pad test results ( þ ve $1 £ 105 M. leprae/foot pad; 2ve ,1 £ 10 4 M. leprae/foot pad).

a

LL BL BL BL LL BL

47 48 49 50 51 52

1996 1994 1994 1996 1996 1993

Class

At diagnosis

Case No. Year

Table 2. continued

Study of 52 referral MB cases relapsing after MDT 247

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V. P. Shetty et al.

Table 3. DCTR in relation to pre treatment BI in 40 cases. No. of cases & DCTR range as below 2–5 years

.10 years

5– 10 years

Treatment taken Pre Rx BI

,3 þ

^ 3þ

,3þ

^ 3þ

,3þ

^ 3þ

NON-FDT FDT 24 months FDT 12 months RO

2 1 0 0

1 0 2 2

0 1 2 0

4 2 0 7

3 2 0 0

9 2 0 0

DCTR ¼ duration between cessation of treatment and actual detection of relapse, NON-FDT ¼ treated till smear negativity, FDT ¼ fixed duration treatment, RO ¼ rifampicin and olfloxacin. FINDINGS ON RELAPSE

Duration between cessation of treatment and relapse In this study, the duration between cessation of treatment and detection of relapse could be estimated based only on the actual year of detection. The mean duration between cessation of treatment and relapse (DCTR) for NON-FDT group (n ¼ 24) was 9.7 ^ 3.2 years. For 24 months MB-MDT (n ¼ 11) also it was 9.7 ^ 3.5. For 12 month MB-MDT (n ¼ 6) it was 6.8 ^ 3.9 and for RO cases (n ¼ 11) it was 6.2 ^ 2.4. Of the 18 BL-LL cases where the DCTR was approximately 11– 15 years, 12 were from NON-FDT group. On the other hand, 4/11 RO treated cases and four cases with multiple episodes of T1R in the past had DCTR of less than 5 years.

Histopathology findings The TRIFF stained sections of skin/nerve lesion biopsies obtained from all but two cases (29 and 31) were studied. Histopathological classification done using Ridley Jopling scale showed features of active BL to LL type of leprosy in 39 and BB type of leprosy in 11 cases. These findings were in agreement with clinical classification. In 10 cases, the skin lesion showed T1R and in four cases T2R. It was also noted that eight of them (57%) had episodes of reaction in the past (see Tables 1 and 2).

Bacteriological findings In 39/52 cases (75%) the highest bacteriological index (BI) recorded in the slit skin smears was between 2 þ to 6 þ . In the remaining 13 cases (25%) the slit skin smears scored very low or negative (1 þ in six cases and negative in seven). However, it was noted that in 10/13 (77%) of these cases, the lesional biopsy homogenate, when injected into the footpads showed unequivocal growth, proving the presence of viable M. leprae. Secondly, in two cases (19 and 39), only nerve homogenate scored positive for M. leprae, while in one case (40) who presented with neuritis, nerve biopsy was not done. Thirdly, in all but four cases (10, 23, 25 and 40) the bacteriological index was low (# 2 þ ) even at the onset. Histopathologically all these showed features of active BB (n ¼ 8) and BL (n ¼ 5).

Study of 52 referral MB cases relapsing after MDT

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Mouse footpad test Skin and/or nerve homogenates from a total of 48 cases were tested in the immunocompetent Swiss White mouse footpad for viability. A positive yield in the footpad ($ 1 £ 105 bacilli/footpad) confirming viability were seen in 39/48 (82%) cases. In nine cases, no increase was seen in the footpad, despite of a high bacterial index in the inocula. The possibility of these cases having received some anti-leprosy treatment prior to biopsy could not be ruled out, which could explain failure to grow in immunocompetent mice.11

Discussion A total of 52 BB-LL cases, relapsing after MDT, during the period 1997– 2003, have been investigated in detail. These cases had received different types of MDT. Use of three drug combinations for leprosy was initiated by the Bombay leprosy project [(BLP) our collaborators in this study], in some slums of Mumbai as early as 1977– 1978. Annually, around 50– 60 smear positive cases were enrolled for treatment at BLP. WHO recommended MB-MDT was in wider use in the urban areas of Mumbai since the year 1982, through national leprosy eradication programmes (NLEP). During the year 1983– 1988, BLP enrolled around 214 MB cases into a 24-month fixed duration MB-MDT regimen. Further during the year 1985– 1989, 190 MB cases were enrolled into the 12 months of MB-MDT and during the year 1991– 1995, 56 MB cases were enrolled into RO regimen.14 The majority of cases (70%) under study were referred by BLP. Notably, 28/52 cases (54%) presenting with relapse were MB cases treated with one of the FDT regimens while others had received MDT till smear negativity (NON-FDT). The DCTR varied from 2 years to 15 years. More than one factor seemed to influence the DCTR, i.e. type of leprosy, duration/type of MDT, reaction episodes and the BI. The lepromatous leprosy (BL-LL) cases generally showed longest average DCTR as compared to borderline (BB) and BT cases recorded elsewhere.14 This implies that DCTR and host immune-status are inversely related. Further, it was interesting to note that the NON-FDT and 24 months MB-MDT group of cases had the longest and closely comparable mean DCTR i.e. 9.7 ^ 3. However attaining smear negativity does not rule out relapse. The findings that type of treatment received, its duration as well as the initial BI make an impact on DCTR, is in line with the suggestion of Pattyn et al.,16 that relapse occurs in two phases: inadequate treatment, resulting in poor killing of M. leprae causes early onset relapse, while persisting M. leprae and drug resistant mutants appear to contribute to late onset relapse. Five of the cases under study had shown presence of drug resistant mutants as proved in the mouse footpad (2, 3, 5, 7 and 35). Notably all but one case were from NON FDT group. Case 3 was resistant to all three drugs, case 5 to DDS and RFP, cases 2 and 35 only RFP and case 7 was resistant to only CLF.12 The concentrations of drug used were compatible with high grade resistance. In all these cases DCTR was approximately 7 years. The presence of viable M. leprae documented in 23% of skin and 46% of nerve biopsies of MB cases completing 2 years of MB-MDT.17 and the clinical manifestations of cases under study support reactivation of disease rather than reinfection. In our opinion this is applicable to both low and high BI cases. A relapse rate of 10% has been recorded in a cohort study of 51 LL patients, relapsed after DDS monotherapy, then treated with RO. The relapse had occurred 24.6 ^ 10.5 months after the cessation of

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V. P. Shetty et al.

treatment.18 The cohort study from Cebu shows that the rate of relapse for patients treated with 2 years of MDT MB followed up at skin clinic for $ 12 years and with a pre treatment BI of $ 2.7 þ was 13%. All except one case had become smear negative. Relapse occurred between 6 and 13 years of actual year of detection, seven occurring at $ 10 years. In their study, all the cases were RFP and CLF sensitive, whereas three showed partial to full DDS resistance. In addition, a notable difference in relapse rate was observed in patients attending the Cebu clinic (9%) versus those examined by the field team (3%) suggesting that relapse detection also depends on the expertise involved.5 In our opinion, another factor that seem to influence the incubation time of relapse is the immune status of the patient. The BT and BB cases and patients with multiple episodes of reaction/usage of steroids had shorter incubation time here as well as in our earlier study. In our earlier study, 25 BT cases treated with MDT presented with recurrence of lesion. Viable M. leprae was detected by MFP in 48% (12/25) of cases and had a mean DCTR of 4 ^ 3.2 years.15 A retrospective analysis data of a group of borderline cases treated with DDS monotherapy by Ramu and Desikan19 showed that the incidence of relapse was higher and earlier in reaction cases as compared to non-reaction cases. Since reaction and intake of steroids go hand in hand, the precise role of corticosteroids versus reaction, in affecting the bacterial killing or relapse requires further investigation. The average incubation period for DDS resistant relapse in BL-LL cases, still receiving DDS, was 15.8 years (range 3 –24 years) after the commencement of DDS monotherapy in Malaysia.20 In Ethiopia, it was 8.7 (range 2 –20 years),21 suggesting that environmental and/ or ethnic factors among others, may also be influencing the incubation time.

RELAPSE OR TREATMENT FAILURE

In the present study, undisputed bacteriological positivity was seen in a total of 39 relapse cases (75%). By definition, true MB relapse refers to cases in which a patient becomes skin smear negative during or after the completion of treatment and at some point in time later, deteriorates clinically and turns smear positive.5 While 38 cases under study fulfil this criterion, follow-up smear reports of other 14 cases are not available. In general, BI values are expected to fall by about 1 log per year. A field based study by BLP show that most of the patients of RO trial reached a state of smear negativity over a period of 6 years.14 In the current study, in 9/14 cases, the DCTR was between 6 and 15 years, therefore smears might have turned negative at some point in time. In the remaining five cases where relapse occurred within 5 years of RFT, two had received 12 months MB-MDT, of which one was a BB case and one presented with neuritis. The remaining three RO treated cases (42, 44 and 47) could be termed as cases of inadequate treatment. In 13 cases (25%), the slit skin smear scores were very low (1 þ in six cases and negative in seven) thus do not confer to bacteriological relapse. However, it should be noted that in 10/13 (77%) cases, the lesional biopsy homogenate, when injected into the footpads showed unequivocal growth, proving the presence of viable M. leprae albeit in small numbers. Secondly, in two cases (19 and 39) only the nerve lesions scored positive for M. leprae, while in one case (40) who presented with neuritis, a nerve biopsy was not done. This is consistent with the observed discrepancy between skin and nerve lesions in leprosy.17,22 Thirdly, the histopathological findings in all these cases were consistent with active BB (n ¼ 8) and BL (n ¼ 5) leprosy. Thus the conclusion that they were borderline relapse cases. Indiscriminate use of corticosteroids in these cases may prove to be counterproductive.

Study of 52 referral MB cases relapsing after MDT

251

The histopathological study of lesions on relapse revealed BL-LL leprosy in 39 and BBtype of leprosy in 11 cases. The clinical manifestations and bacteriological index at registration and on relapse were closely comparable in most cases. None of the cases under study revealed any clinical or histopathological evidence of upgrading, i.e. multi to paucibacillary (BL to BT) between registration and relapse. This is in variance from an earlier finding.23 On the other hand, downgrading (BB to BL-LL) was clearly indicated in at least three cases. Thirdly and most importantly, 8/14 (57%), cases who presented with reaction also had episodes of reaction in the past suggesting their intrinsic tendency to demonstrate hyperimmune responses. At least five cases in this study who had received corticosteroids for late reversal reaction could well be cases of relapses presenting with reaction then. A sharp increase in bacteriological index suggesting downgrading was noted subsequently in three cases. To conclude, we firstly endorse the suggestions of Waters2 that 7– 10 years of follow up is optimally required to assess relapse rates in MB cases. Secondly, use of short duration treatment in high BI cases, as control measures24.25 definitely need re-evaluation. The mouse footpad data revealed presence of drug resistant mutants among four NON -FDT and one FDT case.12 Inadequate treatment and usage of corticosteroids that predispose to early relapse can be remedied. Prevention of relapse due to persisting M. leprae and drug resistant mutants, however, would require a different approach.

Acknowledgements Financial support for this study was from Leprosy Mission India and Tata Education Trust, Mumbai. This data, in part, was presented at the Asian leprosy congress held at Agra, India in the year 2000.

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