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Indian Journal of Dermatology, Venereology and Leprology, Vol. 75, No. 2, March-April, 2009, pp. 126-135 Review Article Relapse in leprosy Kaimal Sowmya, Thappa DevinderMohan Department of Dermatology and STD, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry - 605 006 Code Number: dv09039 Abstract Leprosy is unique in terms of the nature of the causative organism (Mycobacterium leprae), the chronicity of the disease, its prolonged treatment and the definitions of "cure" and "relapse." The principal mode of assessing the efficacy of therapeutic regimens in leprosy is the "relapse rate." There are wide variations in estimates of relapse rates after the World Health Organization (WHO) multidrug therapy in different regions. The important predisposing factors for relapse include the presence of "persister" bacilli, monotherapy, inadequate/irregular therapy, presence of multiple skin lesions/thickened nerves and lepromin negativity. The conventional methods of confirming activity or relapse in an infectious disease (demonstration and/or culture of the etiologic agent) have limited utility in leprosy because of the difficulty in demonstrating bacilli in paucibacillary (PB) cases and absence of a method 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.Keywords: Leprosy, reactivation, reinfection, relapse, resistance Introduction Relapse of diseases, acute or chronic, caused by bacterial infections is quite common. Usually, relapse indicates a failure to treat the infection thoroughly, which is compounded by irregular treatment, particularly in chronic disease. The treatment of leprosy, compared with other infectious diseases, is unique in terms of the fixed dose and duration of regimens and also in terms of the definition of "cure." Often, termination of treatment is based on completion of the recommended duration of treatment rather than disappearance of clinical signs and symptoms, which led to initiation of treatment in the first place. Thus, the principal mode of assessing the efficacy of the therapeutic regimens in leprosy is the "relapse rate." A very low relapse rate over an adequate period of observation indicates that the regimen used has been effective and this is why prolonged periods of surveillance are recommended by the World Health Organization (WHO) for all patients who have been declared "cured" after receiving multidrug regimens. Definition The definition of "relapse" can be understood only in the context of the definition of "cure." In the era of Dapsone monotherapy, a patient with multibacillary (MB) disease was declared "disease arrested" when skin lesions resolved and when 3 monthly consecutive skin smears were negative for acid-fast bacilli (AFB), after which antileprosy treatment was continued for another 5-10 years or even a life time. A paucibacillary (PB) patient was declared "disease free" when all skin lesions resolved, with no infiltration and no erythema and the nerves were no longer painful or tender, after which antileprosy treatment was continued for 3-5 years. [1] With the advent of multidrug therapy (MDT), such rigid clinical criteria for cure have lost their importance. A leprosy patient is defined by the WHO as one who is found to have signs and symptoms of the disease and who requires chemotherapy. As of 1995, WHO recommends 1 year of MDT for MB patients (12 pulses in 18 months) and 6 months (six pulses in 9 months) for PB patients. At any point in time during therapy, the patient should have ingested two-third of the pulses till that time. For operational purposes, once a patient receives adequate chemotherapy, he is considered "cured." Histopathological resolution of the lesions and clinical subsidence of the disease take place months to years after antileprosy treatment is stopped. Several definitions have been proposed for relapse in leprosy. [1]
Relapse Rate There are wide variations in estimates of relapse rates in different regions. This is probably due to variations in the definition of relapse, proportions of previously dapsone-treated and untreated patients, range of skin smear positivity in MB cases and differing durations of follow-up. The risk of relapse is very low, both for PB and for MB patients after completion of MDT, and this is at least 10 times lower than with dapsone monotherapy. [1] The WHO has estimated a risk of relapse of 0.77% for MB and 1.07% for PB patients 9 years after stopping MDT. Various other studies using person-years of observation estimate relapse rates varying from 0.65 to 3.0% for PB and 0.02 to 0.8% for MB leprosy. [1] A retrospective study of data from the Central Leprosy Teaching and Research Institute, Chengalpattu, Tamil Nadu, included 3248 leprosy patients who completed the WHO MDT during the period 1987-2003. [5] The overall relapse rates for MB and PB leprosy were 0.84 and 1.9%, respectively, whereas the rates for person-years of follow-up were 0.86 and 1.92/1000, respectively. The majority of relapses occurred in the first 3 years after release from treatment. If an individual does not relapse within the first 5-6 years, his/her risk of relapsing is negligible. In a recent retrospective analysis of the relapse rate in China after 24 months of WHO MB-MDT for 2374 MB patients who were followed-up for a mean duration of 8.27 years per patient, five patients with relapse were identified with an accumulated relapse rate of 0.21/1000 person-years, which is quite low. [6] Surprisingly, there were no confirmed relapses in 502 patients who completed fixed-duration MDT in the AMFES (ALERT MDT Field Evaluation Study) cohort, a descriptive study of leprosy in Ethiopia, [7] in a follow-up period of up to 8 years after completion of treatment, even in the 57 cases with an initial average BI > 4.0, 20 of whom have been followed-up for more than 5 years after ceasing MDT. This again indicates that the relapse rate after MDT is low. Microbiological Aspects The conventional method of confirming activity or relapse in an infectious disease is demonstration and/or culture of the etiologic agent. These methods unfortunately have limited utility in leprosy because of the difficulty in demonstrating bacilli in PB cases and absence of a method of in vitro cultivation of M. leprae . Unlike PB leprosy, where the criteria for relapse depend heavily on clinical features, bacteriological parameters are useful in MB leprosy. Reappearance of positivity for AFB after the case has become negative has been considered as a feature of relapse in both PB and MB cases. Persisting high BI or increase in BI are also important parameters for diagnosing relapse in MB leprosy. BI persisting at the same level, an increase in BI of 2+, appearance of active lesions with high BI or BI becoming greater than what it originally was in the pre-existing lesion are some of the criteria for diagnosing relapse. However, an increase in BI of even 1+ should be considered as adequate supporting evidence for diagnosing relapse in patients who had earlier become negative or were showing a downward trend in BI after MDT. [8] A number of in vivo and in vitro techniques are available for monitoring the progress of treatment in leprosy, which can also be used as additional objective criteria for confirming relapse. In vivo techniques that measure viability include the use of mouse foot-pads for cultivation of M. leprae . In vitro measures of viability include morphological index, fluorescent diacetate ethidium bromide (FDA-EB) staining, laser microprobe mass analysis (LAMMA), adenosine triphosphate measurements and macrophage-based assays. Molecular techniques include DNA and RNA targeting probes and gene amplification by polymerase chain reaction (PCR). [8] A study conducted at the Schieffelin Leprosy Research and Training Center, Karigiri, India, tested biopsy samples of lepromatous patients who completed 12 and 24 months of MB-MDT for viable M. leprae by mouse foot-pad inoculation. [9] None of the skin or nerve biopsies from patients who completed 24 months of MDT showed any growth whereas a small percentage (3.3%) of patients with a high BI were found to harbor viable bacteria in the skin after 12 doses of MDT. These patients need to be followed-up for a longer period to ascertain whether or not they will relapse. Immunologic Tests for Relapse 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. Lepromatous patients show a significant rise in titer of phenolic glycolipid (PGL) immunoglobulin (Ig) M antibodies during the time of relapse. Tuberculoid (TT)/borderline tuberculoid (BT) cases who relapse to borderline lepromatous (BL)/lepromatous lesion (LL) types may be detected by measuring anti-PGL-1 and anti-35 kD antibodies. [10] The dipstick assay for detection of anti-PGL-1 antibodies has been used as a simple tool for classification of patients and for identification of those patients who have an increased risk of relapse. [11] The natural disaccharide ND-O-Bovine serum antigen (BSA) enzyme-linked immunosorbent assay (ELISA) (ELISA using the ND of the phenolic glycolipid antigen of M. leprae linked to BSA as antigen) is another useful test both for screening for early infection with M. leprae and for predicting a relapse, particularly in cured MB patients. [12] It may be possible to differentiate reinfection from relapse by molecular typing of M. leprae , based on amino acid sequencing as well as to identify relapse at a very early stage using nucleic acid amplification techniques such as PCR. [10] Histopathology Regular skin biopsies and skin smears, at least once in 6 months, from representative lesions should be studied during the period of treatment and the following 5 years after achieving negativity. Histopathology of relapsed lesions in MB leprosy [13] Occasionally, there is infiltration by polymorphs and it is also not uncommon to see LL patients relapsing with upgrading reactions in the form of BL or, rarely, BT lesions. Lesions of BL resolve much faster than polar LL cases and become bacteriologically negative much earlier. Histopathologically, BL lesions leave behind a few focal collections of mononuclear cells around the skin adnexa and foam cells are not usually seen. Relapses in BL manifest as LL, BL or, rarely, as BT. Histopathology of relapsed lesions in PB leprosy [13] The difficulty that arises in PB cases is the differentiation of relapse from reaction. Features that suggest a reaction include edema around the granuloma, dilated lymphatics and proliferating fibroblasts throughout the dermis. A true relapse can be detected histopathologically only after recording complete histological resolution of the lesion, which may take years. Relapse indicates that the bacilli have survived despite antileprosy therapy and have multiplied and released antigens to produce fresh granulomas. This manifests as the appearance of solid-staining organisms inside the fibrosed nerve bundles (where there were none earlier) and the reappearance of a granuloma at the site of the original lesion. This granuloma usually begins as a small focus of lymphocytes and epithelioid cells, which often starts in fibrosed nerve bundles or arrector pili muscle cells. Once the granuloma becomes well established, it grows and involves large portions of the dermis, becoming indistinguishable from the original lesion. Therefore, in PB patients, regular 6-monthly biopsies showing disappearance of the granuloma will confirm "cure" and reappearance of the granuloma will identify "relapse." Rarely, PB cases will relapse as MB, and this is usually due to misdiagnosis of the spectrum of disease and the resultant inadequate treatment in the first place. Relapse Interval Relapse interval is otherwise known as incubation period of relapse. [14] It is different with monotherapy and MDT. Fifty-five to 57% of relapses occurred within
Predisposing Factors for Relapse[14] Persisters Inadequate therapy Irregular therapy Monotherapy High initial BI Number of skin lesions and nerves Lepromin negativity Human immunodeficiency virus (HIV) infection Age: In MB cases, relapse is more common in the older age groups. PB leprosy with single skin lesions is more common in younger age groups and relapse is less common in this group. Sex: Relapses are more common in males, possibly because of the higher prevalence of leprosy in males. Relapses are seen in females in the setting of pregnancy and lactation. Relapse in PB leprosy
Differential Diagnosis Differences between erythema nodosum leprosum (ENL) and relapsed fresh papules and nodules [14] Papules and nodules that occur as part of relapse in the MB spectrum should be differentiated from ENL nodules. The most important point of difference is that ENL nodules are tender and evanescent, unlike lepromatous nodules. Additional differences are listed in [Table - 1]. Differences between reversal reaction and relapse Relapse vs. resistance Relapse vs. reactivation Relapse vs. reinfection Diagnosis The diagnostic criteria for relapse are: [10],[14] Clinical criteria
Bacteriological criteria Therapeutic criteria Histopathological criteria Serologic criteria The first three criteria are sufficient to make a diagnosis of relapse; criteria 4 and 5 are additional and may be used wherever facilities are available. Treatment Relapsed cases of leprosy should be identified and put back on chemotherapy as soon as possible to prevent further disability and transmission of infection. [17] Factors that should be considered in choosing an appropriate regimen are:
Type of leprosy Previous therapy
Drug resistance Although drug resistance ideally is determined using the mouse foot-pad or other techniques, relatively few leprosy centers have such a facility available. Thus, the decision on drug resistance most often is based on clinical information alone. Recommended treatment regimens are given in [Table - 4]. Failure to respond to therapy The WHO defines a "satisfactory result from MDT" in a patient who complies with treatment as - one in which, after the start of therapy, bacilli begin to clear in MB cases and lesions generally, although not necessarily, rapidly improve in both PB and MB cases. Clearance of lesions is related more to the patient′s immune response than to antileprosy treatment; all lesions and bacilli should eventually clear even though clearance may be incomplete at the time treatment is discontinued. [17] MDT regimens being used in the United States [Table - 5] are more robust than the ones being recommended in developing countries by the WHO. Although studies show that relapse rates are very low after WHO MDT, the fact remains that relapses do occur. There is a possibility that more relapses in leprosy may develop if the WHO accepts uniform MDT. Unfortunately, it is not practical to introduce regimens like those in the United States on a large scale in a resource-poor setting like India. However, clinicians may use their judgement and tailor treatment regimens for individual patients wherever practicable. In selected cases, longer regimens similar to those used in the United States may be useful.[18] References
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