Risk-benefit assessment of Bacillus Calmette-Guérin vaccination, anti-phenolic glycolipid I serology, and Mitsuda test response: 10-year follow-up of household contacts of leprosy patients

Abstract: INTRODUCTION: Despite multidrug therapy, leprosy remains a public health issue. The intradermal Bacillus Calmette-Guérin (BCG) vaccine, Mitsuda test (lepromin skin test), and anti-phenolic glycolipid I (PGL-I) serology are widely used in leprosy studies and have shown great epidemiological value. METHODS: This longitudinal study evaluated the relative risks and benefits of these three tools by comparing results observed in household contacts (HHCs) of leprosy patients who developed leprosy with those of HHCs who did not in a population of 2,992 individuals monitored during a 10-year period. RESULTS : Seventy-five (2.5%) new leprosy cases were diagnosed, including 28 (0.9%) co-prevalent cases. Therefore, for the risk-benefit assessment, 47 (1.6%) HHCs were considered as truly diagnosed during follow-up. The comparison between healthy and affected contacts demonstrated that not only did BCG vaccination increase protection, but boosters also increased to 95% relative risk (RR) reduction when results for having two or more scars were compared with having no scars [RR, 0.0459; 95% confidence interval (CI), 0.006-0.338]. Similarly, Mitsuda reactions >7mm in induration presented 7-fold greater protection against disease development compared to reactions of 0-3mm (RR, 0.1446; 95% CI, 0.0566-0.3696). In contrast, anti-PGL-I ELISA seropositivity indicated a 5-fold RR increase for disease outcome (RR, 5.688; 95% CI, 3.2412-9.9824). The combined effect of no BCG scars, Mitsuda reaction of <7mm, and seropositivity to anti-PGL-I increased the risk for leprosy onset 8-fold (RR, 8.109; 95% CI, 5.1167-12.8511). CONCLUSIONS: The adoption of these combined assays may impose measures for leprosy control strategies.

Infection by Mycobacterium leprae of household contacts of lepromatous leprosy patients from a post-elimination leprosy region of Colombia

The Leprosy Control Program of Antioquia, (post-elimination leprosy state of Colombia), had registered by 1999, 56 lepromatous leprosy patients and their household contacts (HHC). Our interest was to detect Mycobacterium leprae infection in these HHC. Clinical examination, acid-fast bacillary staining (AFB) in nasal secretions, and slit skin samples, IgM anti-PGL-I in serum and Lepromine A (Mitsuda) reactivity were tested. Two hundred forty eight HHC were studied, 49 percent were male. After clinical examination, two HHC were diagnosed as multi bacillary patients; 13 percent showed positive IgM anti-PGL-I titers; Mitsuda reaction (> 4 mm) was positive in 59 percent; AFB was negative in all samples, except in the two new patients. HHC were classified according to test results.Group 1: two new multi bacillary patients. Group 2: 15 HHC seropositive, Mitsuda-negative. Group 3: 13 HHC seropositive, Mitsuda-positive. Group 4: 130 HHC seronegative, Mitsuda-positive. Group 5: 88 HHC seronegative, Mitsuda-negative. These results are an indication that the transmission of the infection is still happening in a region considered in the post elimination phase. The two new patients represent an infection source for others contacts, and groups 2 and 3 are infected HHC that could develop the disease in future. Follow up of high risk population is necessary to achieve real elimination of leprosy.

Reactions in borderline leprosy.

This is a retrospective study of 276 patients consisting of 157 active and 119 reactive patients of borderline leprosy. They were followed up for 10 years after sulphone monotherapy. The presenting symptoms were carefully examined from the records and systematically presented. Frequency of reactions was least in BT cases and most in BL cases. Risk factors of reaction appear to be the type of leprosy, multiplicity of lesions, high BI and, possibly, psychological stress. Biopsy of skin lesions was performed in all cases initially, and at the subsidence of the disease. Histological findings closely correlated with clinical classification. While all the cases showed clinical subsidence, histological subsidence was found in 200 (73%) cases, and the condition was static in 36 cases (13%). Immunological upgrading was seen in 110%, while 4% showed downgrading. Bacteriological status and lepromin reaction of active and reactive cases were compared. All these factors need to be taken into consideration for instituting prompt and proper treatment.

Correlation of clinical, histological and immunological features across the leprosy spectrum.

The Ridley-Jopling system of classification of the variegated clinical pattern of leprosy is based on the specific cell-mediated immunity observed in the histopathology of skin lesions conforming to a spectrum from TT at one end to LL at the other. In this study a fairly large sample of 90 patients was classified on clinical grounds; the histopathology of the skin lesions was studied blind. There was an overall concordance of 90% between the clinical and histological classifications. In addition, the systemic cell-mediated and humoral immune responses were studied. The in vivo cell-mediated immune response, namely the Mitsuda skin response, mostly conformed to the clinical classification. While the in vitro lymphoproliferative responses to BCG and its sonicate were high, the lymphoproliferative responses to Dharmendra lepromin were surprisingly poor. Humoral responses to 35 kDA protein of M. leprae and PGL-1 were good in most LL, BL patients and tapered off towards TT. IgG antibodies to recombinant ML 65 kDa proteins denoted mycobacterial presence.

Estudo da relaçao entre os níveis de anticorpos anti-PGL-I e o quadro histopatológico da reaçao de Mitsuda / ?

Estudou-se a reaçao de Mitsuda e os títulos de anticorpos IgM anti-PGL-I em 44 doentes com diagnóstico de hanseníase: 10 casos tuberculóide-tuberculóide, 11 casos dimorfo-tuberculóide, 5 casos dimorfo-dimorfo, 18 casos dimorfo-virchowiano e virchowiano-virchowiano. A reaçao de Mitsuda foi avaliada do ponto de vista clínico, histológico e imunohistoquímico. Os títulos de anticorpos IgM anti-PGL-I foram mais elevados em doentes multibacilares em comparaçao aos paucibacilares e indivíduos normais. Os doentes paucibacilares apresentaram leitura clínica e histológica da reaçao de Mitsuda maior comparando-se com doentes multibacilares, obedecendo ao espectro imunológico da doença. Os elementos celulares marcados pelos anticorpos anti-CD4 e CD8 na reaçao de Mitsuda nao mostraram diferença dentro do espectro da doença

Sensitization and reactogenicity of two doses of candidate antileprosy vaccine Mycobacterium w.

M.w vaccine is one of the antileprosy vaccines under test in an ongoing comparative vaccine trial in South India. The objective of the present study was to examine the sensitizing ability, as measured by skin test reactions to Rees' MLSA and lepromin, and reactogenicity of M.w vaccine in the local population. Two doses of M.w, 1 x 10(9) bacilli and 5 x 10(9) bacilli, were used, in two separate studies of 395 and 400 "healthy" individuals aged 1-65 years. In each study, the study subjects received either M.w vaccine or normal saline (control), by random allocation. The results showed that healing of vaccination lesions was uneventful although the healing process was somewhat prolonged with the higher dose. The mean size of lesions was 7.0 mm and 9.5 mm with the low and high doses of the vaccine, respectively. The results also showed that M.w vaccine in a dose of 1 x 10(9) bacilli, failed to induce post-vaccination sensitization as measured by reactions to Rees' MLSA and by Fernandez and Mitsuda reactions to lepromin-A. However, when the dose of the vaccine was increased to 5 x 10(9) bacilli the mean sizes of post-vaccination reactions to Rees' MLSA and lepromin-A (both early and late) were significantly larger in the vaccine group compared to that in the control group. The sensitizing effect attributable to the vaccine was of the order of 1.5 mm to 1.8 mm.

Induction of lepromin positivity by a candidate anti-leprosy vaccine Mycobacterium w in lepromin negative healthy contacts of multibacillary leprosy patients.

In a hospital based study, 362 household contacts of multibacillary leprosy patients were screened for evidence of leprosy and 54 (14.9%) were found to be having leprosy. The remaining 308 apparently healthy contacts were lepromin tested and 109 (35.4%) were observed to be negative to Mitsuda lepromin. M.w vaccine was administered intradermally to 95 of these 109 lepromin negative contacts. Sixty eight of them could be retested for lepromin A reactivity. Fifty six (82.35%) manifested lepromin conversion. The twelve subjects who did not show lepromin conversion, received a second dose of the vaccine, and eleven subsequently became lepromin positive. The overall lepromin conversion rate was thus 98.5% (67 out of 68). Follow-up of these contacts upto a period of 30 months did not demonstrate reversion of lepromin positivity back to negativity status. No untoward effects of vaccination were observed except for local ulceration at the site of vaccine administration.

Filter paper blood spot test for detection of anti-ND-BSA antibodies in school children.

For identifying individuals at 'high risk' for developing leprosy, a simplified technique of collection of blood samples on filter paper for detection of anti -ND-BSA antibodies, was optimised. Anti-ND-BSA antibody reactivity on the filter paper was lost on storage at room temperature, but was stable at least for a period of 8 wk at lower temperature. Among the 1495 children screened, 166 (11.1%) were lepromin negative and 122 (8.2%) positive for anti-ND-BSA antibody. In the first phase, 7 of 871 children followed up for 2 yr developed leprosy, while in the second phase 2 of 624 children followed-up for 9 yr developed leprosy. The positivity and negativity of anti-ND-BSA antibodies and lepromin in these I children indicate that the positive status for anti-ND-BSA antibodies has a better predictive value than negative lepromin reactivity. Measurement of anti-ND-BSA antibodies was also of value for monitoring the efficacy of therapy and course of the disease. Extrapolation of the two tests to the total population of children evaluated showed that an individual with negative lepromin reactivity along with presence of anti-ND-BSA antibodies is at a higher risk for developing leprosy than those who have both the tests normal. Lepromin reactivity alone was not of much value for the prediction for development of the disease. However, the presence of anti-ND-BSA antibody was a better indicator for the development of the disease. The probability of developing leprosy in a child with any one of the tests abnormal was higher as compared to a child having all the tests normal.

The pathogenesis of leprosy in the nine-banded armadillo and the significance of IgM antibodies to PGL-1.

Twenty-seven nine-banded armadillos captured from the wild and tested free of wild M. leprae infection were distributed into four groups. They were injected at the right hind footpad with saline suspensions of M. Leprae at doses of 10(3), 10(4), 10(5) and 10(6). PGL-1 antibody levels were estimated using an ELISA test, twice during six months before the infection and every two months after the infection. One animal from each group was sacrificed at 6, 12, 18, 24, and 30-month intervals and another eight at unspecified intervals. A thorough autopsy and histopathological examination were conducted on all of them. Of the 27 animals, 18 developed the infection. In 10, there were granulomas at the site of inoculation and in 17 the regional lymph nodes were infected. The disease spread extensively to other lymph nodes and to the liver and spleen and then to the other organs. Peripheral nerves were invaded by M. leprae in only five animals. PGL-1 antibody levels registered a positive reading in only six of the 18 animals with the infection. In armadillo leprosy, the lesions did not persist at the site of entry in all animals M. leprae multiplied in the macrophages at the site of inoculation and the reticuloendothelial cells of the lymph nodes before they spread to other organs. There was evidence of invasion of endothelial cells of capillaries and possible bacteraemia even at an early phase of the infection. Peripheral nerves were not the preferred sites of entry or multiplication of M. leprae. Progressive increase in PGL-1 antibodies was recorded in five lepromatous armadillos with disseminated infection and high bacterial load. However, PGL-1 antibodies response was not sensitive enough to detect early disease.

Subsídios conceituais sobre hanseníase e estados reacionais / Conceptual subsidies about hanseniasis and reactional status

Os autores fazem uma revisäo histórica da hanseníase e sua magnitude no Brasil. Apresentam revisäo atualizada da imunopatia, genética e suas expressöes clínicas na classificaçäo, dando especial enfoque a seus conceitos sobre hanseníase virchowiana e os estados reacionais qeu nela incidem

Leitura clínica e histológica da reaçäo de Mitsuda em comunicantes consanguíneos e näo consanguíneos de pacientes com formas bacilíferas da hanseníase / Clinical and histologic reading of the Mitsuda reaction in consanguineous and non consanguineous contacts of patients with bacilliferous forms of leprosy

Testes de Mitsuda avaliados clínica e histologicamente foram realizados em 17 consanguíneos próximos e em 23 näo consanguíneos que eram comunicantes sadios e pacientes com as formas bacilíferas da hanseníase. A proporçäo de reaçöes histologicamente negativas entre os comunicantes consanguíneos (35,3 por cento) foi significantemente maior do que a observada entre os comunicantes näo consanguíneos (8,7 por cento). Reaçöes de Mitsuda clinicamente positivas (3) e duvidosas (1) sem correspondência histológica foram encontradas entre os comunicantes consanguineos, mas näo entre os comunicantes näo consanguineos de hansenianos. Esses dados indicam que uma reaçäo de Mitsuda positiva somente pode ser atribuída a comunicantes consanguíneos de pacientes com as formas bacilíferas da hanseníase se ela tiver comprovaçäo histológica

ELISA & lepromin skin tests in household contacts of leprosy patients.

A total of 438 household contacts of leprosy patients and 228 non-contacts were studied for anti-PGL-I antibodies and cell mediated immune response to Mycobacterium leprae using ELISA and lepromin tests. The contacts showed relatively higher positivity to ELISA (29.4%) and lepromin (70.5%) as compared to non-contacts who showed 9.6 and 57 per cent positivity. In contacts as well as non-contacts the seropositivity was not found to be influenced by age and sex. However, seropositivity was higher (39.7%) in the contacts of patients with multibacillary leprosy as compared to contacts (27.7%) of patients with paucibacillary leprosy.

Histogenic differentiation of polar tuberculoid granuloma and the "benign" or "malignant" behaviour of hanseniasis

Com base em um novo conceito morfológico e classificaçäo de inflamaçäo granulomatosa: os granulomas polares, na histogênese do granuloma tuberculóide de teste Mitsuda positivo e na relaçäo entre o grau de diferenciaçäo histogenética e comportamento de tumores, os autores concluiram que o comportamento "benign" ou "maligno" da hanseníase depende do grau de diferenciaçäo tuberculóide das lesöes. Se a lesäo é histologicamente bem diferenciada em direçäo a um granuloma polar tuberculóide (hanseníase tuberculóide), ela terá um comportamento "benigno". Ao contrário, se esta diferenciaçäo for ausente (hanseníase virchoviana) ou pobre (hanseníase interpolar), o comportamento da lesäo será "maligno"

Eficácia da MDT no tratamento de pacientes hansenianos paucibacilares: resultados preliminares / Efficacy of multidrug therapy in treatment of paucibacillary leprosy patients: preliminary results

A avaliaçäo da eficácia dos regimes poliquimioterápicos recomendados para pacientes hansenianos paucibacilares pela OMS, é feita principalmente pelo adequado acompanhamento dos pacientes após a alta terapêutica. O critério para inclusäo de pacientes como paucibacilares, é outro ponto de importância. Os autores baseados no seguimento de 66 pacientes que completaram o tratamento e na ausência de recaídas até o momento, recomendam que sejam levados em consideraçäo junto com a classificaçäo clínica, fatores como: teste de Mitsuda, p número de lesöes, e o resultado do exame baciloscópico

Detection of subclinical infection in leprosy: an 8 years follow-up study.

A follow-up study has been carried out using Fluorescent Leprosy Antibody Absorption (FLA-ABS) test in 1069 healthy contacts of multi and pauci-bacillary leprosy patients. Simultaneously lepromin testing with Dharmendra antigen has also been done to determine their delayed type hypersensitivity. In nearly 8 years of follow-up, 46 contacts have developed disease and of these 41 contacts were FLA-ABS positive and lepromin negative. It is inferred that test (along with lepromin) can be used to identify the contacts who are at higher risk of developing the disease. FLA-ABS test has also been found to be highly sensitive for detection of subclinical infection specially in younger age groups. This test could therefore serve as a very sensitive epidemiological tool for assessing the extent of disease in the community and for monitoring the transmission of disease especially after MDT and other intervention measures.

The post-lepromin scar and its significance in the control of HD.

In the past little attention has been paid to the post-lepromin scar (PLS) and its use in controlling Hansen's disease (HD), particularly in the prognosis, classification and measurement of CMI response. The immuno-information of the Mitsuda reaction is thought to be informative only in the extreme range of 10 + mm or in its absence. Previous studies have shown that the range of PLS formation increases proportionally to the degree of lepromin positivity. PLS positive HD patients have a stable form of the disease with good prognosis. Those unable to form a PLS have a marked tendency to downgrade towards the lepromatous form of HD. PLS formation appears to indicate a CMI response to M. leprae implying immunity. It is thought that there exists a correlation between the PLS and the lymphocyte transformation test (LTT), both reaching their optimum measurement three months after the M. leprae injection, either with lepromin or M. leprae suspension used for the anti-HD vaccine. It is proposed to study the use of the PLS in HD control programs on a trial basis with the objective of its general introduction as part of the management of HD control. Considerable improvements in the prognosis, classification and application of treatment can be expected from such a measure. The discovery of the armadilo as a source of M. leprae by Kirchheimer and Storrs facilitates the availability of lepromin A and its purified version, lepromin Ap. The relevant studies have shown that a 40 M/bact/ml lepromin A suspension should be used for the application of lepromin in control programs.(ABSTRACT TRUNCATED AT 250 WORDS)