Late lepromin reaction in untreated patients with indeterminate leprosy under 21 years old in Burma*

Bulil. lOrg.)o~Sd 1973, 48, 113-116Bull. Wld Hlth Org. Late lepromin reaction in untreated patients with indeterminate leprosy under 21 years old in Burma* L. M. BECHELLI,1 P. GALLEGO GARBAJOSA,2 MG MG GYI,3 J. WALTER,' & C. TAMONDONG6 Studies on lepromin reactivity in indeterminate (I) leprosy have usually been carried out amongpatients in whom the disease appeared 1 or more years before testing. This may result in misleadingfindings because a highproportion ofpatients, probably those showing moderate or strong lepromin reactions, seem toprogress to the tuberculoidpole ofleprosy in a relatively short time (<1 year), and in many the lesions heal spontaneously. The object ofthepresent study was to determine the frequency and intensity of late lepromin reactions (macroscopic readings) in untreated Ipatients aged under 21 years who had had the disease for less than 1 year. Of 209 patients tested with lepromin containing 160 x 10" bacilli/ml only a small proportion (> 7 %) showed a negative or doubtful lepromin reaction, while 61.5 % were2+ and3+ reactors. Thesefindings indicate that afavourable outcome may be expected in most I cases in the trial area. The object of this study was to determine the frequency and intensity of late lepromin reactions (macroscopic readings) in untreated patients with indeterminate (I) leprosy aged under 21 years who had had the disease for less than 1 year. Past studies on the lepromin reactivity of patients with I leprosy have usually been carried out in individuals in whom the disease appeared 1 or more years before testing. This may result in somewhat misleading findings. In fact a high proportion of I patients (probably those showing a moderate or strong lepromin reaction) seem to progress to the tuberculoid pole of leprosy in a relatively short time-less than 1 year-and in many the lesions may heal spontaneously. This was observed in the WHO Leprosy BCG Trial area in Burma; spontaneous * Data obtained in connexion with the WHO Leprosy BCG Trial, Burma. Requests for reprints should be addressed to: Chief Medical Officer, Leprosy, World Health Organiza- tion, 1211 Geneva, Switzerland. 1 Formerly Chief Medical Officer, Leprosy, WHO, Gene- va, Switzerland. Present address: Professor of Dermatology, Faculdade de Medicina de Ribeirao Preto, University of SAo Paulo, Brazil. 'Team Leader, WHO Leprosy BCG Trial, Burma. National Counterpart Team Leader, Leprosy Team, Mandalay, Burma. 'Medical Officer, Leprosy, WHO, Geneva, Switzerland. Statistician, WHO Leprosy BCG Trial, Burma. healing of lesions has also been reported by Lara & Nolasco (1956) and Dharmendra (unpublished data, 1966). Thus, when the lepromin test is performed in I cases in which the disease became manifest 1 or more years earlier, the results reflect the reactivity of a preselected sample of patients that has probably been deprived of a high proportion of reactors. To find a sample of I cases in which the duration of the disease does not exceed 1 year, close surveillance of individuals at high risk (household contacts or children and adults living in a hyperendemic area) is necessary. The surveillance of contacts is not easy, and that of part ofa population even more difficult. It may be possible in the course of intensive and prolonged studies. In the WHO Leprosy BCG Trial in Burma, for example, after an initial screening of the child and adult population starting in August 1964, children are reexamined annually; this has been done regularly for 6 years. MATERIALS AND METHODS The materials and methods used were discussed at length in the first report of the WHO Leprosy BCG Trial in Burma (Bechelli et al., 1970). The diagnosis of indeterminate leprosy was made on the basis of clinical examination, type of lesion, 2987 -113 114 L. M. BECHELLI ET AL. impairment of sensation, and histamine test. Because 28 000 children 1 had to be reexamined annually, it was decided not to perform a biopsy on any child. The diagnosis, initially made byP. G. G.,was confirmed by M. M. G. and L. M. B., and by 3 consultants (Dr Qua- gliato, Dr Martinez Dominguez, and Dr Altmann). Since the annual reexaminations took place at 1- year intervals after the initial screening, the duration of the lesions of I leprosy at the time of detection varied from a few days to a maximum of 1 year. Among the 209 cases diagnosed and classified as indeterminate (according to the criteria established by the South American classification and later confirmed at international congresses) a proportion of patients (about 30 %) presented lesions with a possible evolu- tion to the tuberculoid (T) pole of leprosy. In the absence of a histopathological examination and of serial biopsies, these cases were indicated as I- T ?, as described earlier by Bechelli et al. (1970). The lepromin test was performed on the day the cases were detected and read after 28-30 days. The criteria for reading were those proposed by the Committee on Immunology (1959) of the Seventh International Congress of Leprology, Tokyo, 1958, with a slight modification in the definition of a 3+ reaction in line with the recommendations of a group of investigators cooperating with WHO on the standardization of lepromin (see Hanks et al., 1970). The scale is as follows: negative ( - ), no local reaction; doubtful (+), induration <3 mm in diameter; weak positive (1+), frank induration 3-5 mm in diameter; moderate positive (2+), nodular induration 6-10mm in diameter; strong positive (3+), nodule>10 mm in diameter or with ulceration. The lepromin, prepared by Dr M. Abe 2 at the National Institute for Leprosy Research, Tokyo, Japan, contained 160 million bacilli/ml. RESULTS Of the 209 individuals with I leprosy about 40% had been vaccinated with BCG in the initial survey. Because of the differences in lepromin reactivity between the vaccinated and unvaccinated individuals, the results for the 2 groups are shown separately (Table 1). About 6% of all I cases had negative or doubtful 1 Aged 0-14 years at the initial survey; after 6 years of annual follow-up examinations, the oldest children had reached 20 years of age. ' We are grateful to Dr Yoshie and Dr Abe for their assistance. Table 1. Late lepromin reaction in I patients aged less than 21 years, unvaccinated or vaccinated with BCG before the appearance of the disease I patients Lepromin Total reaction Unvaccinated BCG nvaccinae vaccinated -and 8 4 12 + 37 24 61 ++ 24 14 38 + + + 48 50 98 total 117 92 209 Table 2. Late lepromin reaction in I and I-T? patients aged less than 21 years, unvaccinated or vaccinated with BCG before the appearance of the disease. Lepromin I cases I-'TT?cases reaction Un- BCG Un- BCG vaccinated vaccinated vaccinated vaccinated -and 7 4 1 0 + 30 19 7 5 ++ 8 9 16 5 +++ 34 32 14 18 total 79 64 38 28 reactions, 29% had 1 + reactions, and 65% had 2+ or 3+ reactions. There was a higher proportion of strong (3 +) reactors among the vaccinated group but the percentage of 2+ and 3+ reactors combined was similar in the 2 groups; this was also true ofnegative and doubtful reactions and of 1+ reactors. Table 2 compares the results for I and I- T ? cases. In both unvaccinated and BCG-vaccinated I-T? cases there was a tendency to a decrease in the proportion of negative, doubtful, and 1 + reactions, and a consequent increase in that of 2+ and 3+ reactors. DISCUSSION In this study, only a small proportion (4 7 %) of untreated I patients had a negative or doubtful lepromin reaction, even though they were all aged under 21 years. However, the cases had been recently LATE LEPROMN REACTION Table 3. Results of some previous studies of late lepromin reaction in I patients No. Lepromin reaction (% of cases) of cases - and + ++ +++ Rotberg (1944) 182 11.5 24.2 33.4 31.9 Souza Uma & Souza Campos (1948) 216 35.6 20.4 29.2 14.8 Floch & Destombes (1950) 85 54.1 42.3 3.5 0.0 Bechelli et al. (1959) 82 21.8 41.4 26.8 9.7 Quegliato (1959) 85 54.1 22.4 17.6 5.9 Rabello Neto et al. (1963) 75 36.0 35.0 29.0 0.0 detected and many might later evolve to the tuber- culoid type. Taking this into account, it is possible that the findings may accurately indicate the reactiv- ity of I cases. It will be noted that a high proportion (61.5%) of I patients were 2+ and 3+ reactors. The results of some previous studies in each of which more than 501 patients were tested are shown in Table 3. For a number of reasons they are not strictly comparable with the present findings. Most earlier reports have dealt mainly with I leprosy in adults, in whom lepromin reactivity is stronger than in children. The number of patients tested has often been small; the strength of the lepromin used has varied considerably among studies; the reaction has sometimes been read at 21 days instead of28-30 days; and different criteria for classifying the reaction have been applied. In addition, the duration of the disease before testing has differed, and many patients were already being treated. Although a stronger antigen was used in the present study, the findings are similar to those ofRotberg (see Table 3) in Brazil and of a study in Spanish Guinea where out of 317 I patients Martinez Dominguez (1953) reported 5% with negative reactions, 33% with ± and 1+ reactions, and 62% with 2+ and 3 + reactions. The proportion of negative and doubtful reactions may give an indication of the I cases that might evolve to lepromatous (L) leprosy. However, a histological study of the macroscopic reactions would give a better indication. In the study of Bechelli et al. (1959), in which macroscopic and microscopic reactions were correlated, negative macroscopic reactions usually corresponded to a negative histological reac- tion; however, only 8 of 14 ± reactors had a negative histological reaction. Thus a high proportion of doubtful reactors may progress to L leprosy if un- treated. Rotberg (1944) found that 10 of 21 I cases showing negative or doubtful reactions treated with chaulmoogra and followed up for 5-6 years evolved to L leprosy. This progression was observed in 68% of the 60 lepromin-negative I cases followed up by Souza Lima & Souza Campos (1948) for 5-10 years. Bechelli et al. (1959) found that 18% of I patients with 1 + or 2+ reactions were microscopically nega- tive (without the tuberculoid or tuberculoid-like structure). In Rotberg's study (1944) 11 of 44 1+ reactors evolved to L leprosy while none of 59 2+ reactors did so. As a term of reference, the results of the lepromin test in 319 T cases detected in the same trial were as follows: - and + reactions, 14 (4.4%/); 1+, 89 (27.9%); 2+, 56 (17.5%); and 3+, 160 (50.2%). It appears that there was a higher percentage of 3+ reactions in T cases, but the proportion of 2+ and 3+ reactions combined (67.7 %) was only slightly higher than in unvaccinated I cases (61.5%). The difference in negative and doubtful reactions was also small. The findings on the lepromin reactivity of I cases indicate that a favourable outcome of the disease may be expected in most of the cases in the trial area. In addition, some negative or doubtful reactors may change in the course of time, as in the healthy population the frequency and intensity of the reaction tend to increase with age. However, in spite of aging and of treatment with sulfones (which some believe could also strengthen the lepromin reaction) there is a small percentage of I patients who are expected to remain nonreactors. In this group are found the patients more prone to develop L leprosy. Neverthe- less, as Souza Lima & Alayon (1941) stated, some I patients with persistent negative reactions have evolved to T leprosy. 115 116 L. M. BECHELLI ET AL. RECSUMt REACTION TARDIVE A LA LEPROMINE CHEZ DES MALADES DE MOINS DE 21 ANS ATTEINTS DE LtPRE INDETERMINEE ET NON TRAITES, EN BIRMANIE La presente 6tude, men6e dans le cadre de l'essai OMS de prevention de la lepre par le BCG, en Birmanie, visait a determiner la frequence et I'intensite des reac- tions tardives A la lepromine chez des sujets de moins de 21 ans atteints de lepre indeterminee (I) depuis moins d'un an et non traites. Le diagnostic de lepre indeterminee a ete pose chez 209 malades. Le jour meme du diagnostic, on a pratique un test a la l6promine en utilisant un antigene contenant 160 x 106 bacilles par millilitre. La lecture (macrosco- pique) a ete faite apres 28-30 jours, en adoptant les criteres, l6gerement modifi6s, proposes par le comite d'immunologie du VIe Congres international de la lepre (Tokyo, 1958). Moins de 7% des cas de 1epre I non vaccines par le BCG avant I'apparition de la maladie presentaient une reaction negative ou douteuse, 31,6% une reaction 1+ et 61,5% une r6action 2+ ou 3-'-. Aux fins de comparaison, on signale que dans un groupe de 319 malades atteints de lepre tuberculoide (T) les chiffres correspondants etaient de 4,4%, 27,9% et 67,7%, soit un pourcentage plus 6leve de r6actions fortes (3+), mais une proportion tres voisine de reactions negatives, douteuses ou 1+. Parmi les cas de lepre I vaccines par le BCG avant l'apparition de la maladie, on notait une plus forte proportion de reactions fortes (3+) que chez les malades non vaccin6s; la proportion des sujets presentant des reactions 2+ et 3+ et celle des sujets A reactions n6ga- tives, douteuses ou 1+ etaient assez semblables A celles observees chez les sujets non vaccines. Dans les cas de lepre indetermin6e ou se manifestent des indices d'une evolution vers la lepre tuberculoide (cas I-+T?), il semble y avoir une proportion moindre de r6actions negatives, douteuses et 1+, et par conse- quent une augmentation des reactions 2+ et 3+. REFERENCES Bechelli, L. M. et al. (1959) Rev. bras. Leprol., 27, 172-182 Bechelli, L. M. et al. (1970) Bull. Wid Hlth Org., 42, 235-281 Committee on Immunology (1959) The lepromin reaction. In: Transactions of the Seventh International Congress of Leprology, 1958, Tokyo, pp. 463-466 Floch, H. & Destombes, P. (1950) Rev. bras. Leprol., 18, 181-185 Hanks, J. H. et al. (1970) Bull. Wld Hlth Org., 42, 703-709 Lara, C. B. & Nolasco, J. 0. (1956) Int. J. Leprosy, 24, 245-263 Martinez Dominguez, V. (1953) Estudio epidemiologico y clinico de la endemia de lepra en la Guinea Espaniola. In: Memoria del VI Congreso Internacional de Lepro- logia, 1953, Madrid, pp. 1104-1204 Quagliato, R. (1959) Rev. bras. Leprol., 27, 17-32 Rabello Neto, A. et al. (1963) Evolupdo dos casos do grupo indeterminado tratados no dispensario de " Nova Ignafu", no periodo de 1949 a 1960. In: Anais do VIII Congreso Internacional de Leprologia, 1963, Rio de Janeiro, vol. 1, pp. 449-479 Rotberg, A. (1944) Rev. bras. Leprol., 12, 367-377 Souza Lima, L. de & Alayon, F. L. (1941) Sobre a significapao patologica das les5es incaracteristicas (ma- culares simples), Sao Paulo, Departamento de Profi- laxia da Lepra do Estado de S3o Paulo (5.a Mono- grafia do Arquivos do Sanatorio " Padre Bento ") Souza Lima, L. de & Souza Campos, N. de (1948) Int. J. Leprosy, 16, 9-22