A clinical trial of ethionamide and prothionamide for treatment of lepromatous leprosy.

In 1982-1984 we conducted a six-month clinical trial in 50 previously untreated lepromatous leprosy patients randomly assigned to directly observed monotherapy with one of two thioamides, ethionamide or prothionamide, each given six times a week at doses of either 250 mg or 500 mg. The findings of this study have only recently been analyzed, and the potential for the use of these thioamides in leprosy patients placed in perspective. However, because of the small number of patients included in this study, the results must be interpreted with some caution. Clinical improvement was noted in 74% of the patients treated with ethionamide and in 83% of those treated with prothionamide. Therapy was well tolerated and drug-related hepatotoxicity did not require discontinuation of therapy. The 500-mg dose of both ethionamide and prothionamide resulted in loss in Mycobacterium leprae viability more rapidly than did the 250-mg dose, and prothionamide at both dose levels was superior to the equivalent dose of ethionamide. Overall killing of M. leprae in this study was found to be similar to that obtained previously with dapsone and clofazimine, but less than was obtained with rifampin, minocycline, clarithromycin, pefloxacin, and ofloxacin.

Leprosy and fertility

There is evidence that infection with Mycobacterium leprae lowers fertility of some leprosy patients. To test this hypothesis age-specific birth rates of leprous and healthly individuals were compared in a completely ascertained Philippine population in which leprosy is endemic. The fertility of lepromatous males and females after, but not before, and of females during the five-years preceding the onset of leprosy was significantly lower than that of the healthly population. these differences were not seen when the fertility of those with tuberculoid leprosy was compared with that of the healthly population. The implications of these findings for discovering causes and significance of reduced fertility of male and female victims of lepromatous leprosy are discussed.

Association between lepromatous leprosy and Australia antigen

Australia antigen is more common in patients with lepromatous leprosy than in patients with tuberculoid leprosy or in non-leprosy controls. In the combined populations, the frequency is, in general, higher in males than females, and in younger people than in older people. Australia antigen has now been found to be associated with lepromatous leprosy, leukaemia, and hepatitis, and to cluster in families. It is sugegsted that indivuduals with Australia antigen have an inadequate immune response and are especially susceptible to various illness, including lepromatous leprosy.

Cutaneous responses to lepromin and to other mycobacterial antigens. (Human, avian and battey tuberculins, and human and avian tubercle bacilli)

A comparative study has been made of the reactions in healthy Cebu children to lepromin, to human, avian and Battey PPD's, and to heat-killed suspensions of whole M. tuberculosis and M. avium. The bacillary suspensions were given only to nonreactors to the homologous tuberculins to avopid violent reactions and on the assumption that all tuberculin reactors would have responded to the homologous whole bacillus antigen. Of the 746 children in the study, 15.3 per cent gave positive early lepromin (Fernandez) reactions, while 74.1 per cent showed positive late lepromin (Mitsuda) reactions. Of these children 194 had been vaccinated with BCG at some time in the past; there was no difference between these children and others with respect to the frequency of either early or late reactions ....

The origin of natural reactivity to lepromin. The association between the Mitsuda reaction and reactions to graded doses of tuberculin

This study deals with lepromin reactivity of the Mitsuda type, observed in apparently healthy children on MActan Island, Cebu, Philippines. The principal theories which have been offered to explain this type of reactivity are prior infection with M. leprae, with M. tuberculosis, or with some other species of mycobacteria. It is improbable that the majority of these children, and especially those under three years of age, could have been exposed to leprosy. Although there is a positive correlation between reactivity to tuberculin and that to lepromin, the excess of lepromin reactors among tuberculin positives over the number e´xpected if there were no association comprises a very small fraction of the total number reacting to lepromin. This is true both for small doses of tuberculin, reaction to which is regarded as specific for infection with M. tuberculosis, and for larger doses which may indicate prior infection with other species of Mycobacterium. This suggests that lepromin reactivity among these children is caused in most instances by some factor other than infection with M. tuberculosis or any related species. The theory that the test dose of lepromin is the responsible sensitizing factor is not in itself adequate as far as can be judget from the effect of a second lepromin test in a controlled study...

Effect of BCG vaccination, lepromin testing and natural causes in inducing reactivity to lepromin and to tuberculin

1- A report is made of an effort to determine the relative importance of natural causes, initial lepromin testing, and vaccination with BCG in producing reactivity to lepromin and to tuberculin. The possibility is admitted that the final lepromin test may itself cause reactivity of the Mitsuda type but there is no available means of separating this efffect from that of natural causes. 2- The subjects were 550 apparently healthy children, 6 months to 35 months of age, having no known contact with leprosy, living in their homes on Mactan Island, Cebu, Philippines, of whom 483 completed all requirements of the study. 3- A random sample of one-fifth constituted a basic control group, given initially only a tuberculin test (PPD-S, 0.0001 mgm.). The remainder were tested with lepromin and PPD-S, and those negative to both were divided at random into four subgroups. Two were vaccinated intradermally with BCG, one with a fresh preparation and the other with a lyophilized one. The other subgroups were given diphtheria toxoid and saline, respectively. Ninety to 100 days after the BCG and other inoculations, and, on the average, 143 days after the initial tests, all children including the basic controls were tested with lepromin and PPD-S of the same lots, and in the same dosages, as those used at the outset...

A note on the lepromin reaction in males and females of the general population of Cordova, Mactan Island, Cebu, Philippines

In view of the current interpretation of reactivity to lepromin as an indication of resistance to lepromatous leprosy, and of the much greater frequency of lepromatous leprosy in males than in females, a comparison has been made of the results of the lepromin test in 776 males and 1,075 females of the general population of Cordova, Mactan Island, Cebu. Those tested were not known to have had household exposure to leprosy, and all were free from signs of the disease when examined within a year prior to testing. The number of acceptable positive early (fernandez) reactions was extremely small; 3.0 per cent in males and 6.1 per cent in females. The proportion of late (Mitsuda) reactions increased from 17.7 per cent for males and 14.1 per cent for females under 5 years of age to 94.6 and 97.0 respectively, for those of 20 years and over. No substantial difference between the sexes was found in any age group. For all ages, after adjustment for differences in age constitution, the percentage of late positives was for males, 66.5 per cent and for females, 69.9 per cent. As far as reactivity of apparently healthy persons to lepromin may be accepted as an indication of their resistance to leprosy, there is no evidence in these results that males are less resistant than females.

Tuberculization and reactivity to lepromin. Association between lepromin and tuberculin reactions in schoool children in Cordova and opon Cebu, Philippines

1- A study has been made of the association between the reactions to tuberculin (first and second strength PPD) and early and late reactions to lepromin in 544 children of ages 7 to 9, inclusive, attending public schools in Cordova and Opon, Mactan Island, Cebu. In these municipalities the prevalence of leprosy is about 20 per 1,000 of which one-third is of the lepromatous type. Tuberculosis is known to be frequent. 2- The following percentages were positive: First PPD, 14.0; first and second PPD, 71.9; early lepromin (Fernandez), 4.4; and late lepromin (Mitsuda), 65.3. 3- Only 24 children showed an early lepromin reaction of 10 mm. or larger with infiltration. All of these had typical late reactions. Eight of the 24 were positive to first strength PPD; all of the remaining 16 reacted to the second strength. 4- The occurrence and intensity of the Mitsuda reaction were positively associated with occurrence and intensity of reaction to PPD. If it be granted that a high proportion of reactions to the second strength PPD were attributable to infection with the tubercle bacillus, then tuberculization of the population may have been responsible for concurrent acquirement of reactivity to lepromin. 5- There were, however, disagreements in both directions. There were 9.5 per cent of the children who were negative to the second PPD but positive to lepromin (Mitsuda). In all but one of these the lepromin reactions were small. On the other hand, there were 16.2 per cent who were positive to the second strength PPD but negative to lepromin. In 63.6 per cent of 88 children showing this type of disagreement, the reaction to tuberculin was 2 + or larger. The only explanation of these disagreements which is in conformity with thhe tuberculization hypothesis is that in some persons the two types of response are dissociated. Certain individuals are apparently capable of developing tuberculoid lesions when acid-fast bacilli are injected into the skin but have either lost or never possessed hypersensitivity to tuberculin. In other cases, hypersensitivity is present but capacity to localize the bacilli in the skin by formation of a tubercle is absent...

Mortality of persons with leprosy prior to sulfone therapy, Cordova and Talisay, Cebu, Philippines

1- A study is reported of the mortality of leprosy patients in Cordova and Talisay, Cebu Province, Philippines. The data are regarded as exceptionally accurate, having been derived from records of households inncluded in three surveys of Cordova (1933, 1941 and 1948) and two of Talisay (1936-37 and 1950-51), all made by the staff of the Leonard Wood Memorial in cooperation with the Department of Health of the Philippines. For Cordova, there are included 15 years of experience, 1933 to 1948, and for Talisay, 14 years, 1936-37 to 1950-51. Most of the bacteriologically positive patients had been treated for some years at the Eversley Childs Sanitarium. Sulfones were rarely used in therapy at that institution before 1947, and only for a few selected patients until 1951. 2- Standardized death rates have been computed for persons 15 years of age and over for each community and for both combined, by sex, for the total population, and for persons suffering from lepromatous or from nonlepromatous (tuberculoid or indeterminate) leprosy. For Cordova the second survey fortunately divided the experience at a critical point, and rates were obtained for the period 1933 to 1941, which are compared with those of the World War II period and the years immediately following, 1941 to 1948. 3- During the intervals between the initial and last surveys, for both communities combined, the average annual mortality for persons with lepromatous leprosy was 5.1 times that of the general population; for male patients the ratio was 5.1:1.0, and for females 4.4:1.0. Excess mortality over that of the general population was 71.7 per 1000 per year for patients of both sexes - 78.2 for male patients, and 53.3 for female. A larger experience is necessary to determine whether the observed greater excess mortality in males is a genuine characteristics or a chance variation. Patients suffering from the nonlepromatous forms did not have appreciably higher death rates than the general population. 4- Among lepromatous patients of both communities, the ratio of actual deaths to those expected at age specific rates prevailing in the general population. 4- Among lepromatous patients of both communities, the ratio of actual deaths to those expected at age specific rates prevailing in the general population was 4.0:1.0 for patients 15 to 29 years of age, 7.2:1.0 for those 30 to 49 years old, and 2.5:1.0 for those 50 years and over...

A field study of leprosy in Cordova, Philippines resurvey in 1941 after eight years

1- In 1933, a field study of leprosy was made in Corodova, Cebu, during which 99.6 per cent of the enumerated population of 6,063 inhabitants were examined. This includes 62 missed in the first survey but examined during a follow-up in 1935. Including patients already in segregation, the total prevalence in 1933 was found to be 19.0 per 1,000, 64 or 57.7 per cent of the 115 cases being of that type. 2- In 1941 after an eight-year interval, during which the population was kept under observation, a resurvey of the same area was made along lines similar to those followed in the first survey. Of an enumerated population of 7,026.98.9 per cent were examined. For total leprosy the prevalence rate was found to be 17.9 per 1,000, but for lepromatous leprosy it had decreased to 8.0 per 1,000, and lepromatous cases constituted only 44 per cent of the total of 126 cases found. 3- Of 49 patients with active lepromatous lesions in 1933, in segregation at the start of the study or found in the survey, 7 or 14 per cent became bacteriologically negative and were paroled during the eight-year period between the two surveys. Of 15 paroled before 1933, 4, or 27 per cent, lapsed during the same period, and 2 others of the 7 paroled after 1933 are known to have relapsed before 1941. The rate at which paroled lepromatous patients relapsed thus appears to be higher than the rate of parole over the same lenght of time...

Historical inquiry as a method of estimating the trend of leprosy

The records of Cordova and Talisay, Cebu, Philippine Islands, which have been the basis of several previous studies, have been utilized to illustrate the value of the historical method (as opposed to prolonged observation) in determining trend. A modified life table method of analysis was used. When the total experience of both communities was divided into years of life lived prior to and subsequent to January 1, 1915 and the study was limited also to the incidence of lepromatous leprosy only, it was found that there was evidence of a downward trend. The ratio of the incidence rate for the earlier to that for the later period was found to be, for males 1.3 to 1 and, for females, 2.0 to 1. Since in this comparison the later life experience of many persons exposed in the first period was included in the second, two groups of individuals were selected in such a manner that the life experiences of the groups were mutually exclusive. For the earlier period individuals born between 1896 and 1910 were selected and their life experience was included only to the year 1920. For the later period those born between 1911 and 1925 were chosen and their experience was included up to the year 1935. Thus, no individual in the first group was included in the second. Also all individuals, except those residing in the community less than ten years, had a minimum period of ten years of observation between entrance and termination of observation and none had more than twenty-five years of life experience. The downward trend of lepromatous leprosy was more strikingly evident in this second comparison than in the first. The ratio of the incidence rate for the earlier period to that for the later is for males, 2.0 to 1, and for females, 2.4 to 1. Evidently incidence had declined in the communities taken as a whole. The next question that arose was whether this downward trend could be detected in the experience of those who were known to have lived in the same household as a person with leprosy. Comparison was again made between the experience of those born between 1896 and 1910 and those born between 1911 and 1925. Only those who were known to have been living in household association with lepromatous leprosy were considered as exposed and their experience was contrasted with that of those for whom no history of exposure to any type of leprosy could be ascertained...