Ian Sutherland

The development of clinical tuberculosis following infection with tubercle bacilli. 1. A theoretical model for the development of clinical tuberculosis following infection, linking from data on the risk of tuberculous infection and the incidence of clinical tuberculosis in the Netherlands.

Information on the risk of tuberculous infection in the Netherlands has been linked with information on the incidence of tuberculosis, in an attempt to estimate the risks of developing the disease following infection or reinfection. It was postulated that: (a) those with a recent primary infection had a characteristic risk of developing progressive primary tuberculosis; (b) those with a distant (i.e. not recent) primary infection and a recent reinfection had a characteristic risk of developing exogenous tuberculosis; and (c) those with a distant primary infection but no recent reinfection had a characteristic risk of developing endogenous tuberculosis. The information on the risk of tuberculous infection was used to estimate the size of the population in each of these infection classes for different age-groups and calendar years in the Netherlands. Using multiple regression to link these population figures with the information on tuberculosis incidence in the same age group and calendar year, it was possible to estimate the above risks of developing tuberculosis. For Netherlands males aged 15-69 years during the period 1951-70 the three risks of developing pulmonary tuberculosis were estimated to be: (a) 5.06 per cent annually (for 5 years) following primary infection; (b) 1.91 per cent annually (for 5 years) following reinfection; (c) 0.0253 per cent annually, after the first 5 years following primary infection, in the absence of reinfection. The corresponding (and significantly different) estimated annual risks of development of pulmonary tuberculosis for females were 5.85, 1.10 and 0.0020 per cent respectively. From these risks, it may be estimated that the degree of protection conferred by a distant primary infection, against pulmonary tuberculosis arising from a recent reinfection, was 63 per cent for males and 81 per cent for females. The estimated relative proportions of cases of progressive primary, exogenous and endogenous tuberculosis varied considerably with age and calendar year. Progressive primary tuberculosis was dominant at the younger ages, exogenous and endogenous tuberculosis at older ages. At these older ages, the great majority of cases in the Netherlands in the early 1950s appeared to be exogenous in origin, but by 1970, with the decrease in the risk of infection, the exogenous contribution had dwindled substantially, especially among males.

First results of a randomized clinical trial of fast neutrons compared with X or gamma rays in treatment of advanced tumours of the head and neck. Report to the Medical Research Council.

Results of the first randomized clinical trial to compare the effects of fast neutrons and those of x or gamma rays (photons) in treating patients with advanced tumours of the head and neck are reported. In 37 out of 52 patients treated with neutrons and 16 out of 50 treated with photons the local tumour completely regressed; the tumour later recurred in nine of the 16 photon patients but in none of the 37 neutron patients. The advantages to the neutron-treated patients were seen in tumours of well and poorly differentiated histology and in each site. Complications after treatment did not differ significantly between the groups. Despite these substantial differences in local control of the tumour there were no significant differences in mortality between the series. A detailed study of the effective doses and the response of tumours and normal tissue in each series indicated that the improved results from neutron therapy were due to differences in the biological quality of the beam and not to the rather higher average effective dose in the neutron series. To assess the long-term effects of neutron treatment patients in earlier stages of disease and with smaller tumours should be included in the next phase of the trial.

The immunity conferred by effective BCG and vole bacillus vaccines, in relation to individual variations in induced tuberculin sensitivity and to technical variations in the vaccines

Summary An analysis of the ten-year incidence of tuberculosis in various subgroups of participants in the Medical Research Council trial of tuberculosis vaccines has confirmed that the (liquid) BCG and vole bacillus vaccines used were highly effective in preventing tuberculosis. The percentage efficacy of the BCG vaccine (Danish substrain) was 80%, and of the vole bacillus vaccines (four substrains) was 74%, 91%, 78% and 86% respectively. The immunity conferred by the BCG vaccine did not depend on the degree of tuberculin sensitivity induced in the individual, which varied widely even though the average level was high. The immunity conferred by the vole bacillus vaccines also did not depend on the degree of tuberculin sensitivity induced in the individual; this conclusion held equally for substrain I (which induced a low average level of sensitivity) and for substrains 2 to 4 (which induced much higher average levels of sensitivity, similar to that induced by BCG vaccine). The average level of tuberculin sensitivity induced by the BCG vaccine was greater for the batches with higher viable counts than for those with lower viable counts, but there was no definite association of the protective efficacy with viable count. The average level of tuberculin sensitivity induced by the BCG vaccine increased with two successive improvements in manufacturing and issuing technique, but protective efficacy was not definitely influenced thereby. The average level of tuberculin sensitivity induced by substrain 1 of the vole bacillus vaccine was greater after an increase in opacity standard (but still remained well below the level induced by substrains 2 to 4). The protective efficacy was not definitely influenced. It is concluded that with highly effective tuberculosis vaccines, the degree of protection conferred on the individual is independent of the degree of tuberculin skin sensitivity induced in that individual by the vaccination. Moreover, in this study technical variations between the various batches of vaccine, within the normal production range, affected the average level of induced tuberculin sensitivity, but did not have an important influence on the protective efficacy of the vaccine.

The protective effect of BCG vaccination as indicated by autopsy studies.

In a detailed study of the pathology of tuberculous infection made in Finland in 1961, tuberculous foci were found at autopsy in 61 of 67 non-vaccinated subjects and in 35 of 83 BCG-vaccinated subjects, all of whom had died between the ages of 1 and 45 years (with 2 exceptions from causes other than tuberculosis). In the present note on the same material, national information on tuberculin sensitivity and tuberculosis mortality has been used to calculate the risk of tuberculous infection in Finland at different times and ages during the lifetime of these subjects. From these risks of infection in Finland it was estimated that 63 or 64 of the non-vaccinated subjects had been infected during their lifetime and that between 25 and 31 of the BCG-vaccinated subjects were expected to have been naturally infected (had they not been vaccinated) between the time of vaccination and death. It is concluded that virtually all tuberculous infections in unvaccinated subjects lead to pulmonary foci, which are demonstrable at autopsy. Further, the same appears to be so in vaccinated subjects; there is no evidence to support the suggestion that in man BCG vaccine can prevent the establishment of infection in an exposed subject. The effects of BCG (as demonstrated in the earlier paper) appear to be confined to limiting the multiplication and dissemination of the bacilli and the development of lesions following infection.

A fourth study of case-finding methods for pulmonary tuberculosis in Kenya

Abstract This investigation is the fourth of a series of case-finding studies in Kenya. It explored in a new area (the Baragwi location of Kirinyaga), five methods of case-finding involving the examination of the sputum by smear and culture of symptomatic tuberculosis suspects in the community identified (i) by interrogation of the Elders, (ii) by interrogation of household heads, (iii) by tracing all patients registered during the previous 10 years in the District Tuberculosis Register, (iv) by the examination of all their close contacts and (v) from outpatients attending peripheral health units. The initial interrogation of the Elders yielded 123 suspects with bacteriological results, of whom seven were culture-positive, including four smear-positive. A second interrogation three to six months later produced a further 66 suspects and four more culture-positive cases (all smear-negative). The examination of a second sputum specimen after three to six months from all the suspects from both interrogations produced a further culture-positive smear-negative case. A single interrogation of household heads in a house-to-house survey yielded 867 suspects and 15 culture-positive cases, including eight smear-positive. Of 862 suspects with no history of tuberculosis, 778 (90%) claimed they had attended a medical facility for their respiratory symptoms during the previous year, the most recent visit being within the previous month in 24%. All except 1% of the total had attended on more than one occasion, the average number of attendances being 5·3. 83% said they had attended the peripheral health units and 37% had attended the Central District Hospital, yet 65% of the suspects had had neither a chest radiograph nor their sputum examined bacteriologically. Of the 114 cases of tuberculosis registered in the District Tuberculosis Register during the previous 10 years, nine were currently culture-positive, seven being smear-positive. The examination of a second sputum specimen from 105 yielded one more culture-positive case. Of 577 household contacts of the registered cases, seven were culture-positive, three being smear-positive. The examination of a second sputum specimen from 568 yielded two more culture-positive cases. During a full year, only 45 suspects were registered among out-patients attending seven health units serving the area (population 27,500), of whom four were smear-positive. This indicates a failure of the staff to take appropriate actions.

The risk of tuberculous infection in uganda, derived from the findings of national tuberculin surveys in 1958 and 1970☆

Abstract The World Health Organization made a tuberculin survey in Uganda in 1958 as part of an assessment of the prevalence of tuberculosis in that country. This paper describes a second tuberculin survey made in Uganda in 1970-71, to assess changes in the situation. The second survey was made deliberately in the same ten randomly chosen geographical areas as were surveyed in 1958, using the same techniques for registration and testing of the population, the same tuberculin, and employing as tester and reader the same WHO tuberculin testing nurse as had made and read the majority of the tests in 1958. Very few BCG vaccinations had been made in the interim in these areas. In 1970–1971 a total of 7,912 subjects (91·4 per cent of the registered population of the areas) completed the tuberculin test. This total included 2,038 subjects who had also been tested in the 1958 survey, and were still alive and resident in the area. The distribution of the diameters of induration in the tests was closely similar in the two surveys, the mode of the larger reactions being at 17 mm in both. The same criterion for the percentage with tuberculous infection could therefore be used in 1970–1971 as in 1958, namely the percentage with reactions of 17 mm or more, multiplied by two. For studying the changes in the prevalence of tuberculous infection, test results were available for 5,719 subjects in 1958, and for 6,875 subjects (258 of whom were tuberculin negative and had been given BCG vaccine at the 1958 survey) living in the identical geographical areas in 1970–1971. To obtain unbiased estimates of the percentages infected in the whole population in 1970–1971, it was necessary to estimate the numbers of infections which would have occurred by 1970–1971 in the 258 subjects, if they had not been vaccinated in 1958. The findings for the percentages infected at different ages at the two surveys have been used to estimate the annual risks of tuberculous infection during the period from about 1940 to 1970, and the association of the risk of infection with age of the subject. Based on the findings up to age 30 years, it is estimated that the annual risk of infection (at age 10) was 2·8 per cent in 1940, 2·6 per cent in 1950, 2·4 per cent in 1960 and 2·3 per cent in 1970. The slight decrease (amounting each year to less than 1 per cent of the risk) is not statistically significant. There does, however, appear to be a definite increase in the risk with age. The estimates of the risks at ages 5, 10 and 15 years in 1970 were 1·9, 2·3 and 2·8 per cent (amounting to a rise of 4 per cent of the risk with each year of age). It is concluded that the tuberculosis situation in Uganda has shown little improvement during the 1212 years between the two surveys, and that there is still a substantial risk of tuberculous infection there. There is thus considerable scope in Uganda for benefit from BCG vaccination and other modern methods of tuberculosis control which include simplified case finding and chemotherapy.

Incidence of Intrathoracic Sarcoidosis Among Young Adults Participating in a Trial of Tuberculosis Vaccines

In the course of the Medical Research Councils clinical trial of tuberculosis vaccines (Medical Research Council, 1956, 1959, 1963) records have been kept of the cases of definite or possible sarcoidosis which developed among the participants. These findings have now been analysed from several points of view; (1) The effect of tuberculin status on entry to the trial, and of B.C.G. and vole-bacillus vaccination, on the subsequent incidence of sarcoidosis. (2) The attack rate of intrathoracic sarcoidosis in the total participants, originally living in urban or suburban areas in England, and observed between the ages of about 15 and 25 years. (3) The relation between sarcoidosis and tuberculin sensitivity, as shown by the periodic tuberculin tests made during the trial.

A Third Study Of Case-finding Methods For Pulmonary Tuberculosis In Kenya, Including The Use Of Community Leaders

Five methods of identifying tuberculosis suspects were investigated in the Machakos District of Kenya by: (1) 3-monthly interrogation of the Community Elders, (2) interrogation of household heads, (3) identifying suspects amongst outpatients attending local health units, (4) examination of patients registered during the previous 10 years in the District Tuberculosis Register and also (5) their close contacts. Sputum was bacteriologically examined by smear and culture from suspects found by all the methods. The initial interrogation of the Elders yielded 216 suspects, of whom 9 were culture-positive, including 6 smear-positive. Reinterrogating the Elders 4 times at 3-monthly intervals produced a further 114 suspects including 4 culture-positive cases (3 being smear-positive). The examination of a second sputum specimen from suspects after a 3-month interval yielded 4 further culture-positive cases (all smear-negative) but the examination of a third specimen after a further 3 months yielded no further cases. A single interrogation of 1093 household head suspects yielded 22 culture-positive cases, including 11 smear-positive. The response in 5 health units covering a population of about 24 500 was poor. During a 2-year period only 109 suspects were recorded; 7 were culture-positive, including 3 smear-positive. Of 61 cases of tuberculosis registered during the previous 10 years, 8 were currently culture-positive, 5 being smear-positive. Of 318 household contacts of these cases, 6 were culture-positive cases, 2 being smear-positive. The problems presented by different active case-finding methods are discussed, identifying those that appear promising and those unpromising.

Studies of tuberculosis in an in relation to infection in cattle

A study has been made in Sweden to investigate whether the risk of tuberculous infection and its trend with time in man in different areas were related to varying prevalences of tuberculous infection in cattle. It was found that the level of the infection risk in man was related to the prevalence of tuberculous infection in cattle, varying from 3-4 per cent in 1935 at age 15 in counties with less than 2 per cent infected cattle to 5-8 per cent in counties with 20 per cent infected cattle or more. However, the downward trend to the risk of infection with time was not to found be associated with the prevalence of tuberculous infection in cattle. The correlation between the risk of infection in man and the prevalence of infection in cattle in the 24 Swedish counties was positive and highly significant (+0-79). The relationship between cattle tuberculosis and tuberculosis in man was further studied by correlating infection in cattle with tuberculosis mortality and morbidity in man. The correlation with mortality was negative and highly significant (-0-77), i.e. counties with little cattle tuberculosis had a high tuberculosis mortality in man, and vice versa. There were similar large negative correlations with measures of tuberculosis incidence. When variations between the counties in relevant environmental factors, namely capital, urbanization and overcrowding, were taken into account, a strong positive association remains between the prevalence of infected cattle and the risk of tuberculous infection in man, but the associations with tuberculous mortality and morbidity, though they remain negative, become weaker. It is suggested that the probable explanation of these findings is the long-term protection against adult infection with human tubercle bacilli conferred by bovine infection in childhood.

Studies of case-finding for pulmonary tuberculosis in outpatients at 4 district hospitals in Kenya.

This investigation is the sixth in a series of case-finding studies in Kenya. It explores the potential for case-finding by the identification of tuberculosis suspects (individuals with a cough for 1 month or more) through careful screening of general outpatients attending 4 district hospitals for the first time. Of 2299 suspects identified among 87 845 new outpatients attending the hospitals, 4.7% had culture-positive pulmonary tuberculosis, 3.6% having sputum positive on smear as well. In the 3 hospitals with radiographic facilities, 1.3% of suspects (whose sputum was negative on culture) were considered on review of their clinical history and chest radiograph by an independent assessor to have radiographically active tuberculous lesions and a further 2.5% to have inactive lesions. The proportion of bacteriologically positive cases per 1000 of the general population aged 6 years or more decreased as the distance of their homes from the hospital increased (P less than 0.001 for the trend). However, the proportion of cases per 1000 of the suspects identified increased as the distance of their homes from the hospital increased (P less than 0.001 for the trend). History of cough for between 1 and 12 months was the most useful factor for the identification of cases of tuberculosis among the suspects, and would have identified 92% of the smear-positive cases from the examination of 70% of the suspects; a history of weight loss identified 84% of the smear-positive cases from the examination of 64% of the suspects. A history of weight loss and/or a history of cough for between 1 and 12 months would have detected all the smear-positive cases from the examination of 89% of the suspects. The proportion of bacteriologically positive cases in the younger suspects aged 9-32 years (who had been eligible for a mass BCG campaign) was greater among the non-vaccinated than among the vaccinated suspects, 4.9% and 2.3% respectively (P=0.04), implying protection from vaccination of the order of 50%.