Читать книгу Tuberculosis and War - Группа авторов - Страница 37

The tool to measure infection with M. tuberculosis has long been the tuberculin skin test, but currently is gradually being replaced by the introduction of interferon-gamma release assays [7]. Various methods of applying tuberculin have been developed, mostly in the first decade of the 20th century, chiefly percutaneous [8] and intracutaneous testing [9, 10]. Infection with M. tuberculosis results in a cell-mediated immunologic response that can be elicited by a tuberculin skin test. Like any test, the tuberculin skin test has the intrinsic operating characteristics of sensitivity and specificity. Lack of sensitivity (i.e., the proportion with a false-negative result) is determined by the immune status of the person tested and is also reduced by faulty tuberculin reagents and technical errors [11–13]. The most prominent causes for lack of specificity (i.e., the proportion with a false-positive result) are cross-reactions attributable to infection with other mycobacteria, notably several types of environmental mycobacteria and the Bacille Calmette-Guérin (BCG) vaccine strain M. bovis BCG. The predictive value of a positive test diminishes rapidly with decreasing prevalence of the sought-after condition if the operating characteristics remain unchanged.

The estimated annual incidence of M. tuberculosis infection has dropped below 10% in industrialized countries by about 1910, and became even substantially lower by the time of World War II (WWII) [3]. In other words, a relatively small and increasingly smaller problem would require at least 2 sequential tuberculin surveys 1 year apart to determine the annual incidence of transmission of infection by M. tuberculosis. During World War I (WWI), BCG was not yet in use anywhere, but by WWII, most European countries – with the notable exceptions of Germany [14], the Netherlands [15], and the United Kingdom [16] – had begun introducing BCG vaccination nationally in a systematic manner. Thus, prior BCG vaccination adversely affected the tuberculin test specificity, and thus the predictive value of a positive test result in a large number of countries in Europe. Of lesser importance among younger population groups, repeat tuberculin testing can boost the response and falsely suggest incident infection [17]. To solve the problem of extracting incidence information from serial prevalence measurements [18, 19], the incidence of infection was approximated by the calculation of an average annual risk of infection, algebraically derived from single or repeat tuberculin skin test prevalence surveys [20, 21]. Whereas this approach ingeniously circumvents these difficulties, it has an intrinsic problem that it calculates an average over the lifetime of a person (Fig. 2). A tuberculin skin test survey is conducted among persons born in year b at calendar time b + a, where a is the age of the birth cohort under consideration. The annual risk of the observed prevalence of infection with M. tuberculosis is the algebraically derived average (using a compound interest calculation approach) of the probability of becoming infected (or reinfected) during the course of 1 year. By convention [22], it is put on the calendar time in between the years of birth and survey conducted as a pragmatic approximation. The actual incidence of infection, however, may have decreased or increased over the life span of the tested individual, or even taken a more complex course, and there is no way to actually know its precise current level. It follows that the younger the tested population, the closer the calculated annual risk of infection approximates to the actual incidence of infection, while conversely, the older the population tested, the less certain one can be about the actual magnitude of current transmission. Thus, a recent increase in infection incidence will show up only with a substantial delay and is averaged out to a much-diluted value.

Fig. 2. Difference between calculated average annual risk of infection and actual incidence of infection with M. tuberculosis.

Fig. 3. Secular trend in the average annual risk of infection with M. tuberculosis in selected European countries. Adapted from data given in [20, 23–27]. A straight line (The Netherlands, Norway) is only shown if there were annual data. If only occasional surveys were available, this is denoted by a dashed line (almost overlapping for Serbia and Poland) and a hollow circle (triangle for France) to denote the time points for which the annual risk of infection could be calculated. A slope reference is shown as an inlet to allow visual estimation of the average annual decline in the annual risk of infection: for instance, the average annual decline for The Netherlands after 1940 is roughly between 10 and 15%.

Tuberculin surveys also take substantial resources and are rarely carried out annually. The secular trend in the average annual risk of infection with M. tuberculosis in selected European countries is shown in Figure 3, which is adapted from [3] with data from [20, 23–27]. It summarizes analyses from a multitude of tuberculin skin test surveys conducted in Europe (largely but not exclusively in Western Europe) during the 20th century, converting the prevalence measurements into a series of annual risks of infection with M. tuberculosis from which the secular trend was derived. First of all, the overall picture demonstrates that all examined countries show a substantial reduction in the annual risk of infection. Second, while the absolute level at any given point in time may differ between countries, the speed of decline is remarkably similar everywhere. Among the seven countries depicted, only the Netherlands had annual prevalence data covering every WWII year, from which a series of annual risks could be calculated. After 1947, the surveys were performed yearly among military recruits, but from 1926 to 1947 the information was obtained from prevalence surveys among children up to age 13 years. Thus, in contrast to surveys among recruits, the age of children allowed calculation of an average risk of infection that must have approximated the actual incidence relatively closely.

No increase was noted at any time during the war years in both England and Wales and in the Netherlands, but there was an abrupt change in 1940 when the continuity of the downward trend in the risk of infection accelerated substantially. The authors report, however, difficulties with the interpretation of these data from Amsterdam [20]. First, the surveys were not conducted every year. Second, the von Pirquet (percutaneous) testing method that was used was difficult to quantify. Third, the original data were lost and data were read from graphs. Finally, the proportion of reactors among children under the age of 2 years was much larger than would have been expected from older children. A possible interpretation postulates that this might have been attributable to infection from M. bovis as mandatory pasteurization of milk did not begin in the Netherlands until 1940. The introduction of obligatory pasteurization of milk appears to coincide temporally with the acceleration in the decline of the risk of infection. However, such an interpretation is highly questionable if one considers that a delay must be expected between the time point a change in infection incidence occurs and the time this change becomes reflected in a change in the calculated average annual infection risk. There is no such delay here – the change is abrupt and occurs in 1940. Thus, the temporal coincidence between measures against bovine tubercle bacilli and the change in the risk of infection may not be entirely causal.

Rist reported on 2 comparative tuberculin skin test surveys carried out in about 12,000 French students annually (von Pirquet method) in 1938 and 1943, respectively [28]. Among the 19-year-olds, the prevalence of positive results was 56 versus 50% in 1939 and 1943, respectively. The respective percentages among the 20-year-olds were 59 and 56% and among the 21-year-olds 62 and 54%. The author noted that morbidity decreased in parallel while mortality increased. He hypothesized that the decrease in infection prevalence might have been attributable to accelerated and increased deaths resulting in higher mortality, thereby diminishing the opportunity for transmission. As discussed before, the early life experience of the tested cohorts of a diminishing risk of infection was so substantial over the first 15 years after birth that even a relative increase in the risk of infection over the most recent 5 years did not translate into a measurable effect in the calculated average. We note thereby (as shown in Fig. 3) that the average annual decline between 1900 and the end of WWII had already been in the order of close to 5%. Rist confirmed this by using data from a hospital for sick children in Paris, where the prevalence of infection among 5-year-old children declined from 54 to 35% between 1919 and 1925, a 6% average annual decline, and in addition declined on average by 5.4% among 10-year-old children [28].

Tuberculin skin test survey data were available among school children aged 7–11 years in some villages in the Akkar district of north Lebanon [29]. The first survey data were obtained from 1980 to 1984, and the second data set was obtained in 1990 from the same villages. In the initial survey, the prevalence of infection was 3.8% (16 of 421 children reacting positively), and in the second 10.0% (28 of 281 children). There was no evidence for an increase in BCG vaccination coverage. The civil war in Lebanon lasted from 1975 to 1990; accordingly, the majority of children in the first and all children in the second survey were born during war years. Contemporaneously, the number of new TB cases attending a clinic in Tripoli, also in north Lebanon, reported a fairly constant number of around 30 cases annually from 1980 through 1985, when TB cases started to increase to over 400 in 1990 [29, 30].

One may conclude that as far as transmission of M. tuberculosis is concerned, there are no data from WWI, and those from WWII are sketchy at best. Surveys from children in Amsterdam in the Netherlands and from young adults and a selected group of children in France are difficult to interpret, but they do not suggest that there was an excess of transmission of M. tuberculosis to children during WWII years. This might be due to problems in interpreting tuberculin skin test prevalence data that typically lag in showing effects of changing transmission incidence. Alternatively or in combination, it might indeed be that while the incidence of infectious TB may have increased, case fatality was accelerated, shortening the average duration of infectiousness. The latter hypothesis will be examined more closely in the following sections. In contrast, when comparative repeat tuberculin test surveys were available from young children, case notification data showed in parallel a tenfold increase in TB; moreover, the prevalence of tuberculin positivity in the children during the civil war in Lebanon more than doubled. The conclusion, therefore, is inescapable that transmission to the youngest generation increased as a result of a massively deteriorating TB situation temporally correlated with the war.