Depending on the epidemiological situation and the local infectious pressure, the probability of development of clinical disease after infection with
Mycobacterium tuberculosis varies. It is often stated that among those infected, about 10% progress to active disease over their liftetime [
1]. The risk of disease development is highest within the first year, estimated then to be 1%, and considerably lower the second year (0.3%) after which the risk is further gradually reduced [
2]. The risk of late-appearing clinical disease is mainly due to the ability of
M. tuberculosis to enter into a dormant stage followed by reactivation. After infection, latency can be defined as a state with no signs or symptoms of active tuberculosis. Skin test reactivity determined by intracutaneous injection of purified protein derivative (PPD) of
M. tuberculosis and/or x-ray demonstration of a healed, calcified lesion have generally been used as evidence of previous infection or primary tuberculosis disease [
3], while interferon-gamma release assays represent an important technical development for diagnosis of latent tuberculosis [
4]. Observations on latent tuberculosis with
M. tuberculosis residing in healthy individuals were made already by Opie and Aronson who cultured
M. tuberculosis from apparently normal tissues of individuals who died from other causes, and who had no pathological evidence of tuberculosis disease [
5]. During latency the bacilli show a characteristic location outside of the primary complex, i.e. in the upper lobes corresponding to the main location of cavernae in reactivation tuberculosis [
6]. These findings have been extended with molecular methods [
7]. Polymerase chain reaction for the IS
6110 sequence revealed
M. tuberculosis DNA in paraffin sections of macroscopically normal upper lobe lung tissue from 15 of 47 Ethiopian and Mexican individuals dying from causes other than tuberculosis. There are also observations indicating that the same bacterial strain induced active disease more than 20 years after original infection. From Denmark particularly interesting observations were made by comparing clinical isolates from the 1960s with isolates from the 1990s [
8,
9]. Two
M. tuberculosis strains isolated from a father in 1961 and his son in 1994 had identical IS
6110 restriction fragment length polymorphism (RFLP) pattern. The father had smear positive pulmonary tuberculosis with a one year case history in 1961, successfully treated for 12 months with streptomycin, isoniazid and para-aminosalicylic acid. His son was then 7 years old, left the home in 1972 without further contact with his father, and presented with pulmonary tuberculosis in 1994. This identical RFLP pattern of the two isolates was not found in any other strain, either among 130 historical strains collected 1961-1967 or among 4008 recent strains collected 1992-1999 [
8].
An important question is for how long the latent stage of tuberculosis is continuing with a risk of reactivation and development of clinical disease. It is widely assumed that latency is life-long and that most new cases of active tuberculosis in low-endemic countries arise from a growing proportion of latently infected individuals [
10], and that infected individuals thus face an increasing risk of reactivation as they grow older [
11]. It is, however, possible that infected individuals gradually tend to clear the latent infection. If this is the case one may predict that the rate of reactivated tuberculosis decreases as a function of time since primary infection.
When tuberculosis came under control in Norway after the Second World War, the annual incidence of new infections diminished rapidly, and the majority of clinical cases now occurred after reactivation of remote infection [
12,
13]. Data from molecular epidemiological characterization of isolated
M. tuberculosis strains in low incidence countries show that there is very little recent transmission of tuberculosis in the native population under these conditions [
14‐
16]. Molecular fingerprinting data from Norway shows a very diverse strain repertoire with very little clustering of cases among native Norwegians. This is as expected when reactivation occurs sporadically.
The National Tuberculosis Registry and Statistics Norway provide data for new cases of bacillary tuberculosis in 10 year cohorts from the age of 20. Data are given as incidence, i.e. cases per 100,000 population per year, making it possible to follow the rate of tuberculosis in birth cohorts from young adulthood until old age. Analysis of tuberculosis in sequential birth cohorts was originally introduced by Kristian Andvord studying tuberculosis mortality at the end of the 19
th and beginning of the 20
th century [
17‐
19]. Our analysis aimed to determine whether these data from the Norwegian experience after the Second World War can be used to estimate the duration of the latent stage and the associated risk of reactivation and development of clinical disease.