AIMS: In 1936 the Finnish Anti-Tuberculosis Association founded the first nursery, "Joulumerkkikoti", into which infants born into tuberculous families were admitted and given BCG vaccination to reduce the risk of tuberculosis. This prophylactic regimen was effective in reducing infant mortality and morbidity of tuberculosis. We investigated the mortality of these children later in childhood and adulthood. METHODS: The index cohort consisted of 3,020 subjects born between 1945 and 1965 in Finland and isolated from their family immediately after birth. The average separation time was 218 days. The subjects alive on 1 January 1971 were identified. For every index subject two reference subjects were chosen, the matching criteria being sex, year, and place of birth. Data on causes of deaths were obtained from the Finnish Cause of Death Registry by the end of 1998. RESULTS: The relative mortality rate (RR) was higher in the index cohort than in the reference cohort for all causes of death (RR 1.4; 95% CI 1.2-1.7), and particularly for unnatural deaths: RR 1.5 (1.1-1.9) for men and RR 1.9 (1.0-3.7) for women. CONCLUSIONS: The mortality in the index subjects later in childhood and adulthood was somewhat elevated. This may be explained by a variety of risks experienced during pregnancy, delivery, and childhood. The fall in the socioeconomic status of the family of origin due to tuberculosis may partially explain the result. Another interpretation is that the very early separation from the mother had unfavourable effects on later psychological developments in some children.
OBJECTIVES: To evaluate whether, in patients with carcinoma in situ (CIS) of the urinary bladder, alternating instillation therapy with mitomycin C (MMC) and bacillus Calmette-Guerin (BCG) was more effective and less toxic than conventional BCG monotherapy. METHODS: Patients were stratified prospectively for primary, secondary, and concomitant CIS and randomized to one of two regimens. Patients in the alternating group received six weekly intravesical instillations of MMC 40 mg, followed by alternating monthly instillations of BCG 120 mg and MMC for one year. In the monotherapy group, only BCG was instilled on the same schedule. RESULTS: Of 323 enrolled patients, 304 were eligible for analysis. After an overall median follow-up of 56 months, the Kaplan-Meier disease-free estimate for BCG monotherapy was significantly better than that for alternating therapy (p=0.03; log rank test). Risk for progression appeared lower in the BCG monotherapy group (p=0.07), but no differences existed in survival. Besides the regimen, CIS category also predicted outcome to some extent. BCG monotherapy caused significantly more local side-effects and premature cessation of instillation treatment than did the alternating therapy. However, no differences were observed in the number of serious side-effects. CONCLUSION: One-year BCG monotherapy was more effective than the alternating therapy for reducing recurrence and compared well with the best regimens reported from substantially smaller series. The alternating therapy was better tolerated.
An ultrasonicated lysate of Corynebacterium cutis (Ultracorn, Virbac, France) was administered to 10-day-old calves, 5-month-old calves, and pregnant dams kept under Egyptian environmental conditions. Ninety-five calves and 50 dams were used in the study. All animals were treated with 2 ml/100 kg body weight of killed C cutis. Its effects on body weight gain and on calf mortality and morbidity were recorded. The results obtained showed that treated calves had greater weight gains, reduced susceptibility to common viral pathogens, and lower mortality. When given simultaneously with rinderpest vaccine, an immunopotentiating or adjuvant effect was seen. Thus, treated calves had higher neutralizing antibody titers to rinderpest as compared with untreated calves. When administered to pregnant cows in the last month of pregnancy, the offspring of these animals had higher birth weight, better weight gain, and reduced morbidity.
Studies from low-income countries report positive non-specific effects of early Bacillus Calmette-Gu?rin (BCG) immunisation on childhood health and survival. Neonatal immunisation with BCG may prime the immune system and offer partial protection against other infectious and possibly allergic diseases. The potential clinical value of these non-specific effects has not yet been examined in a large randomised trial in high-income countries.
The Danish Calmette Study is a multicentre randomised clinical trial conducted between October 2012 and November 2015. Within the first 7 days of life, infants were randomly assigned to intra-dermal vaccination with BCG or no intervention. At 3 and 13 months of age structured telephone interviews and clinical examinations of the children were conducted. In a subgroup of children blood samples were drawn and stool samples collected at age 4 days, 3 and 13 months. Thymus index was assessed by ultrasound in a subgroup at randomisation and at 3 months. The primary study outcome is hospitalisation within the first 15 months of life as assessed in Danish health registers. Secondary outcomes include infectious disease hospitalisations, wheezing, eczema, use of prescribed medication, growth, development, thymus index, T- and B-cell subpopulations assessed by flow cytometry, in vitro cytokine responses and specific antibody responses to other vaccines. Adverse reactions were registered.
With participation of 4184 families and more than 93% adherence to clinical follow-up at 3 and 13 months, this randomised clinical trial has the potential to create evidence regarding non-specific effects of BCG vaccination in a high-income setting.
The Bacillus Calmette-Guérin vaccine (BCG), which is used to protect against tuberculosis, has been associated with a variety of other effects since it was developed almost 100 years ago. Most notably, observational studies and randomized clinical trials from low-income countries indicate that it protects against unrelated infections, i.e. a so-called non-specific effect. The Danish Calmette Study was conducted to study these effects in a high-income population. The immune response to BCG is not fully understood but involves a pro-inflammatory profiling of the immune system, also when exposed to unrelated pathogens. Immune changes have been implicated in changes in both child growth and child development and for that reason we also studied these outcomes. We randomized 4262 children at birth to receive BCG vaccination at birth or to a no-intervention control group. We had pre-specified subgroup analyses of child sex, prematurity, and maternal BCG vaccination. The statistical analysis plan was finalized prior to unblinding of the data. Follow-up for the outcomes reported in this thesis consisted of telephone interviews and clinical examination at age 3 and 13 months, as well as online developmental questionnaires distributed to the parents at 12 months and additionally to the parents of premature children at age 6 and 22 months. The outcomes of this thesis were number of parent reported infections, child growth and body composition, and child psychomotor development. Overall, there was no effect of BCG on either incidence of infections, growth, body composition or psychomotor development. A subgroup analysis of children of mothers who were BCG vaccinated showed a reduced incidence of infections from 0 to 3 months among BCG vaccinated children (incidence rate ratio = 0.62, CI: 0.39 to 0.98), but there was no effect from 3 to 13 months. Previous research has shown that maternal exposure to BCG or mycobacteria can alter the effect of BCG in the offspring, and thus the unexpected lack of effect on overall infections can possibly be explained by the lack of maternal exposure to BCG in our study, as only 17% of the mothers were BCG vaccinated. In the studies where non-specific protective effects of BCG have previously been found, most of the mothers were BCG vaccinated or exposed to mycobacteria. Premature children had a non-significant increased risk of infection, which was corroborated by an analysis of hospitalizations for infections (not reported in this thesis). This was also unexpected as previous research indicated a more beneficial effect among low birth weight children. The study did not have power enough to exclude a negative effect of BCG on the development of premature children, and thus a cautious approach to vaccinating premature children may be prudent in a high-income setting. We succeeded in recruiting the planned number of participants and had high follow-up rates for most outcomes. A limitation is that it was not feasible to blind the parents to the randomization group. In conclusion, BCG did not have any public health benefit on incidence of infections and did not affect child growth or child development in the present study.
The results of study of a tuberculosis infection course in different conditions and its association with BCG revaccination are presented. The Moscow region was tentatively divided into 3 groups of regions. Children of Group 1 were not given revaccination at 7 and 12 years, those of Group 2 at 12 years and those of group 3 received revaccination according to the routine techniques at 7, 12 and 17 years. BCG revaccination withdrawal caused no increase in tuberculosis morbidity and tuberculin sensitivity. Tuberculosis detections were unassociated with the frequency of previous BCG revaccination.
It is necessary to reassess tuberculosis (TB) control among Canadian Indians and Inuit, particularly the policy of BCG vaccination, because of the perceived decreased risk of TB among Indians and Inuit as well as the uncertainty surrounding BCG effectiveness due to conflicting results from several large-scale trials in different regions of the world. An attempt is made here to assess the epidemiological situation of TB among the Indian and Inuit population in Canada, to review publications on BCG and TB control, focusing on their relevance to the Canadian situation; and to consider policy options for TB control among Canada's Native population. On the basis of special studies conducted in Frobisher Bay, Northwest Territory, Brzybowski et al. estimated the annual risk of infection among the Inuit to be 3%-4% in 1971 and 1.5%-2% in 1974, ignoring tuberculin sensitivity attributed to BCG. 5 surveys over 20 years in Alaska, where mass BCG had not been applied universally, showed a marked decline in the prevalence of tuberculin sensitivity. A 1957 survey of the total population of Manitoulin Island, Ontario, which included 1475 unvaccinated Indians, revealed a prevalence of tuberculin positivity much higher than in whites in all age groups. Among Indians, 18% of the under 15, 63% of the 15-39, and 82% of the over 40 age groups were tuberculin positives. Springett concluded that vaccination was indicated in a population where not more than 20% were tuberculin positive, but the risk of new infection should exceed 10% over the next 10 years. An urgent need exists to conduct a series of tuberculin surveys of representative samples of Natives at different age groups to determine the current situation. If one wants to eliminate "false-positives" due to the effects of BCG on tuberculin sensitivity, then the suggestion that BCG be withheld from selected cohorts which are then put under intensive surveillance and tested at periodic intervals should be adopted. 2 randomized controlled trials of BCG vaccination -- the American Indian Trial and Ferguson and Sime's Saskatchewan Indian trial, initiated during the 1930s--showed high protective efficacy in the 80% range. Both were conducted at a time when the risk of infection, the case rate, and the mortality rate were all very high. A 5-year retrospective study among 2500 Inuit who were free of active disease in 1964 found that those who were vaccinated had a 1.2% mean annual incidence rate of active TB, lower than the incidence among the nonvaccinated. The complications arising from BCG vaccination usually are mild and infrequent. Research needs and policy options are outlined.
From: Fortuine, Robert et al. 1993. The Health of the Inuit of North America: A Bibliography from the Earliest Times through 1990. University of Alaska Anchorage. Citation number 1784.
In Sweden, BCG-vaccination is recommended to certain risk groups only, as the incidence of TB is very low. Children from high-endemic areas, as well as health care personnel, especially those working in risk areas, are the most important target groups. The efficacy of BCG vaccination has varied in different investigations, but early Nordic studies have shown approximately 80 percent protection. Vaccination prevents disseminated but not localized pulmonary disease. There are no data supporting revaccination. Today some Swedish children are vaccinated without a clear indication, due to caretakers' fear of TB. The risk of new infection is very low in Sweden today, and is for all practical purposes limited to the closest family members of affected individuals. If large numbers of refugees from high-endemic countries arrive in Sweden, the epidemiological situation must be closely monitored.
It is evident from follow-up studies of tuberculosis in the Netherlands (without BCG vaccination), Sweden (discontinuation of BCG vaccination since 1975) and in both parts of Germany (FRG discontinuation since 1975), as well as from the favourable tuberculosis situation in both parts of Germany (low tuberculosis incidence and very low infection risk) that general vaccination of babies is no longer warranted. For this reason the German Central Committee for Combatting Tuberculosis is considering in consultation with the Federal Bureau of Health to abstain from continuing to recommend general BCG vaccination of all newborn. BCG vaccination should be recommended only in enhanced-risk groups (children of foreign parents and children sharing their living quarters or household with a person suffering from acute, i.e. infectious tuberculosis).