Both very low- and very high in vitro cytokine responses were associated with infant death in low-birth-weight children from Guinea Bissau.

BACKGROUND: The mechanisms behind heterologous immunity and non-specific effects of vaccines on mortality are not well understood. We examined associations between cytokine responses and subsequent mortality in low-birth-weight infants in Guinea-Bissau. METHODS: A low-birth-weight trial randomized children to Bacille Calmette-Guérin (BCG) at birth or later according to local policy. Blood samples were obtained from a sub-group at age 6 weeks. Interleukin (IL)-5, IL-10, IL-13, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were measured in whole-blood cell cultures stimulated with lipopolysaccharide (LPS), phytohaemagglutinin (PHA), or purified protein derivative (PPD). The outcome was mortality between bleeding and 1 year of age. Non-linear associations between cytokine responses and mortality were examined. RESULTS: Cytokine measurements were available from 390 children. The mortality rate (MR) was high (6.8/100 person-years-observation (PYO)). Both low and high cytokine responses to LPS and PHA were associated with high mortality (MR up to 25/100 PYO in the lowest 10% and 9.2/100 PYO in the highest 10%). In BCG-vaccinated children, higher IFN-γ responses to PPD were associated with better survival (MR ratio = 0.43 (0.24-0.77)). CONCLUSIONS: Data presented a rare opportunity to explore associations between cytokine responses and mortality. Both low and high cytokine responses were associated with high mortality; a balanced response to invading pathogens seems preferable.

Vitamin A supplementation and risk of atopy: long-term follow-up of a randomized trial of vitamin A supplementation at six and nine months of age.

BACKGROUND: The World Health Organization recommends high-dose vitamin A supplementation (VAS) for children above six months of age in low-income countries. VAS has been associated with up-regulation of the Th2 response. We aimed to determine if VAS is associated with atopy in childhood. METHODS: Infants in Guinea-Bissau were randomly allocated VAS or placebo, either at six and nine months of age, or only at nine months of age. At six months of age, children were furthermore randomized to measles vaccine or inactivated polio vaccine. At nine months of age all children received measles vaccine. Children were revisited seven years later and skin prick testing was performed. Atopy was defined as a skin prick reaction ≥ 3 mm. RESULTS: 40 of 263 children (15%) were atopic. Overall VAS had no significant effect on the risk of atopy (Prevalence Ratio 1.23; 95% CI 0.69-2.18). The Prevalence Ratio was 1.60 (0.66-3.90) for males and 1.00 (0.46-2.15) for females. CONCLUSIONS: There was no significant effect of VAS in infancy on atopy later in childhood. The role of infant VAS in the development of atopy is still unclear.

The immunological effect of revaccination with Bacille Calmette-Guérin vaccine at 19 months of age.

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccination has important non-specific immune effects. In a randomized trial in Guinea-Bissau, BCG revaccination was associated with significantly increased survival in children who received diphtheria-tetanus-pertussis (DTP)-booster vaccine before enrolment and in children who did not receive micronutrient supplementation (MN). Within the trial we assessed the immunological effects of BCG revaccination. METHODS: Children were randomized to BCG or nothing. Blood was sampled 6-11 weeks after randomization (early sample group) or 5-9 months later (late sample group). In vitro cytokine responses (interferon (IFN)-γ, interleukin (IL)-13, tumor-necrosis-factor (TNF)-α, and IL-10) were assessed in whole blood cultures stimulated with lipopolysaccharide (LPS), purified protein derivative (PPD) or phytohaemagglutinin (PHA). Effect-modification by sex, DTP-booster vaccination and MN was studied. RESULTS: Cytokines were measured in 345 infants. BCG was associated with significantly increased IFN-γ (geometric mean ratio (GMR)=4.54 (95% confidence interval: 3.13-6.58)) and IL-13 (GMR=1.43 (1.00-2.05)) PPD responses, the effect being strongest in the early sample group. Across all three conditions BCG tended to increase IL-10 (LPS, PHA, PPD: GMR=1.20, 1.12, 1.20), most pronounced in the late sample group. BCG reduced the TNF-α/IL-10 ratio in boys with DTP-booster at bleeding and increased it in those without (interaction test: p=0.03). In children without MN, BCG was associated with reduced TNF-α response in the early sample group (p=0.006), and increased IL-10 in the late sample group (p=0.03). CONCLUSION: BCG revaccination resulted in a strong IFN-γ response to PPD, which waned slightly over time. BCG also affected the pro-/anti-inflammatory balance, with reduced TNF-α and increased IL-10 responses to LPS, PHA and PPD. This effect depended on sex, DTP-booster vaccination and micronutrient supplementation, being most pronounced in children who had received DTP-booster before enrolment and children who had not received MN, i.e. the group of children which also had lower mortality after BCG revaccination.

The effect of at-birth vitamin A supplementation on differential leucocyte counts and in vitro cytokine production: an immunological study nested within a randomised trial in Guinea-Bissau.

Vitamin A supplementation (VAS) at birth was not associated with improved survival in a randomised, placebo-controlled trial in Guinea-Bissau. However, a negative sex-differential effect, which became evident after diphtheria-tetanus-pertussis (DTP) vaccination, was noted; among girls who had received DTP, VAS at birth was associated with two-fold higher mortality than placebo. The objective of the present study was to investigate the immunological effects of VAS at birth within a subgroup of participants in the randomised trial. Guided by the mortality results, we further explored whether VAS had a differential effect according to sex and DTP status. At 6 weeks after randomisation and supplementation, we measured differential leucocyte counts and TNF-α, interferon-γ, IL-10, IL-13 and IL-5 production in a whole-blood culture assay. A total of 471 children were included. VAS compared with placebo at birth was associated with a higher proportion of monocytes (relative risk ratio 1·26, 95 % CI 1·07, 1·49, P=0·04), while spontaneous TNF-α production was lower in the VAS group (geometric mean ratio 0·54, 95 % CI, 0·37, 0·78, P=0·001). Stratified analysis showed that VAS was associated with lower TNF-α and IL-10 production for girls without DTP and boys with DTP, resulting in significant three-way interactions between VAS, sex and DTP vaccination status (P=0·03 and P=0·04, respectively) for spontaneous TNF-α and IL-10 production. The results substantiate the potential role of VAS as an immunomodulatory intervention, which has different effects depending on concomitant health interventions and the sex of the recipient.

Testing the hypothesis that diphtheria-tetanus-pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries.

BACKGROUND: Measles vaccines (MV) have sex-differential effects on mortality not explained by protection against measles infection. OBJECTIVE: The authors examined whether whole-cell diphtheria-tetanus-pertussis (DTP) vaccine has sex-differential and non-specific effects. DATA SOURCES AND ELIGIBILITY: Following previous reviews and a new search, the effect of DTP on mortality up to the next vaccination was assessed in all studies where DTP was given after BCG or DTP was given after MV and there was prospective follow-up after ascertainment of vaccination status. SETTING: High-mortality countries in Africa and Asia. METHODS: The initial observation of negative effect of DTP generated six hypotheses, which were examined in all available studies and two randomised trials reducing the time of exposure to DTP. MAIN OUTCOME: Consistency between studies. RESULTS: In the first study, DTP had negative effects on survival in contrast to the beneficial effects of BCG and MV. This pattern was repeated in the six other studies available. Second, the two 'natural experiments' found significantly higher mortality for DTP-vaccinated compared with DTP-unvaccinated children. Third, the female-male mortality ratio was increased after DTP in all nine studies; in contrast, the ratio was decreased after BCG and MV in all studies. Fourth, the increased female mortality associated with high-titre measles vaccine was found only among children who had received DTP after high-titre measles vaccine. Fifth, in six randomised trials of early MV, female but not male mortality was increased if DTP was likely to be given after MV. Sixth, the mortality rate declined markedly for girls but not for boys when DTP-vaccinated children received MV. The authors reduced exposure to DTP as most recent vaccination by administering a live vaccine (MV and BCG) shortly after DTP. Both trials reduced child mortality. CONCLUSIONS: These observations are incompatible with DTP merely protecting against the targeted diseases. With herd immunity to whooping cough, DTP is associated with higher mortality for girls. Randomised studies of DTP are warranted to measure the true impact on survival.

High risk of non-sentinel node metastases in a group of breast cancer patients with micrometastases in the sentinel node.

Axillary lymph node dissection (ALND) in breast cancer patients with positive sentinel nodes is under debate. We aimed to establish two models to predict non-sentinel node (NSN) metastases in patients with micrometastases or isolated tumor cells (ITC) in sentinel nodes, to guide the decision for ALND. A total of 1,577 breast cancer patients with micrometastases and 304 with ITC in sentinel nodes, treated by sentinel lymph node dissection and ALND in 2002-2008 were identified in the Danish Breast Cancer Cooperative Group database. Risk of NSN metastases was calculated according to clinicopathological variables in a logistic regression analysis. We identified tumor size, proportion of positive sentinel nodes, lymphovascular invasion, hormone receptor status and location of tumor in upper lateral quadrant of the breast as risk factors for NSN metastases in patients with micrometastases. A model based on these risk factors identified 5% of patients with a risk of NSN metastases on nearly 40%. The model was however unable to identify a subgroup of patients with a very low risk of NSN metastases. Among patients with ITC, we identified tumor size, age and proportion of positive sentinel nodes as risk factors. A model based on these risk factors identified 32% of patients with risk of NSN metastases on only 2%. Omission of ALND would be acceptable in this group of patients. In contrast, ALND may still be beneficial in the subgroup of patients with micrometastases and a high risk of NSN metastases.

Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial.

BACKGROUND: Studies from low-income countries have suggested that diphtheria-tetanus-pertussis (DTP) vaccine provided after Bacille Calmette-Guerin (BCG) vaccination may have a negative effect on female survival. The authors examined the effect of DTP in a cohort of low birthweight (LBW) infants. METHODS: 2320 LBW newborns were visited at 2, 6 and 12 months of age to assess nutritional and vaccination status. The authors examined survival until the 6-month visit for children who were DTP vaccinated and DTP unvaccinated at the 2-month visit. RESULTS: Two-thirds of the children had received DTP at 2 months and 50 deaths occurred between the 2-month and 6-month visits. DTP vaccinated children had a better anthropometric status for all indices than DTP unvaccinated children. Small mid-upper arm circumference (MUAC) was the strongest predictor of mortality. The death rate ratio (DRR) for DTP vaccinated versus DTP unvaccinated children differed significantly for girls (DRR 2.45; 95% CI 0.93 to 6.45) and boys (DRR 0.53; 95% CI 0.23 to 1.20) (p=0.018, homogeneity test). Adjusting for MUAC, the overall effect for DTP vaccinated children was 2.62 (95% CI 1.34 to 5.09); DRR was 5.68 (95% CI 1.83 to 17.7) for girls and 1.29 (95% CI 0.56 to 2.97) for boys (p=0.023, homogeneity test). While anthropometric indices were a strong predictor of mortality among boys, there was little or no association for girls. CONCLUSION: Surprisingly, even though the children with the best nutritional status were vaccinated early, early DTP vaccination was associated with increased mortality for girls.

Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period?

BACKGROUND: Observational studies have suggested that BCG may have nonspecific beneficial effects on survival. Low-birth-weight (LBW) children are not given BCG at birth in Guinea-Bissau; we conducted a randomized trial of BCG at birth (early BCG) vs delayed BCG. METHODS: In the period 2004-2008 we recruited 2320 LBW children in Bissau. The children were visited at home at 2, 6, and 12 months of age. With a pretrial infant mortality of 250 per 1000, we hypothesized a 25% reduction in infant mortality for LBW children. RESULTS: Infant mortality was only 101 per 1000 during the trial. In the primary analysis, infant mortality was reduced insignificantly by 17% (mortality rate ratio [MRR] = .83 [.63-1.08]). In secondary analyses, early BCG vaccine was safe with an MRR of .49 (.21-1.15) after 3 days and .55 (.34-.89) after 4 weeks. The reduction in neonatal mortality was mainly due to fewer cases of neonatal sepsis, respiratory infection, and fever. The impact of early BCG on infant mortality was marked for children weighing <1.5 kg (MRR = .43 [.21-.85]) who had lower coverage for diphtheria-tetanus-pertussis vaccinations. CONCLUSIONS: Though early BCG did not reduce infant mortality significantly, it may have a beneficial effect in the neonatal period. This could be important for public health because BCG is often delayed in low-income countries.

Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial.

OBJECTIVE: To examine in a randomised trial whether a 25% difference in mortality exists between 4.5 months and 3 years of age for children given two standard doses of Edmonston-Zagreb measles vaccines at 4.5 and 9 months of age compared with those given one dose of measles vaccine at 9 months of age (current policy). DESIGN: Randomised controlled trial. SETTING: The Bandim Health Project, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area. PARTICIPANTS: 6648 children aged 4.5 months of age who had received three doses of diphtheria-tetanus-pertussis vaccine at least four weeks before enrolment. A large proportion of the children (80%) had previously taken part in randomised trials of neonatal vitamin A supplementation. INTERVENTION: Children were randomised to receive Edmonston-Zagreb measles vaccine at 4.5 and 9 months of age (group A), no vaccine at 4.5 months and Edmonston-Zagreb measles vaccine at 9 months of age (group B), or no vaccine at 4.5 months and Schwarz measles vaccine at 9 months of age (group C). Main outcome measure Mortality rate ratio between 4.5 and 36 months of age for group A compared with groups B and C. Secondary outcomes tested the hypothesis that the beneficial effect was stronger in the 4.5 to 9 months age group, in girls, and in the dry season, but the study was not powered to test whether effects differed significantly between subgroups. RESULTS: In the intention to treat analysis of mortality between 4.5 and 36 months of age the mortality rate ratio of children who received two doses of Edmonston-Zagreb vaccine at 4.5 and 9 months of age compared with those who received a single dose of Edmonston-Zagreb vaccine or Schwarz vaccine at 9 months of age was 0.78 (95% confidence interval 0.59 to 1.05). In the analyses of secondary outcomes, the intention to treat mortality rate ratio was 0.67 (0.38 to 1.19) between 4.5 and 9 months and 0.83 (0.83 to 1.16) between 9 and 36 months of age. The effect on mortality between 4.5 and 36 months of age was significant for girls (intention to treat mortality rate ratio 0.64 (0.42 to 0.98)), although this was not significantly different from the effect in boys (0.95 (0.64 to 1.42)) (interaction test, P=0.18). The effect did not differ between the dry season and the rainy season. As neonatal vitamin A supplementation is not WHO policy, the analyses were done separately for the 3402 children who did not receive neonatal vitamin A. In these children, the two dose Edmonston-Zagreb measles vaccine schedule was associated with a significantly lower mortality between 4.5 and 36 months of age (intention to treat mortality rate ratio 0.59 (0.39 to 0.89)). The effect was again significant for girls but not statistically significant from the effect in boys. When measles cases were censored, the intention to treat mortality rate ratio was 0.65 (0.43 to 0.99). CONCLUSIONS: Although the overall effect did not reach statistical significance, the results may indicate that a two dose schedule with Edmonston-Zagreb measles vaccine given at 4.5 and 9 months of age has beneficial non-specific effects on children's survival, particularly for girls and for children who have not received neonatal vitamin A. This should be tested in future studies in different locations. TRIAL REGISTRATION: Clinical trials NCT00168558.

Oral polio vaccine influences the immune response to BCG vaccination. A natural experiment.

BACKGROUND: Oral polio vaccine (OPV) is recommended to be given at birth together with BCG vaccine. While we were conducting two trials including low-birth-weight (LBW) and normal-birth-weight (NBW) infants in Guinea-Bissau, OPV was not available during some periods and therefore some infants did not receive OPV at birth, but only BCG. We investigated the effect of OPV given simultaneously with BCG at birth on the immune response to BCG vaccine. METHODS AND FINDINGS: We compared the in vitro and the in vivo response to PPD in the infants who received OPV and BCG with that of infants who received BCG only. At age 6 weeks, the in vitro cytokine response to purified protein derivate (PPD) of M. Tuberculosis was reduced in LBW and NBW infants who had received OPV with BCG. In a pooled analysis receiving OPV with BCG at birth was associated with significantly lower IL-13 (p = 0.041) and IFN-gamma (p = 0.004) and a tendency for lower IL-10 (p = 0.054) in response to PPD. Furthermore, OPV was associated with reduced in vivo response to PPD at age 2 months, the prevalence ratio (PR) of having a PPD reaction being 0.75 (0.58-0.98), p = 0.033, and with a tendency for reduced likelihood of having a BCG scar (0.95 (0.91-1.00), p = 0.057)). Among children with a scar, OPV was associated with reduced scar size, the regression coefficient being -0.24 (-0.43-0.05), p = 0.012. CONCLUSIONS: This study is the first to address the consequences for the immune response to BCG of simultaneous administration with OPV. Worryingly, the results indicate that the common practice in low-income countries of administering OPV together with BCG at birth may down-regulate the response to BCG vaccine.

Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau.

OBJECTIVE: To determine whether BCG revaccination at 19 months of age reduces overall child mortality. DESIGN: Randomised trial, with follow-up to age 5. SETTING: A health project in Bissau, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area with 90 000 inhabitants. PARTICIPANTS: 2871 children aged 19 months to 5 years with low or no reactivity to tuberculin and who were not severely sick on the day of enrollment. INTERVENTION: BCG vaccination or no vaccination (control). MAIN OUTCOME MEASURE: Hazard ratios for mortality. RESULTS: 77 children died during follow-up. Compared with controls, the BCG revaccinated children had a hazard ratio of 1.20 (95% confidence interval 0.77 to 1.89). Two hundred and fifty children were admitted to hospital for the first time between enrollment and the end of the study, with an incidence rate ratio for BCG revaccinated children versus controls of 1.04 (0.81 to 1.33). The trial was stopped prematurely because of a cluster of deaths in the BCG arm of the study. This increase in mortality occurred at a time when many children had received missing vaccinations or vitamin A or iron supplementation; the hazard ratio for BCG revaccinated children compared with controls was 2.69 (1.05 to 6.88) in the period after these campaigns. Throughout the trial, the effect of BCG revaccination on mortality was significantly different (P=0.006) in children who had received diphtheria-tetanus-pertussis (DTP) booster vaccination before enrollment (hazard ratio 0.36, 0.13 to 0.99) and children who had not received the booster before enrollment (1.78, 1.04 to 3.04). CONCLUSIONS: There was no overall beneficial effect of being revaccinated with BCG. The effect of BCG revaccination on mortality might depend on other health interventions. Trial registration Clinical Trials ICA4-CT-2002-10053-REVAC.

Sex differences in the effect of vaccines on the risk of hospitalization due to measles in Guinea-bissau.

BACKGROUND: Routine immunizations have non-specific and sex-differential effects on childhood mortality and morbidity in low-income countries; BCG and measles vaccine (MV) may reduce and diphtheria-tetanus-pertussis vaccine (DTP) may increase the mortality of girls relative to boys. SETTING: Urban area in Guinea-Bissau, with a demographic surveillance system and registration of all pediatric hospitalizations. Guinea-Bissau experienced a large outbreak of measles infection in 2003-2004. DESIGN: We used hospital and community data to examine the impact of other vaccines on the risk of hospitalizations for measles infection. Vaccine efficacy (VE) against hospitalization for children aged 6 to 59 months of age was examined. We assessed whether VE depended on vaccination status for other vaccines and whether the pattern differed for boys and girls. MAIN OUTCOME MEASURE: Sex-specific vaccine efficacy against hospitalization for children aged 6 to 59 months of age. RESULTS: The VE depended on sex and the sequence of vaccinations. The VE of MV against hospitalization for measles was better for girls than for boys. Among children who had received MV as the most recent vaccine VE against hospitalization was as high as 96% for girls, but only 81% for boys (P = 0.002). Among children who had received DTP simultaneously with MV or DTP after MV, VE declined for girls (91%) and increased for boys (90%). Compared with having received MV as most recent vaccination, DTP simultaneously with MV or DTP after MV improved the efficacy significantly for boys and the effect was significantly different for boys and girls (P = 0.023). The female-male risk ratio of hospitalization varied significantly, depending on the most recent vaccination (P = 0.014); it was 0.28 (0.11-0.68) for MV alone, but 1.21 (0.82-1.77) for DTP but no MV, and 1.13 (0.58-2.18) for DTP simultaneously with MV or after MV. Among MV-unvaccinated children, BCG-vaccinated girls had a lower risk of measles hospitalization than DTP-vaccinated girls (RR=0.0 (0.0-0.99), exact test).

Girls may have lower levels of maternal measles antibodies and higher risk of subclinical measles infection before the age of measles vaccination.

BACKGROUND: Previous studies have suggested that girls may have lower maternal measles antibody levels than boys. Girls might therefore be more likely to contract measles infection before the normal age of measles vaccination at 9 months of age. METHODS: In connection with a clinical trial of different measles vaccination strategies, we collected pre-measles vaccination blood samples at 4.5 months of age from two subgroups of children. Samples from these children were used to assess possible differences in maternal antibody levels for boys and girls. At 9 months of age another subgroup of children was sampled before the normal measles vaccination; these samples were used to assess the frequency of subclinical measles infection among boys and girls. RESULTS: We determined measles-specific antibody levels for 812 children at 4.5 months of age and for 896 children at 9 months of age. At 4.5 months of age girls were less likely to have protective maternal antibody levels, the male-female ratio for protective antibody level being 1.23 (1.00-1.51). Among children sampled at 9 months of age, girls were more likely to have protective levels, the female-male ratio for having protective antibody levels being 1.65 (0.98-2.78) (p=0.054) and the geometric mean titre was significantly higher for girls (p=0.007). Children who lived in houses with known measles cases were more likely to have protective levels at 9 months of age even though they had not reported measles infection. Since we had excluded children with known measles infection, girls may have been more likely to have had subclinical measles infection. Combining clinical and possible subclinical measles infection, girls tended to be more likely than boys to contract measles infection before 9 months of age, the RR being 1.36 (0.97-1.90). CONCLUSIONS: Girls lost maternal measles antibodies more rapidly than boys and well before 9 months of age. They may be more likely to contract subclinical measles infection before the current age of measles vaccination.

Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial.

RATIONALE: Vitamin D has been shown to be involved in the host immune response toward Mycobacterium tuberculosis. OBJECTIVES: To test whether vitamin D supplementation of patients with tuberculosis (TB) improved clinical outcome and reduced mortality. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in TB clinics at a demographic surveillance site in Guinea-Bissau. We included 365 adult patients with TB starting antituberculosis treatment; 281 completed the 12-month follow-up. The intervention was 100,000 IU of cholecalciferol or placebo at inclusion and again 5 and 8 months after the start of treatment. MEASUREMENTS AND MAIN RESULTS: The primary outcome was reduction in a clinical severity score (TBscore) for all patients with pulmonary TB. The secondary outcome was 12-month mortality. No serious adverse effects were reported; mild hypercalcemia was rare and present in both arms. Reduction in TBscore and sputum smear conversion rates did not differ among patients treated with vitamin D or placebo. Overall mortality was 15% (54 of 365) at 1 year of follow-up and similar in both arms (30 of 187 for vitamin D treated and 24 of 178 for placebo; relative risk, 1.19 [0.58-1.95]). HIV infection was seen in 36% (131 of 359): 21% (76 of 359) HIV-1, 10% (36 of 359) HIV-2, and 5% (19 of 357) HIV-1+2. CONCLUSIONS: Vitamin D does not improve clinical outcome among patients with TB and the trial showed no overall effect on mortality in patients with TB; it is possible that the dose used was insufficient. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN35212132).

Protective efficacy of standard Edmonston-Zagreb measles vaccination in infants aged 4.5 months: interim analysis of a randomised clinical trial.

OBJECTIVE: To examine the protective efficacy of measles vaccination in infants in a low income country before 9 months of age. DESIGN: Randomised clinical trial. PARTICIPANTS: 1333 infants aged 4.5 months: 441 in treatment group and 892 in control group. SETTING: Urban area in Guinea-Bissau. INTERVENTION: Measles vaccination using standard titre Edmonston-Zagreb vaccine at 4.5 months of age. MAIN OUTCOME MEASURES: Vaccine efficacy against measles infection, admission to hospital for measles, and measles mortality before standard vaccination at 9 months of age. RESULTS: 28% of the children tested at 4.5 months of age had protective levels of maternal antibodies against measles at enrolment. After early vaccination against measles 92% had measles antibodies at 9 months of age. A measles outbreak offered a unique situation for testing the efficacy of early measles vaccination. During the outbreak, 96 children developed measles; 19% of unvaccinated children had measles before 9 months of age. The monthly incidence of measles among the 441 children enrolled in the treatment arm was 0.7% and among the 892 enrolled in the control arm was 3.1%. Early vaccination with the Edmonston-Zagreb measles vaccine prevented infection; vaccine efficacy for children with serologically confirmed measles and definite clinical measles was 94% (95% confidence interval 77% to 99%), for admissions to hospital for measles was 100% (46% to 100%), and for measles mortality was 100% (-42% to 100%). The number needed to treat to prevent one case of measles between ages 4.5 months and 9 months during the epidemic was 7.2 (6.8 to 9.2). The treatment group tended to have lower overall mortality (mortality rate ratio 0.18, 0.02 to 1.36) although this was not significant. CONCLUSIONS: In low income countries, maternal antibody levels against measles may be low and severe outbreaks of measles can occur in infants before the recommended age of vaccination at 9 months. Outbreaks of measles may be curtailed by measles vaccination using the Edmonston-Zagreb vaccine as early as 4.5 months of age. TRIAL REGISTRATION CLINICAL TRIALS: NCT00168558 [ClinicalTrials.gov].

Thymus size at 6 months of age and subsequent child mortality.

OBJECTIVE: To examine determinants of thymus size at age 6 months and investigate whether thymus size at this age is a determinant of subsequent mortality. STUDY DESIGN: Thymus size was measured by transsternal sonography in 923 6-month-old children participating in a measles vaccination trial in Guinea-Bissau. RESULTS: Thymus size was strongly associated with anthropometric measurements. Boys had larger thymuses than girls, controlling for anthropometry. Crying during sonography made the thymus appear smaller. Children who were not vaccinated with Bacille Calmette-Guérin (BCG) or were vaccinated with BCG in the preceding 4 weeks before inclusion into the study had larger thymuses. Children who had malaria or had been treated with chloroquine or Quinimax in the previous week before inclusion had smaller thymuses. Controlled for background factors associated with thymus size and mortality, small thymus size remained a strong and independent risk factor for mortality (hazard ratio = 0.31; 95% confidence interval = 0.18 to 0.52). CONCLUSIONS: Small thymus size at age 6 months is a strong risk factor for mortality. To prevent unnecessary deaths, it is important to identify preventable factors predisposing to small thymus size.

Effect of 50,000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial.

OBJECTIVE: To investigate the effect of high dose vitamin A supplementation given with BCG vaccine at birth in an African setting with high infant mortality. DESIGN: Randomised placebo controlled trial. Setting Bandim Health Project's demographic surveillance system in Guinea-Bissau, covering approximately 90,000 inhabitants. Participants 4345 infants due to receive BCG. INTERVENTION: Infants were randomised to 50,000 IU vitamin A or placebo and followed until age 12 months. MAIN OUTCOME MEASURE: Mortality rate ratios. RESULTS: 174 children died during follow-up (mortality=47/1000 person-years). Vitamin A supplementation was not significantly associated with mortality; the mortality rate ratio was 1.07 (95% confidence interval 0.79 to 1.44). The effect was 1.00 (0.65 to 1.56) during the first four months and 1.13 (0.75 to 1.68) from 4 to 12 months of age. The mortality rate ratio in boys was 0.84 (0.55 to 1.27) compared with 1.39 (0.90 to 2.14) in girls (P for interaction=0.10). An explorative analysis revealed a strong interaction between vitamin A and season of administration. CONCLUSIONS: Vitamin A supplementation given with BCG vaccine at birth had no significant benefit in this African setting. Although little doubt exists that vitamin A supplementation reduces mortality in older children, a global recommendation of supplementation for all newborn infants may not contribute to better survival. TRIAL REGISTRATION: Clinical trials NCT00168597.

HIV progression and predictors of mortality in a community-based cohort of Zambian adults.

This article describes immunological HIV progression, mortality, and its predictors in 974 Zambian adults. During 3138 person-years of follow-up, 281 deaths occurred, and the overall mortality rate was 9.0 per 100 person-years. Thirty-six percent of patients were dead within 5 years of enrollment. The median survival in patients with baseline CD4 count ≥500 cells/mm³ was 5.62 years, with CD4 count between 200 and 499 cells/mm³ 5.46 years, and with CD4 count <200 cells/mm³ 3.89 years. The mortality rate increased significantly with older age (6.9 in patients <25 years, 9.3 in individuals aged 25-39 years, 10.2 in patients ≥40 years) and was higher in women (rate ratio 1.29). The median annual change of progression markers was -29.6 cells/mm³ for CD4 count, -3.0% for CD4 count percentage, 1.2 nmol/L for neopterin, -1.9 g/L for hemoglobin, and -70 cells/mm³ for total lymphocyte count. Hemoglobin and neopterin were as accurate as CD4 count to predict mortality.

Effect of vitamin A supplementation with BCG vaccine at birth on vitamin A status at 6 wk and 4 mo of age.

BACKGROUND: The effect of vitamin A supplementation (VAS) at birth on subsequent vitamin A status has not been studied. OBJECTIVE: The objective was to study the effect of 50,000 IU vitamin A administered with BCG vaccine at birth on vitamin A status in both sexes. DESIGN: Within a randomized placebo-controlled trial of VAS, we obtained blood from 614 children at 6 wk of age and from 369 mother-infant pairs at 4 mo of age. We assessed vitamin A status on the basis of serum retinol-binding protein (RBP) and measured serum C-reactive protein to monitor for concurrent infections. RESULTS: RBP concentrations indicated vitamin A deficiency in 32% of the children at age 6 wk and in 16% at age 4 mo. VAS was not associated with higher RBP concentrations overall or in either sex. However, the effect of VAS varied with maternal education (P for interaction = 0.004): At age 6 wk, VAS was associated with higher (9%; 95% CI: 2, 17%) RBP concentrations in children of noneducated mothers but not in children of educated mothers. Overall, RBP concentrations increased between 6 wk and 4 mo of age. The increase correlated inversely with the number of diphtheria-tetanus-pertussis (DTP) vaccines received in the interval (P = 0.009), particularly in girls (P for interaction = 0.01) and in vitamin A recipients (P = 0.01). CONCLUSIONS: Overall, VAS at birth had no effect on vitamin A status. However VAS may temporarily improve vitamin A status in the subgroup of children of noneducated mothers. In vitamin A recipients, subsequent DTP vaccines affected vitamin A status negatively. The main trial was registered at clinicaltrials.gov as NCT00168597.

Effect of high-dose vitamin A supplementation on the immune response to Bacille Calmette-Guerin vaccine.

BACKGROUND: Vitamin A supplementation (VAS) at birth has been associated with decreased mortality in Asia. Bacille Calmette-Guérin (BCG) vaccine is given at birth in tuberculosis-endemic countries. Previous studies suggest that VAS may influence the immune response to vaccines. OBJECTIVE: Our objective was to examine whether VAS influences the immune response to simultaneously administered BCG vaccine. DESIGN: Within a randomized trial of 50,000 IU vitamin A or placebo given with BCG vaccine at birth in Guinea-Bissau, 2710 infants were examined for BCG scar formation and delayed-type hypersensitivity (DTH) to purified protein derivative of Mycobacterium tuberculosis (PPD) at 2 and 6 mo of age. The ex vivo cytokine response to PPD was measured in 607 infants. RESULTS: At 2 mo of age, 39% (43% of the boys and 34% of the girls) responded to PPD. The prevalence ratio of a measurable PPD reaction for VAS compared with placebo recipients was 0.90 (95% CI: 0.80, 1.02) for all infants, 0.81 (95% CI: 0.69, 0.95) for boys, and 1.04 (95% CI: 0.86, 1.26) for girls. At 6 mo of age, 42% of the infants responded to PPD. No difference was observed between VAS and placebo recipients. The prevalence of BCG scar was not affected by VAS. The ex vivo interferon-gamma response to PPD was increased by VAS (means ratio: 1.40; 95% CI: 1.03, 1.91). CONCLUSIONS: VAS with BCG vaccination does not appear to interfere with the long-term immune response to BCG. However, VAS temporarily altered the DTH reaction to PPD in boys at 2 mo of age, suggesting sex differences in the immunologic response to VAS given with BCG. This trial was registered at www.clinicaltrials.gov as #NCT00168597.