Kim Knudsen

A randomized double-blind trial comparing a two-component acellular to a whole-cell pertussis vaccine in Senegal

A randomized, double-blind trial comparing a diphtheria-tetanus-acellular pertussis vaccine (DTaP) (pertussis toxoid and filamentous hemagglutinin) with a whole-cell vaccine (DTwP) was conducted. A case-contact study was nested in the trial to estimate absolute efficacy. From 1990 through 1994, 4181 children were randomized to receive one of the vaccines at 2, 4, and 6 months. Severe adverse events were monitored weekly during two visits after vaccination. Fewer serious adverse events were observed after DTaP. Surveillance for cough illnesses persisting more than 7 days, in children under 15 years of age, was made by weekly home visits. Examining physicians, blind to vaccination status, took samples for culture and serologic testing. Pertussis was defined as 21 or more days of cough confirmed by culture, serology, or contact with a culture-confirmed person. Beginning 28 days after the third vaccine dose, the overall ratio of pertussis incidence in the DTaP group relative to the DTwP group (RRac/wc) was 1.54 (95% CI, 1.23-1.93). In children younger than 18 months of age, RRac/wc was 1.16 (95% CI, 0.77-1.73) and 1.76 (95% CI, 1.33-2.33) in children older than 18 months, which suggests a shorter duration of protection with the acellular vaccine (P = 0.090). Absolute efficacy estimates derived from the case-contact study confirmed the lower protection afforded by the acellular vaccine compared with the whole-cell vaccine: 31% (95% CI, 7-49) versus 55% against the protocol case definition, and 85% (95% CI, 66-93) versus 96% for the more severe WHO case definition. Although vaccination with DTaP provided a lower degree of protection than the highly effective DTwP, this difference was less prominent before 18 months of age, the customary age for a fourth dose. The safer DTaP vaccine may prove a valuable substitute for whole-cell vaccines when used in a schedule that includes a booster-dose.

Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries

Abstract Objective: To examine whether the reduction in mortality after standard titre measles immunisation in developing countries can be explained simply by the prevention of acute measles and its long term consequences. Design: An analysis of all studies comparing mortality of unimmunised children and children immunised with standard titre measles vaccine in developing countries. Studies: 10 cohort and two case-control studies from Bangladesh, Benin, Burundi, Guinea-Bissau, Haiti, Senegal, and Zaire. Main outcome measures: Protective efficacy of standard titre measles immunisation against all cause mortality. Extent to which difference in mortality between immunised and unimmunised children could be explained by prevention of measles disease. Results: Protective efficacy against death after measles immunisation ranged from 30% to 86%. Efficacy was highest in the studies with short follow up and when children were immunised in infancy (range 44-100%). Vaccine efficacy against death was much greater than the proportion of deaths attributed to acute measles disease. In four studies from Guinea-Bissau, Senegal, and Burundi vaccine efficacy against death remained almost unchanged when cases of measles were excluded from the analysis. Diphtheria-tetanus-pertussis and polio vaccinations were not associated with reduction in mortality. Conclusion: These observations suggest that standard titre measles vaccine may confer a beneficial effect which is unrelated to the specific protection against measles disease.

Long-term survival after Edmonston-Zagreb measles vaccination in Guinea-Bissau: increased female mortality rate

In an urban area of Guinea-Bissau, 384 children were enrolled in a randomized trial comparing morbidity and mortality rates after receiving high-titer Edmonston-Zagreb (EZ) measles vaccine administered from 4 months of age, with a control group receiving inactivated poliomyelitis vaccine at 4 months of age and the standard Schwarz vaccine from 9 months of age. Children were followed to the age of at least 3 years. The mortality ratio of the EZ vaccinees compared with control subjects was 1.79 (range, 1.06 to 3.02; p = 0.027) if children were excluded at the time of migration; if deaths after migration were included, the mortality ratio was 1.53 (range, 0.94 to 2.49; p = 0.087). Girls in the EZ group had significantly higher mortality rates than girls in the control group (mortality ratio = 1.95; range, 1.07 to 3.56; p = 0.027); there was no difference for the boys (mortality ratio = 0.98; range, 0.41 to 2.30). Adjustment for background factors in a Cox regression model did not modify these estimates. Furthermore, female recipients of EZ vaccine had more days with diarrhea (relative risk = 1.35; range, 1.17 to 1.56; p = 0.00003) and were more likely than control subjects to visit a health center in the month after vaccination (relative risk = 1.86; range, 1.05 to 3.31; p = 0.027); those who consulted were more likely to die subsequently (mortality ratio = 2.31; range, 0.99 to 5.41; p = 0.054). These observations were unplanned and require confirmation in larger studies.

TRIAL OF HIGH-DOSE EDMONSTON-ZAGREB MEASLES VACCINE IN GUINEA-BISSAU: PROTECTIVE EFFICACY

In a randomised study of 558 children in an urban African community, the protective effect of the Edmonston-Zagreb (EZ) measles vaccine given in a dose of 40,000 plaque forming units from the age of 4 months was compared with the effects of a standard dose (6000 tissue culture infectious units) of Schwarz measles vaccine given from the age of 9 months. During two years of follow-up, all 14 clinical cases of measles occurred in the Schwarz group; 10 of the children contracted measles before vaccination and 4 after measles vaccination. Thus the EZ vaccine provided significant protection against measles both before and after the usual age of vaccination. Among the children who were exposed to measles at home, those given EZ vaccine were better protected than either unvaccinated children or those given the Schwarz vaccine.

A community study of T lymphocyte subsets and malaria parasitaemia

In a community survey of 312 children aged 3-6 years in urban Guinea-Bissau, we examined Plasmodium falciparum parasitaemia and T cell subsets. 183 children (59%) had parasites in their blood, 13 had fever > or = 37.5 degrees C, and 9 (3%) had fever and a parasite density > 5000/microL (clinical malaria). Compared with children with no parasitaemia or asymptomatic parasitaemia, children with acute malaria had lymphopenia and significantly lower total CD4 and CD8 cell counts, but there was no significant difference in white blood cell count percentages of CD4 and CD8 cells, or the CD4/CD8 ratio. Children with parasitaemia but without fever had a significantly lower percentage of CD4 cells than children without parasites (P = 0.031), but did not differ in any other haematological index. Controlling for other factors, the CD4 cell percentage was inversely correlated with the density of malaria parasites (P = 0.024), whereas there was no association with CD8 cell percentage or the CD4/CD8 ratio. Asymptomatic parasitaemia may be an important confounder in general community studies of T cell subsets in the tropics.

No persistent T lymphocyte immunosuppression or increased mortality after measles infection : a community study from Guinea-Bissau

BACKGROUND Because measles immunization is reducing overall childhood mortality in addition to mortality from acute measles infection, it has been suggested that postmeasles cases have excess mortality, possibly related to persistent immunosuppression after measles infection. After an epidemic in 1988 in Guinea-Bissau, we therefore examined T lymphocyte subsets and long term survival among measles cases and controls. METHODS We examined 69 children < 3 years of age with a median delay of 2 months after measles infection and 71 controls who did not contract measles. The immunoalkaline method was used to determine T lymphocyte subsets. The children were followed for 5 years. RESULTS Compared with controls, there were no significant differences in white blood cell count, absolute lymphocyte count, CD4 percentage, CD8 percentage, total CD4 count and total CD8 count, although measles cases examined > 2 months after infection had slightly higher CD4 counts than controls (P = 0.06). Adjusted for age, sex and immunization status, postmeasles cases had a mortality rate ratio of 0.50 (95% confidence interval, 0.22 to 1.16) (P = 0.11) compared with controls. CONCLUSIONS There is no indication of persistent suppression of T cell subsets after measles infection, and postmeasles cases did not have higher mortality than uninfected community controls.

The value of mucus hypersecretion as a predictor of mortality and hospitalization. An 11-year register based follow-up study of a random population sample of 876 men.

The value of mucus hypersecretion as a predictor of mortality and hospitalization was studied in a random population sample of 876 men, aged 46-69 years. The cohort was examined in 1974 with the British Medical Research Council questionnaire and lung function tests. A total of 219 men had died between 1974 and 1985. Twenty-seven men died from lung cancer and 14 died from other respiratory diseases. Mucus hypersection was not found to be significantly related to overall mortality after controlling for age, smoking and FEV1. Similarly, mucus hypersection was not a predictor of lung cancer mortality after controlling for age and smoking habits. The predictive value concerning death due to respiratory disease could not be examined because of the limited number of deaths in the cohort from these diseases. Mucus hypersecretion was not significantly related to hospitalization in general. Mucus hypersecretion had a significant predictive value concerning hospitalization due to respiratory disease in general, but the value was insignificant after controlling for FEV1. In contrast to this, mucus hypersecretion was a significant predictor of hospitalization due to COPD, even after controlling for FEV1. We conclude that the predictive value of mucus hypersecretion concerning mortality is of no value. Concerning morbidity, our results show that, although secondary to airflow obstruction, mucus hypersecretion must be viewed as an indicator of severity of COPD.

A comparison of vaccine efficacy and mortality during routine use of high-titre Edmonston-Zagreb and Schwarz standard measles vaccines in rural Senegal

Vaccine efficacy and mortality in successive cohorts of children who routinely received either Edmonston-Zagreb high-titre (EZ-HT) or Schwarz standard (SW-STD) measles vaccines have been examined in a rural area of Senegal. The 2 vaccines were equally protective against measles infection (vaccination efficacy: EZ-HT 94%; SW-STD 93%). Children who did not attend a scheduled session to receive measles vaccine had a higher mortality rate between 9 months and 2 years of age than did children receiving either EZ-HT (mortality ratio [MR] = 1.81, 95% confidence interval [CI] 1.06-3.08) or SW-STD measles vaccine (MR = 1.74, 95% CI 0.95-3.21). Children of either sex vaccinated with EZ-HT had lower mortality than their equivalents who had not received any measles vaccine. There was no difference in overall mortality between recipients of EZ-HT and SW-STD (MR = 0.96, 95% CI 0.70-1.30). Using a Cox regression analysis to adjust for sex, age and significant background factors (season and death of mother), mortality rates tended to be lower for male recipients of EZ-HT than for boys receiving SW-STD (MR = 0.73, 95% CI 0.50-1.11) and higher for girls receiving EZ-HT than for girls receiving SW-STD (MR = 1.30, 95% CI 0.81-2.09) (test of interaction between sex and vaccine, P = 0.067). The tendency to reduced survival benefit for girls following receipt of high-titre measles vaccines substantiated observations from randomized trials in Guinea-Bissau, Senegal and Haiti. Existing data provide little support for the notion that high-titre vaccine is deleterious but it may not have the same beneficial effects as standard-titre measles vaccine.

Exposure to cement dust at a Portland cement factory and the risk of cancer.

The relation between exposure to cement dust and cancer was examined in a population of 546 cement workers and a reference population of 858 randomly sampled men of similar age and area of residence. In 1974 all men gave lifelong occupational and smoking histories; information on incidence of cancer in the period 1974-85 was obtained from the Danish Cancer Registry. No increased risk of overall cancer was found among cement workers. Among men with more than 20 years exposure to cement dust, 14 cases of respiratory cancer were observed (observed/expected (O/E) 1.52, 95% confidence interval (95% CI) 0.90-2.57) when compared with all Danish men. Men with 1-20 years exposure had O/E 1.14 (95% CI 0.59-2.19) based on nine cases of cancer. After excluding all men with documented exposure to asbestos during employment in an asbestos cement factory no increased risk of overall cancer or respiratory cancer was found among cement workers compared with white collar workers from the local reference population, using a Cox regression model controlling for age and smoking habits. Relative risks were 0.5 (95% CI 0.1-1.5) and 1.0 (95% CI 0.4-2.6) for men with 1-20 and more than 20 years of exposure to cement dust respectively compared with white collar workers.

Increased risk of death from measles in children with a sibling of opposite sex in Senegal.

OBJECTIVE--To examine whether contracting measles from a sibling of the opposite sex affects mortality. DESIGN--Prospective registration during 15-20 years of all births and deaths, including 243 measles related deaths. Measles infection was not registered; however, as in fatal cases measles was probably contracted from a maternal sibling the risk of dying during measles outbreaks was examined in families with two boys, two girls, or a boy and a girl. SETTING--31 small villages in two rural areas of eastern Senegal. SUBJECTS--766 children living in families with two children aged under 10 years during outbreaks of measles, 107 (14%) of whom died of measles. MAIN OUTCOME MEASURE--Deaths from measles, size of village, age and sex of maternal siblings. RESULTS--The interval between outbreaks in the same village was greater than 10 years. The risk of dying of measles was significantly related to age, increasing with the age difference between siblings and decreasing with the size of village. In a multiple logistic regression analysis adjusting for these background factors, children in families with a boy and a girl had a significantly higher mortality than children in families with two boys or two girls (odds ratio = 1.81, 95% confidence interval 1.17 to 2.82). The increase in risk was the same for boys and girls in families with two children one of whom was a boy and one a girl. CONCLUSION--Cross sexual transmission may be an important determinant of severity of measles infection.