Peter D. Christenson

A Comparative Efficacy Trial in Germany in Infants Who Received Either the Lederle/Takeda Acellular Pertussis Component DTP (DTaP) Vaccine, the Lederle Whole-Cell Component DTP Vaccine, or DT Vaccine

Background. The goal of the trial was to determine the efficacy of a multicomponent acellular pertussis vaccine against Bordetella illnesses in comparison with a whole-cell product and DT. Design. In a randomized, double-blind fashion, 2- to 4-month-old infants received 4 doses of either DTP or DTaP vaccine at 3, 4.5, 6, and 15 to 18 months of age. The controls received 3 doses (3, 4.5, 15 to 18 months of age) of DT vaccine. The DTP vaccine was Lederle adsorbed vaccine (licensed in the United States) and DTaP was Lederle/Takeda adsorbed vaccine. Follow-up for vaccine efficacy started 2 weeks after the third dose (DTP/DTaP) and at the same age (6.5 months) in DT recipients. Reactogenicity of all doses of all three vaccines was documented by standardized parent diary cards. In addition, all subjects were monitored for respiratory illnesses and serious adverse events by biweekly phone calls. Results. From May 1991 to January 1993, a total of 10 271 infants were enrolled: 8532 received either DTP or DTaP and 1739 received DT. Specific efficacy against B pertussisinfections with cough ≥7 days duration was 83% (95% confidence interval [CI]: 76–88) and 72% (95% CI: 62–79) for DTP and DTaP, respectively; results for DTP and DTaP based on ≥21 days of cough with either paroxysms, whoop or posttussive vomiting (PWV) were 93% (95% CI: 89–96) and 83% (95% CI: 76–88), respectively. For DTaP vaccine, efficacy was higher after the fourth dose as compared with its efficacy after the third dose (78% vs 62% for cough ≥7 days and 85% vs 76% for cough ≥21 days with PWV). For DTP vaccine, efficacy was less varied after the third and fourth dose (78% vs 85% for cough ≥7 days and 93% vs 93% for cough ≥21 days with PWV). In contrast with DTP, the DTaP vaccine had some efficacy against B parapertussisinfection (point estimate for cough ≥7 days: 31% [95% CI: −10–56]). All vaccines were generally well-tolerated. However, side reactions were significantly less after DTaP compared with DTP. Conclusions. Like other multicomponent acellular pertussis vaccines, the Lederle/Takeda DTaP vaccine demonstrated good efficacy against mild and typical pertussis due to B pertussisinfections. Interestingly, it also may have some efficacy againstB parapertussis. Based on the results of this trial, the vaccine was licensed in the United States in December 1996 for all 5 doses of the currently recommended immunization schedule in this country.

Acute secondary adrenal insufficiency after traumatic brain injury: A prospective study

Objective:To determine the prevalence, time course, clinical characteristics, and effect of adrenal insufficiency (AI) after traumatic brain injury (TBI). Design:Prospective intensive care unit–based cohort study. Setting:Three level 1 trauma centers. Patients:A total of 80 patients with moderate or severe TBI (Glasgow Coma Scale score, 3–13) and 41 trauma patients without TBI (Injury Severity Score, >15) enrolled between June 2002 and November 2003. Measurements:Serum cortisol and adrenocorticotropic hormone levels were drawn twice daily for up to 9 days postinjury; AI was defined as two consecutive cortisols of ≤15 &mgr;g/dL (25th percentile for extracranial trauma patients) or one cortisol of <5 &mgr;g/dL. Principal outcome measures included: injury characteristics, hemodynamic data, usage of vasopressors, metabolic suppressive agents (high-dose pentobarbital and propofol), etomidate, and AI status. Main Results:AI occurred in 42 TBI patients (53%). Adrenocorticotropic hormone levels were lower at the time of AI (median, 18.9 vs. 36.1 pg/mL; p = .0001). Compared with patients without AI, those with AI were younger (p = .01), had higher injury severity (p = .02), had a higher frequency of early ischemic insults (hypotension, hypoxia, severe anemia) (p = .02), and were more likely to have received etomidate (p = .049). Over the acute postinjury period, patients with AI had lower trough mean arterial pressure (p = .001) and greater vasopressor use (p = .047). Mean arterial pressure was lower in the 8 hrs preceding a low (≤15 &mgr;g/dL) cortisol level (p = .003). There was an inverse relationship between cortisol levels and vasopressor use (p = .0005) and between cortisol levels within 24 hrs of injury and etomidate use (p = .002). Use of high-dose propofol and pentobarbital was strongly associated with lower cortisol levels (p < .0001). Conclusions:Approximately 50% of patients with moderate or severe TBI have at least transient AI. Younger age, greater injury severity, early ischemic insults, and the use of etomidate and metabolic suppressive agents are associated with AI. Because lower cortisol levels were associated with lower blood pressure and higher vasopressor use, consideration should be given to monitoring cortisol levels in intubated TBI patients, particularly those receiving high-dose pentobarbital or propofol. A randomized trial of stress-dose hydrocortisone in TBI patients with AI is underway.

Clinical characteristics of illness caused by Bordetella parapertussis compared with illness caused by Bordetella pertussis

In conjunction with a pertussis vaccine efficacy trial in Germany, nasopharyngeal specimens were collected from May, 1992, to March, 1993, from patients with cough illnesses. Clinical data were obtained by initial and follow-up questionnaires. Bordetella parapertussis was isolated from 38 patients (mean age, 3.5 years; 68% girls). Clinical characteristics in these cases were compared with those of 76 patients (matched by age and sex) with illness caused by Bordetella pertussis during the same period. Findings were: (B. pertussis/B. parapertussis): cough > 4 weeks 57%/37% (P = 0.06); whoop 80%/59% (P = 0.07); whoop > 2 weeks 26%/18% (P = 0.05); paroxysms 90%/83% (P = 0.5); body temperature > or = 38 degrees C 9%/0% (P = 0.17); vomiting 47%/42% (P = 0.69); and mean leukocyte and lymphocyte counts 12,500/mm3 and 7600/mm3 (P < 0.0001) and 7800/mm3 and 3500/mm3 (P < 0.0001), respectively. Illness caused by B. parapertussis was typical of pertussis but less severe than that caused by B. pertussis. In contrast with B. pertussis infection, lymphocytosis is not a characteristic of B. parapertussis infection. This is most likely a result of the lack of production of lymphocytosis-promoting factor toxin by B. parapertussis.

Quantifying interictal metabolic activity in human temporal lobe epilepsy

The majority of patients with complex partial seizures of unilateral temporal lobe origin have interictal temporal hypometabolism on [18F]fluorodeoxyglucose positron emission tomography (FDG PET) studies. Often, this hypometabolism extends to ipsilateral extratemporal sites. The use of accurately quantified metabolic data has been limited by the absence of an equally reliable method of anatomical analysis of PET images. We developed a standardized method for visual placement of anatomically configured regions of interest on FDG PET studies, which is particularly adapted to the widespread, asymmetric, and often severe interictal metabolic alterations of temporal lobe epilepsy. This method was applied by a single investigator, who was blind to the identity of subjects, to 10 normal control and 25 interictal temporal lobe epilepsy studies. All subjects had normal brain anatomical volumes on structural neuroimaging studies. The results demonstrate ipsilateral thalamic and temporal lobe involvement in the interictal hypometabolism of unilateral temporal lobe epilepsy. Ipsilateral frontal, parietal, and basal ganglial metabolism is also reduced, although not as markedly as is temporal and thalamic metabolism.

Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis

BACKGROUND Hormonal methods for safe, reliable, and reversible contraception based on the suppression of spermatogenesis could soon become available. We have investigated the rate, extent, and predictors of reversibility of hormonal male contraception. METHODS We undertook an integrated multivariate time-to-event analysis of data from individual participants in 30 studies published in 1990-2005, in which sperm output was monitored every month until recovery. The primary outcome was the time for the sperm concentration to recover to a threshold of 20 million per mL, an indicator of fertility. We undertook univariate and multivariate analyses, using Kaplan-Meier and Coxs methods. FINDINGS 1549 healthy eugonadal men who were white (n=965), Asian (almost all Chinese men; n=535), or of other origins (n=49) and aged 18-51 years underwent 1283.5 man-years of treatment and 705 man-years of post-treatment recovery. These data represented about 90% of all published data from individuals using androgen or androgen-progestagen regimens. The median times for sperm to recover to thresholds of 20, 10, and 3 million per mL were 3.4 months (95% CI 3.2-3.5), 3.0 months (2.9-3.1), and 2.5 months (2.4-2.7), respectively. Multivariate Coxs analysis showed higher rates of recovery with older age, Asian origin, shorter treatment duration, shorter-acting testosterone preparations, higher sperm concentrations at baseline, faster suppression of spermatogenesis, and lower blood concentrations of luteinising hormone at baseline. The typical probability of recovery to 20 million per mL was 67% (61-72) within 6 months, 90% (85-93) within 12 months, 96% (92-98) within 16 months, and 100% within 24 months. INTERPRETATION Hormonal male contraceptive regimens show full reversibility within a predictable time course. Various covariables affect the rate but not the extent of recovery, although their effect sizes are minor. These data are crucial for the further safe and practical development of such regimens.

Comparison of acellular and whole-cell pertussis-component diphtheria-tetanus-pertussis vaccines in infants

In a multicenter, double-blind, randomized, longitudinal study, 252 children received licensed Lederle diphtheria-tetanus toxoids and pertussis vaccine adsorbed (DTP) at 2, 4, and 6 months of age, and 245 children received a DTP vaccine with the Lederle/Takeda acellular pertussis component (APDT) at the same ages. Both groups of children received APDT vaccine at 18 months of age. After each of the first three immunizations, APDT vaccine recipients had fewer local and systemic reactions than did DTP vaccinees. Reactions after the 18-month APDT vaccination were minimal in severity regardless of the vaccine previously received. Antibody responses to lymphocytosis-promoting factor and agglutinogens were more pronounced in DTP recipients; however, APDT recipients had a better serologic response to filamentous hemagglutinin, and responses to the 69K protein were equivalent. This APDT vaccine produces fewer reactions than the standard whole-cell DTP vaccine. The protective significance of the serologic responses to the APDT vaccine is unknown, but the greater response to filamentous hemagglutinin and equivalent response to the 69K protein compared with those to DTP vaccine seem promising.

Comparative study of Lederle/Takeda acellular and Lederle whole-cell pertussis-component diphtheria-tetanus-pertussis vaccines in infants in Germany

In preparation for a large efficacy trial in Germany, a pilot study was initiated in December 1990. In this study 149 infants were enrolled; with double-blind randomization 75 received Lederle/Takeda acellular pertussis component diphtheria-tetanus-pertussis vaccine (APDT) and 74 received Lederle whole-cell pertussis component diphtheria-tetanus-pertussis vaccine (DTP). The mean age at first dose was 3.5 months, and the second and third doses followed at 6-week intervals. Reactions were relatively mild with both vaccines; in general they were less frequent following APDT. The IgG antibody responses to lymphocytosis promoting factor (LPF) and fimbriae-2 were similar in both groups whereas the responses to pertactin and filamentous haemagglutinin (FHA) were greater in APDT recipients. DTP recipients had greater responses to tetanus and diphtheria toxoids. When age of first dose was examined (8-12 weeks versus 16-20 weeks), it was found that young age had a suppressive effect on antibody responses in DTP but not APDT recipients to LPF toxoid, pertactin, fimbriae-2, and tetanus and diphtheria toxoids. High values of transplacentally acquired antibody lessened the response to LPF toxoid and tetanus toxoid in DTP recipients and to tetanus toxoid in APDT vaccinees. The IgG immune response to LPF toxoid, FHA and fimbriae-2 was found to be more uniform in APDT recipients than in DTP vaccinees. An IgA antibody response to fimbriae-2 was noted in 13% of DTP recipients but in no APDT vaccinees. The broad immunogenicity and mild reactogenicity of this APDT vaccine justifies its use in the German efficacy trial.

Relationship of pertussis immunization to the onset of neurologic disorders: a retrospective epidemiologic study.

A retrospective epidemiologic study examining the relationship of the time of onset of neurologic disorders with the time of pertussis immunization in two cohorts of children who received pertussis immunization at different ages is reported. Before April 1970, children in Denmark were vaccinated with diphtheria and tetanus toxoids with pertussis vaccine at 5, 6, 7, and 15 months of age. Since 1970, children were given monovalent pertussis vaccine at 5 and 9 weeks and at 10 months of age. A total of 554 cases of epilepsy with onset between 28 days and 24 months of age were reviewed, 286 from the 1967-1968 period and 268 from the 1972-1973 period. There was no relationship between the age of onset of epilepsy and the scheduled age of administration of pertussis vaccine. A total of 2199 children with febrile seizures were reviewed, 830 from the 1967-1968 period and 1369 from the 1972-1973 period. There was a statistical association between first febrile seizures and the scheduled age of administration of pertussis vaccine (p = 0.004). No relationship between pertussis immunization and the occurrence of central nervous system infections was noted.

Clinical and laboratory diagnosis of pertussis in the regions of a large vaccine efficacy trial in Germany.

As a support service for a pertussis vaccine efficacy trial, a central diagnostic laboratory was established. Physicians in the geographic areas of the planned study were encouraged to send nasopharyngeal specimens from children and household contacts with cough illnesses whether or not the illnesses were typical of pertussis. From April, 1991, to February, 1992, 3629 specimens were received and in 601 instances (16.6%) Bordetella pertussis was isolated. Only 3.3% of patients with positive cultures had received pertussis vaccine whereas 16.1% of culture-negative patients had received vaccine (P > 0.0001). Fever was more common (12.2%) in patients with negative cultures compared with those with positive cultures (5.4%) (P > 0.0001). B. pertussis isolation rates fell markedly after 21 days of cough. Significantly more patients with negative cultures compared with those with positive cultures had been treated with erythromycin (8.5 vs. 2.9%; P > 0.0001). Patients with cough for greater than 4 weeks and specimen collection within 2 weeks of cough onset had a B. pertussis isolation rate of 59%. Similarly if whoop occurred under the same circumstances the isolation rate was 80%. In this study 25.5% of patients with culture confirmed pertussis had illnesses with cough of less than 21 days duration. This finding suggests to us that a pertussis case definition in efficacy trials that requires cough of 21 days is excessively restrictive.

Correlation of clinical and pathologic findings in early onset neonatal group B streptococcal infection with disease severity and prediction of outcome

This study analyzed the clinical characteristics of 69 neonates who were admitted to the University of Minnesota Hospital between January, 1972, and June, 1984, with early onset Group B streptococcal infection (EOGBS) and determined those features associated with fatal infection. The incidence of EOGBS was 1.6 cases/1000 live births among 7960 inborn infants; the mortality rate for inborn and outborn infants was 28%. Multivariate analysis identified five features adequately predicting fatal outcome: birth weight less than 2500 g, absolute neutrophil count less than 1500 cells/mm3, hypotension, apnea and a pleural effusion on the initial chest radiographs. With these five variables and an initial blood pH less than 7.25, a clinical score was constructed that correctly predicted outcome in 93% of patients in this study (87% sensitivity, 95% specificity). Autopsy findings in 16 of 19 infants with fatal EOGBS suggested that surfactant deficiency respiratory distress syndrome was common in preterm infants with EOGBS and contributed to their higher mortality compared with term infants.