A trial of acellular pertussis vaccine in hospital workers during the Cincinnati pertussis epidemic of 1993.

The safety and immunogenicity of acellular pertussis (AP) vaccine in outbreak control was determined in a randomized, double-blind, controlled trial. Participants received AP vaccine (n=102), which contained 25 microg of pertussis toxoid (PT) and 3 microg of filamentous hemagglutinin (FHA), or licensed meningococcal vaccine (MN; n=97). Local reactions (pain or tenderness, redness, swelling, and induration) and systemic reactions (fever, sleepiness or lethargy, and irritability) were similar among AP and MN vaccinees. One month after AP vaccination, the geometric mean level of IgG anti-PT was 33.1 microg/mL, with 2-fold increases in 85% of patients and 4-fold increases in 73% of patients; for IgG anti-FHA, the respective values were 34.7 microg/mL, 92%, and 63%. After 6 months of follow-up, no serological evidence of pertussis was seen among symptomatic or asymptomatic subjects. However, recent evidence of Bordetella pertussis infection before immunization was shown. Thus, AP vaccine was safe and immunogenic in adults.

The increasing incidence of pertussis in Massachusetts adolescents and adults, 1989-1998.

From 1989 to 1998, the incidence of pertussis increased in Massachusetts adolescents and adults, reaching 71 and 5 per 100,000, respectively, by 1998, whereas the incidence in children remained stable. By 1998, 92% of cases occurred in adolescents and adults. Nationally, in contrast, adolescents and adults had incidences of only 5 and 0.8 per 100,000, respectively, and accounted for 47% of cases. The availability of a specific serologic test and active surveillance by public health personnel in Massachusetts are at least partial explanations. The rise in incidence may be real, however, because, as diagnostic efforts increased, the percentage of patients with a positive serologic test result also increased. Cases identified in adolescents and adults were quite severe: 83% and 87%, respectively, experienced paroxysmal cough, 45% and 41% experienced vomiting, and 41% and 52% experienced a cough lasting >4 weeks. Administration of acellular pertussis vaccine in these age groups could prevent this substantial morbidity.

The changing epidemiology of invasive bacterial infections in Massachusetts children, 1984 through 1991.

Coincident with the licensure of Haemophilus influenzae b conjugate vaccines from 1987 to 1990, the incidence of meningitis and other invasive infections caused by H influenzae type b declined in Massachusetts children by 87% and 91%, respectively. By 1991, Neisseria meningitidis had replaced H influenzae b as the leading cause of bacterial meningitis, accounting for 57% of cases. During the period 1984 through 1991, serogroup C displaced sero-group B as the most common cause of N meningitidis disease. Streptococcus pneumoniae caused 92% of nonmeningitis invasive disease, with sero-groups 14, 6, 19, 18, 4, 23, and 9 causing 94.5% of infections. These findings have implications for the development of additional polysaccharide-protein conjugate vaccines for the prevention of childhood infections.

The 1993 epidemic of pertussis in Cincinnati. Resurgence of disease in a highly immunized population of children.

BACKGROUND: In 1993 there was a resurgence of pertussis in the United States. Altogether, 6335 cases were reported, the most in 26 years. METHODS: Using active microbiologic surveillance, we investigated the epidemic of pertussis in Greater Cincinnati in 1993. The population of 1.7 million in this area is served by a single children's hospital and pertussis laboratory. We prospectively followed patients given a new diagnosis of pertussis in July through September 1993 to determine the characteristics of the epidemic. RESULTS: From 1979 to 1992, there was a cumulative total of 542 cases of pertussis. In 1993, 352 cases were diagnosed, an increase of 259 percent over the 1992 total. Sixty-three percent of the cases had positive cultures for Bordetella pertussis, 18 percent were positive on direct fluorescent-antibody testing only, and 19 percent were diagnosed clinically. The outbreak began in the suburbs during the summer and spread through Greater Cincinnati. Of 255 total cases diagnosed in July through September (195 excess cases over the maximal base-line level of 20 per month in the previous 14 years), 75 percent were in white patients and 67 percent of the patients had private insurance or paid for care out of pocket. In 1993, as compared with 1979 through 1992, there was a shift in incidence from younger infants to older children; the percentages of cases according to age group were as follows: 0 to 6 months, 53 percent from 1979 through 1992 and 35 percent in 1993 (P < 0.001); 7 months to 5 years, 33 percent and 43 percent (P < 0.002); 6 to 12 years, 5 percent and 11 percent (P < 0.001); and more than 12 years, 5 percent and 11 percent (P < 0.003). Immunization records revealed that 74 percent (75 of 101) of the children with pertussis who were 19 months to 12 years old had received four or five doses of the combined diphtheria-pertussis-tetanus (DPT) vaccine, and that 82 percent (103 of 126) of those 7 to 71 months old had received at least three doses of DPT vaccine. The whole-cell vaccines used came from both of the major manufacturers (Connaught Laboratories and Lederle Laboratories). Disease was not severe, but 80 of the 255 children (31 percent) given diagnoses during the three epidemic months were hospitalized. There were no deaths. CONCLUSIONS: Since the 1993 pertussis epidemic in Cincinnati occurred primarily among children who had been appropriately immunized, it is clear that the whole-cell pertussis vaccine failed to give full protection against the disease.

Pertussis in Massachusetts, 1981-1991: incidence, serologic diagnosis, and vaccine effectiveness.

Massachusetts provides diphtheria-tetanus toxoid-pertussis (DTP) vaccine, and since 1980 has monitored pertussis with a statewide diagnostic service. The incidence of bacteriologically confirmed pertussis was 104.5 per 100,000 person-years in 1-month-old infants and declined progressively thereafter. Infants < 6 months old experienced disproportionate morbidity: 44% of bacteriologically confirmed pertussis, 64% of hospitalizations, and 71% of hospital days. Most children with pertussis had received < 3 DTP doses during childhood, whereas 87% of adolescents with pertussis had received > or = 4 doses. Serodiagnosis by single serum anti-pertussis toxin antibody ELISA increased the incidence of confirmed pertussis in persons 11-19 years old from 3.0 to 12.9 per 100,000 and in persons > or = 20 years old from 0.16 to 0.56 per 100,000. Bacteriologic methods underestimate pertussis incidence, but a single serum anti-pertussis toxin antibody ELISA is a practical method for population-based diagnosis in adolescents and adults.

Bacterial polysaccharide immune globulin for prophylaxis of acute otitis media in high-risk children.

We evaluated the prevention of recurrences of acute otitis media (AOM) by bacterial polysaccharide immune globulin (BPIG), a hyperimmune human immune globulin prepared by immunizing donors with bacterial polysaccharide vaccines. We used a randomized, stratified, double-blind, placebo-controlled design. Children < or = 24 months of age with 1 to 3 prior episodes of AOM received BPIG, 0.5 ml/kg, or saline placebo intramuscularly at entry and 30 days later. During the 120-day follow-up period, AOM was diagnosed by using clinical criteria and was confirmed with tympanocentesis and culture of the middle ear exudates. Eighty-eight episodes of AOM were observed in 76 patients who completed the study. The incidence of AOM during the entire 120-day study period was similar in BPIG and placebo recipients. Pneumococcal AOM was significantly less frequent in BPIG recipients (0.21 episode per patient) than in placebo recipients (0.45 episode per patient; p = 0.05). Time spent free of AOM was significantly prolonged in recipients of BPIG, in comparison with placebo recipients (51 vs 35 days; p = 0.034). This study demonstrated that circulating antibody, even without stimulation of specific local immunity, may prevent infection of the middle ear. The use of immune globulin preparations for longer periods or at a higher dosage might decrease the incidence of recurrent AOM in otitis-prone children, and deserves further evaluation.

Efficacy of Haemophilus influenzae type b vaccines in Massachusetts children 18 to 59 months of age.

Since 1987 Haemophilus influenzae b (Hib) conjugate vaccines have been licensed for use in children ages 18 months and older. Before licensure there were no clinical trials of a single dose of any conjugate vaccine in children ages 18 months or older. To fulfill this need we performed an age- and residence-matched case-control study of the efficacy of Hib vaccines. In our study population the protective efficacy (PE) of Hib-diphtheria toxoid conjugate vaccine was 88% (95% confidence interval, 45 to 98%). No vaccine failures were observed with Hib oligosaccharide CRM197 diphtheria protein conjugate vaccine, but usage was not sufficient to establish efficacy: PE = 100% (95% confidence interval, -37 to 100%). The protective efficacy of Hib capsular polysaccharide vaccine was 18% (95% confidence interval -487 to 89%). We conclude that for children ages 18 to 60 months a single dose of the Hib conjugate vaccine, PRP-D, is protective against invasive Hib infections. Consistent with most studies Hib polysaccharide vaccine provided suboptimal protection.

Measuring the comparative efficacy of antibacterial agents for acute otitis media: the "Pollyanna phenomenon".

In randomized, double-blind trials of antibiotic therapy for acute otitis media that determined both clinical and bacteriologic outcomes, clinical success rates were (93%) 236 of 253 for patients with bacteriologic success, (62%) 25 of 40 for those with bacteriologic failure, and (80%) 124 of 155 for those with nonbacterial acute otitis media. These rates were used to calculate the effectiveness of three strategies for assessing drug efficacy: (1) tympanocentesis and culture before and during therapy (bacteriologic efficacy), (2) tympanocentesis before therapy and assessment of clinical efficacy in bacterial acute otitis media, and (3) no tympanocentesis and assessment of clinical efficacy in clinical (total) acute otitis media. For a drug with a bacteriologic efficacy of 100%, calculated clinical efficacy was 93% for bacterial acute otitis media and 89% for clinical acute otitis media. For a drug with bacteriologic efficacy of 27%, a rate consistent with no antibacterial therapy, efficacy was 71% for bacterial acute otitis media and 74% for clinical acute otitis media. We conclude that if efficacy is measured by symptomatic response, drugs with excellent antibacterial activity will appear less efficacious than they really are and drugs with poor antibacterial activity will appear more efficacious than they really are. The predominant phenomenon is that drugs with poor antibacterial activity will appear to be clinically effective in the treatment of acute otitis media.

Host factors and early therapeutic response in acute otitis media.

To evaluate the relationship between eradication of bacterial infection and clinical improvement in children with otitis media, we reviewed the clinical outcome of bacterial otitis media in patients enrolled in double-blind trials of antibacterial therapy from 1979 to 1988. Cultures of middle ear exudates showed the distribution of bacterial pathogens to be similar to that observed in other geographic areas. Two hundred ninety-three patients had otitis media caused by bacterial pathogens and underwent repeat tympanocentesis after 3 to 6 days of therapy. Bacteriologic success was demonstrated in 253 patients (86%); 40 patients (14%) had bacteriologic failure. Children who had bacteriologic failure were younger than those with bacteriologic success (median age 10.6 vs 18.5 months; p = 0.001); 38% of patients who had bacteriologic failure were black, compared with 18% of patients with bacteriologic success (p = 0.007). Gender, history of frequent otitis media, and presence of bilateral otitis media were not risk factors for bacteriologic failure. Clinical success was demonstrated in 261 patients (89%); 32 patients (11%) had clinical failure. Agreement between clinical and bacteriologic response was 86% (95% confidence interval: 81.6% to 89.6%). Ninety-three percent (236/253) of subjects whose infection was eliminated had clinical resolution, whereas 37% (15/40) of those with bacteriologic failure had persisting symptoms or signs of clinical failure. We conclude that failure to eliminate bacteria from the middle ear is often associated with persistent signs and symptoms. Bacteriologic failure affects children less than 18 months of age almost exclusively. Bacteriologic and clinical failure are frequently discordant; mechanisms unrelated to the bacterial infection may explain some of the persisting clinical signs.

Acute phase reactants and risk of bacterial meningitis among febrile infants and children.

STUDY OBJECTIVE: To test the hypothesis that quantitation of either C-reactive protein (CRP) or the total peripheral WBC count can improve clinical detection of underlying bacterial meningitis among young febrile children. DESIGN: Cross-sectional survey of selected symptoms of central nervous system infection, signs of meningeal irritation and/or elevated intracranial pressure, levels of CRP in serum, and total peripheral WBC counts among unselected pediatric patients undergoing lumbar punctures for evaluation of acute febrile illnesses. SETTING: Emergency department and acute care "walk-in" clinic of an urban, university-affiliated general hospital. PARTICIPANTS: 160 previously well, acutely febrile infants and children (median age, 6 months). RESULTS: The prevalence of bacterial meningitis was 6%. Sensitivity of symptoms was 1.00 and specificity was 0.17. Sensitivity of signs was 0.70 and specificity was 0.81. Of the acute phase reactants, sensitivity of a CRP level of more than 1.0 mg/dL was 0.80, while that of a total peripheral WBC count of more than 15,000/mm3 was 0.40. The presence of signs and/or a CRP level of more than 1.0 mg/dL correctly identified all children with bacterial meningitis (sensitivity, 1.00). The absence of signs and a CRP level of 1.0 mg/dL or less correctly identified 71 of 150 children without bacterial meningitis (specificity, 0.47). Of 125 children without meningeal signs, the combination of symptoms and a CRP level of more than 1.0 mg/dL correctly identified all three children with bacterial meningitis (sensitivity, 1.00). The absence of these symptoms and/or a CRP level of 1.0 mg/dL or less correctly identified 80 of 122 children without bacterial meningitis (specificity, 0.66). CONCLUSION: Quantitation of CRP but not the total peripheral WBC count can increase the sensitivity of physical examination findings and the specificity of symptoms for the diagnosis of bacterial meningitis. Measurement of CRP in serum is useful as an adjunct to history and physical examination for the detection of acute bacterial meningitis in the acutely febrile child.

Spectrum of disease due to Branhamella catarrhalis in children with particular reference to acute otitis media.

For many years Branhamella catarrhalis was regarded as a non-pathogenic inhabitant of the respiratory tract. This article outlines the spectrum of B. catarrhalis disease in childhood and the extent of the evidence for a pathogenic role of the organism. B. catarrhalis is a rare etiologic agent in septicemia, meningitis, and other systemic illness in both apparently normal and immunocompromised infants and children. It is an unusual cause of ophthalmia neonatorum, but can be confused with Neisseria gonorrhoeae. Whether or not B. catarrhalis is acquired from the birth canal in these cases has not been established. B. catarrhalis is most common as a respiratory tract pathogen in children, including pneumonia, bacterial tracheitis, sinusitis, and otitis media. Since it is difficult to rigorously document pathogenicity of any bacterium in bronchopulmonary infections in children, it is probable that the spectrum of B. catarrhalis disease is wider than that reported to date. The evidence for pathogenicity in acute otitis media is more extensive than for other infections. Otitis media due to B. catarrhalis is clinically similar to that due to other pathogens. B. catarrhalis can be isolated in pure culture from the middle ear exudate and persists if there is no antibacterial treatment. Gram-negative intracellular and extracellular diplococci can be seen on smears of the inflammatory exudate. There is preliminary evidence that there is an antibody response in B. catarrhalis otitis media. B. catarrhalis has emerged as an important and common pathogen in neonates, infants, and children.

Persistence of antibody and booster responses to reimmunization with Haemophilus influenzae type b polysaccharide and polysaccharide diphtheria toxoid conjugate vaccines in children initially immunized at 15 to 24 months of age.

To evaluate the persistence of antibody after Haemophilus influenzae type b polysaccharide vaccine (PRP) and H influenzae type b polysaccharide diphtheria toxoid conjugate vaccine (PRP-D), a group of 141 infants initially immunized between 15 and 24 months of age were studied 1 year later. One month after immunization with PRP, the man anti-PRP antibody level was 0.27 microgram/mL and 1 year later was 0.29 microgram/mL (not significant). In the group immunized with PRP-D, the levels were 1.34 micrograms/mL and 1.20 micrograms/mL (not significant), respectively. To evaluate immunogenicity and safety of a booster immunization 1 year after initial vaccination, subjects were randomly assigned to receive saline, PRP, or PRP-D. In addition, 73 age-matched previously unimmunized subjects were vaccinated with PRP or PRP-D. In all groups, adverse reactions were minor and resolved by 48 hours. Subjects receiving booster immunization with PRP or PRP-D had significantly greater antibody responses than children of the same age receiving their first dose of vaccine. The highest antibody levels were achieved in children initially immunized with PRP-D, regardless of whether the booster vaccine was PRP (112.8 micrograms/mL) or PRP-D (122.0 micrograms/mL) (not significant). Antibody levels after booster vaccine were significantly lower in those initially given PRP compared with those initially given PRP-D but significantly higher than in age-matched previously unimmunized control subjects (PRP booster 3.16 micrograms/mL vs control of 0.62 microgram/mL [P less than .05]; PRP-D booster 12.31 micrograms/mL vs control 2.31 micrograms/mL [P less than .01]).

Depression of anticapsular antibody after immunization with Haemophilus influenzae type b polysaccharide-diphtheria conjugate vaccine.

Invasive Haemophilus influenzae type b infections have been observed in the week after immunization with capsular polysaccharide vaccine. We sought to document depression of antibody concentrations after immunization of 18-month-old infants with H. influenzae type b capsular polysaccharide-diphtheria conjugate vaccine. All 9 infants with detectable preimmunization anticapsular antibody had depression of antibody concentrations on the second day after immunization (P = 0.002). By Day 7 all had achieved anticapsular antibody concentrations greater than 0.15 micrograms/ml, a level believed to provide protection to immediate challenge with H. influenzae type b. Of those without detectable preimmunization antibody, 7 of 21 (33%; 95% confidence interval, 11 to 56%) had not achieved concentrations of greater than 0.15 mg/ml 1 week after immunization. We conclude that there is depression of anticapsular antibody concentrations during the first week after immunization with H. influenzae type b capsular polysaccharide-diphtheria conjugate vaccine. We speculate that H. influenzae type b infections after immunization with H. influenzae type b vaccines may be the result of: (1) low antibody concentrations because of either depression of antibody concentrations or failure to develop antibody; and (2) exposure to H. influenzae type b. Depression of antibody concentrations could be explained by binding of in vivo antibody to the vaccine.

The Red Ear-drum: To Treat or Not To Treat?

Acute otitis media is typified by the patient with fever, earache, and a "red" ear-drum. Suppurative otitis media, however, often presents without specific symptoms, and redness is the least reliable physical finding. Impaired tympanic membrane mobility on pneumatic otoscopy and bulging and opacification of the ear-drum are more reliable and important physical signs. Review of placebo-controlled trials reveals that antimicrobial therapy produces more rapid relief of fever and earache in patients with the most symptoms. Effects on patients with fewer symptoms are more modest. Amoxicillin remains the standard first-line treatment. Reasonable indications for alternative therapy are reviewed.

Serous and recurrent otitis media. Pharmacological or surgical management?

The management of recurrent acute otitis media and serous otitis media is both challenging and controversial. The efficacy of antimicrobial prophylaxis of children at high risk for recurrent acute otitis media is established, but the indications for such therapy are controversial. Tympanostomy tube insertion also decreases the frequency of recurrent otitis media. High-risk children can be successfully managed with chemoprophylaxis from autumn through to spring. If this fails, then tympanostomy tube insertion should be considered. Serous otitis media that follows acute otitis media resolves spontaneously in more than 90% of cases. Serous otitis media of unknown onset also has a strong tendency to resolve without treatment. Antihistamines and decongestants, although popular, have no significant effect on the course of serous otitis media. Antimicrobial therapy has a modest effect on the resolution of serous otitis media. Tympanostomy tubes usually improve the conductive hearing loss associated with serous otitis media and should be used when bilateral serous otitis media fails to resolve spontaneously. If repeated tympanostomy tube insertion fails, then adenoidectomy should be considered. With the course of management outlined, most children will have a successful outcome with conservative therapy and the need for surgery will be minimised.