Microbial etiology of community-acquired pneumonia in the adult population of 4 municipalities in eastern Finland.

To determine the etiology of community-acquired pneumonia in the adult population of a defined area, specific antibody responses in paired serum samples, levels of circulating pneumococcal immune complexes in serum samples, and pneumococcal antigen in urine were measured. Samples (304 paired serum samples and 300 acute urine samples) were obtained from 345 patients > or =15 years old with community-acquired, radiologically confirmed pneumonia, which comprised all cases in the population of 4 municipalities in eastern Finland during 1 year. Specific infecting organisms were identified in 183 patients (including 49 with mixed infection), as follows: Streptococcus pneumoniae, 125 patients; Haemophilus influenzae, 12; Moraxella catarrhalis, 8; chlamydiae, 37 (of which, Chlamydia pneumoniae, 30); Mycoplasma pneumoniae, 30; and virus species, 27. The proportion of patients with pneumococcal infections increased and of those with Mycoplasma infections decreased with age, but for each age group, the etiologic profile was similar among inpatients and among outpatients. S. pneumoniae was the most important etiologic agent. The annual incidence of pneumococcal pneumonia per 1000 inhabitants aged > or =60 years was 8.0.

Etiology of childhood pneumonia: serologic results of a prospective, population-based study.

BACKGROUND: To investigate the etiology of pediatric community-acquired pneumonia, we conducted a prospective, population-based study covering the total population <15 years of age (n = 8851) in 4 municipalities in eastern Finland. MATERIALS AND METHODS: The number of patients was 201; chest radiographs were available for all cases and paired sera for serologic assays were available for >90% of cases. The methods included assays for antibody response to 3 pneumococcal antigens, specific pneumococcal immune complex assays and conventional antibody tests for mycoplasmal, chlamydial and viral infections. RESULTS: Serologic evidence of specific microbial etiology was obtained in 133 (66%) of the pneumonia patients. Bacterial infection was diagnosed in 102 cases (51%) and viral infection in 51 cases (25%). Streptococcus pneumoniae was the most common agent (57 cases; 28%), followed by Mycoplasma pneumoniae (44; 22%), respiratory syncytial virus (43; 21%) and Chlamydia spp. (29; 14%). Haemophilus influenzae was identified in only 6% and Moraxella catarrhalis in only 3% of the children. More than one specific infection was found in 51 patients (25%). The proportion of pneumococcal cases varied from 24 to 36% by age. Mycoplasma infections were seen mostly in patients > or =5 years and Chlamydia infections in patients > or =10 years of age. CONCLUSIONS: The results of our prospective, strictly population-based study confirm the importance of S. pneumoniae in the etiology of community-acquired pneumonia in children of all ages. M. pneumoniae and Chlamydia pneumoniae are important from the age of 5 years onwards.

Spectrum of 2,836 cases of invasive bacterial or fungal infections in children: results of prospective nationwide five-year surveillance in Finland. Finnish Pediatric Invasive Infection Study Group.

In a prospective nationwide laboratory-based surveillance study of all invasive bacterial and fungal infections among children < 16 years of age, 2,836 clinical cases were registered during the 5-year period 1985-1989. Of these cases, 136 were polymicrobial. During the study period, nationwide administration of Haemophilus influenzae type b conjugate vaccine reduced the incidence rates of invasive infection caused by this organism. The most common clinical diagnosis (48% of cases) was bacteremia without an identified focus of infection. The age-specific annual incidence rates of all invasive infections in children < or = 15 years of age, in children < or = 4 years of age, in children < or = 1 year of age, and in children < or = 28 days of age were 55.8, 141.4, 272.7, and 2,749.0 cases/100,000 person-years, respectively. Thirty percent of the children in the study had an underlying condition predisposing to infection. The case-fatality rate was 4.1% for all cases of invasive infection.

Immunologic priming by one dose of Haemophilus influenzae type b conjugate vaccine in infancy.

Immunogenicity of one dose of Haemophilus influenzae type b (Hib) conjugate vaccine in infancy and its ability to induce immunologic memory was studied in infants immunized at 4 and 14 months with either PRP-OMP (Hib polysaccharide conjugated with Neisseria meningitidis group B outer membrane protein complex) or PRP-T (Hib polysaccharide-tetanus toxoid conjugate) and compared with three doses of the same vaccines at 4, 6, and 14 months. Each group received diphtheriatetanus-pertusis vaccine at 3, 4, and 5 months of age. At 7 months of age, both vaccines were immunogenic after one dose, even though higher antibody concentrations were achieved after two doses. A booster dose given at 14 months resulted in a high antibody concentration and a strongly IgG-dominated isotype distribution, speaking for a secondary-type response in all groups, including those who had received only one dose in infancy. Subsequent persistence of antibodies suggestive of full protection for up to 36 months was similar in all groups.

Pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine is immunogenic in infants and children.

Sixty-two infants and 31 toddlers were vaccinated with the tetravalent pneumococcal conjugate vaccine PncOMPC consisting of the capsular polysaccharide of pneumococcal types 6B, 14, 19F, and 23F conjugated to the outer membrane protein complex of Neisseria meningitidis. Infants were vaccinated at 2, 4, and 6 months (group A) or at 4, 6, and 14 months (group B); toddlers were vaccinated at 24 or at 24 and 26 months of age. The IgG responses to the four pneumococcal polysaccharide types were measured by EIA. In infants, types 14 and 19F induced a significant response after the first dose and types 6B and 23F after the second dose. A clearcut booster response was seen to the booster dose given at 14 months, indicating immunologic priming by the primary series at 2-6 months of age. The responses of the toddlers to one or two doses of the vaccine were very similar to the responses in infants.

Risk factors for primary invasive pneumococcal disease among children in Finland.

OBJECTIVE: To study risk factors for invasive pneumococcal disease among children. DESIGN: A population-based, case-control study of 149 cases and 284 controls matched for age, sex, and place of residence. SETTING: Finland, November 1986 through November 1989. PATIENTS AND CONTROLS: Patients were identified from a prospective nationwide surveillance for invasive bacterial diseases among children (0 to 15 years of age) through a network of bacteriologic laboratories. Two matched controls were selected for 135 of the cases and one matched control for 14 of the cases from the respective cases' child health center or school. Questionnaires evaluating potential risk factors were mailed to families of cases and controls. RESULTS: An increased risk for invasive pneumococcal disease among children younger than 2 years was associated with day care center attendance (odds ratio [OR] = 36; 95% confidence interval [CI], 5.7 to 233), family day care (OR = 4.4; 95% CI, 1.7 to 12), and history of frequent otitis media (OR = 8.8; 95% CI, 2.5 31). For those at least 2 years of age, existence of siblings younger than school-age indicated increased risk for invasive pneumococcal disease (OR = 2.2; 95% CI, 1.1 to 4.4). CONCLUSIONS: Day care center attendance is a major risk factor for invasive pneumococcal disease for children younger than 2 years, with significantly higher risk than the risk associated with family day care.

Incidence of community-acquired pneumonia in the population of four municipalities in eastern Finland.

Between September 1, 1981, and August 31, 1982, all patients with suspected or confirmed pneumonia among the 46,979 inhabitants of four municipalities in the province of Kuopio, Finland, were reported to a pneumonia register by their attending physicians. In addition, two study pathologists reported all cases of pneumonia found at autopsy, and two permanent registers were checked for retrospective identification of patients. Chest radiographs were obtained from 97% of all patients. The final diagnosis was based on radiologic or autopsy criteria. A total 546 patients (323 males and 223 females) had community-acquired pneumonia; of these, 37% were less than 15 years of age, and 31% were 60 years of age or older. Nineteen percent of the patients had defined chronic conditions, and 42% were admitted to hospital. The case fatality rate was 4%. The overall incidence of community-acquired pneumonia per 1,000 inhabitants per year was 11.6 (13.9 in males, 9.4 in females). The age-specific incidence per 1,000 inhabitants per year was as follows: age < 5 years, 36.0; age 5-14 years, 16.2; age 15-59 years, 6.0; age 60-74 years, 15.4; and age > or = 75 years, 34.2.

Preceding respiratory infection predisposing for primary and secondary invasive Haemophilus influenzae type b disease.

Cases (117) with invasive Haemophilus influenzae type b (Hib) disease and their family members reported symptoms of respiratory infection during the 4-week period before the onset of Hib disease significantly more often than age-, sex- and residence-matched controls (225) and their family members during the same time period. Viral (adenovirus; influenza A and B; parainfluenza types 1, 2 and 3; and respiratory syncytial virus) and Mycoplasma pneumoniae serology was performed in 84 paired sera from cases and 112 paired sera from controls, who were healthy children matched to the cases by age, year and season. Viral or M. pneumoniae infection was diagnosed equally often among cases and controls (18% for both groups). However, patients who were associated cases of Hib disease (i.e. either the primary or secondary case of a case pair) had a diagnostic viral serology more often (50%) than did sporadic cases (13%) (odds ratio, 7.0; 95% confidence interval, 1.6 to 33; P = 0.006). These results suggest that some infectious agent(s) caused symptoms among the patients and circulated among the patients' closest contacts immediately before their development of Hib disease and possibly predisposed for invasive Hib disease. For the development of associated Hib disease among close contacts of an index case, adenovirus, influenza A, respiratory syncytial virus or para-influenza type 1, 2 and 3 infections may be important.

Susceptibility to invasive Haemophilus influenzae type b disease and the immunoglobulin G2m(n) allotype.

There has been considerable controversy about the role of the immunoglobulin G2m(n) allotype and risk of invasive Haemophilus influenzae type b (Hib) disease. This allotype was studied in a large cohort of Finnish children (178) with invasive Hib disease. The G2m(n) allotype distribution was similar to that in the normal white Finnish population. No increased risk of Hib disease could be associated with the n-/n- genotype [i.e., lack of G2m(n) allotype]. Thus, the G2m(n) allotype does not seem to be a major determinant of susceptibility to Hib infection among white populations in industrialized countries.

Antibody responses to four Haemophilus influenzae type b conjugate vaccines.

Serum antibody responses to four Haemophilus influenzae type b capsular polysaccharide-protein conjugate vaccines (PRP-D, HbOC, C7p, and PRP-T) were studied and compared in 175 infants, 85 adults and 140 2-year-old children. Antibodies to the H influenzae type b polysaccharide vaccines were determined with a Farr-type radioimmunoassay. The infants received two doses of vaccine at the ages of 4 and 6 months. After the first dose of vaccine, the geometric mean antibody concentration measured at the age of 6 months was 0.09 to 0.10 mg/L, only marginally higher than that measured before immunization in all infants who had received PRP-D, HbOC, or C7p but increased to 0.82 mg/L in those who had received PRP-T. One month after the second dose, the geometric mean antibody concentration was increased in all vaccine groups. No significant differences were noted between recipients of HbOC, C7p, or PRP-T (geometric mean antibody concentrations, 4.32, 3.10, and 6.10 mg/L, respectively), whereas the PRP-D recipients had a significantly lower geometric mean antibody concentration (0.63 mg/L). In contrast, PRP-D, HbOC, C7p, and PRP-T were all highly immunogenic in adults, with no differences noted among them. The 2-year-old children also responded to one dose of these vaccines with a high antibody concentration.

A randomized, prospective field trial of a conjugate vaccine in the protection of infants and young children against invasive Haemophilus influenzae type b disease.

BACKGROUND: Haemophilus influenzae type b is the leading cause of invasive bacterial disease in young children. The capsular polysaccharide vaccine does not protect children at greatest risk (those under the age of 18 months), but a polysaccharide-protein conjugate vaccine has proved to be more immunogenic in this age group. METHODS: We enrolled 114,000 infants in Finland in an open, prospective, randomized trial of a H. influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine (polyribosylribitol phosphate-diphtheria toxoid [PRP-D]). Children born on odd-numbered days were vaccinated at the ages of 3, 4, 6, and 14 to 18 months; those born on even-numbered days formed the control group and received the same vaccine at the age of 24 months. RESULTS: After three doses of the vaccine there were 4 cases of verified bacteremic H. influenzae type b disease in the group receiving early vaccination, as compared with 64 cases in the control group, between the ages of approximately 7 and 24 months. The protective efficacy of the vaccine was thus 94 percent (95 percent confidence interval, 83 to 98). No serious adverse effects were reported. The immune response to the conjugate vaccine was characteristic of a T-cell-dependent response when studied in a cohort of 120 infants. The primary immunization series resulted in a geometric mean concentration of anticapsular antibody of 0.53 micrograms per milliliter at the age of seven months, and the fourth dose evoked an anamnestic response, with a mean antibody concentration of 45.22 micrograms per milliliter. CONCLUSIONS: A new conjugate vaccine consisting of the capsular polysaccharide of H. influenzae type b covalently linked to a protein carrier (PRP-D), administered to infants beginning at the age of 3 months, is highly effective in protecting young Finnish children (7 to 24 months old) against invasive H. influenzae type b infections.

Reactogenicity and immunogenicity of combined vaccines for bacteraemic diseases caused by Haemophilus influenzae type b, meningococci and pneumococci in 24-month-old children.

To find a wide spectrum vaccine against bacteraemic disease in childhood, we immunized 293 Finnish children at 24 months of age intramuscularly with different combinations of the currently available vaccines, namely Haemophilus influenzae type b polysaccharide-protein conjugate vaccine (PRP-D) mixed with meningococcal and/or pneumococcal capsular polysaccharide vaccines. All the vaccines were immunogenic. The increase in antibody concentration after vaccinations was not affected by the number of polysaccharide antigens. Although no serious reactions were seen, the frequency of both local and fever reactions was greater in groups that received several vaccine antigens. Halving of the vaccine dose decreased the reactogenicity without impairing the immunogenicity.

Immunogenicity of Haemophilus influenzae oligosaccharide-protein and polysaccharide-protein conjugate vaccination of children at 4, 6, and 14 months of age.

At 4 and 6 months of age, 118 infants were vaccinated with either one of two Haemophilus influenzae type b capsular polysaccharide-protein conjugate vaccines: 72 infants received the polysaccharide coupled to diphtheria toxoid (PRP-D group), and 46 infants received polysaccharide-derived oligosaccharides coupled to CRM197 protein, a nontoxic mutant form of diphtheria toxin (HbOC group). A third dose of the same vaccine was given to 40 children in the PRP-D group and 25 children in the HbOC group at 14 months of age. Antibodies to the H influenzae type b capsular polysaccharide were measured by Farr-type radioimmunoassay in serum samples taken before each vaccination and 1 month after the second and the third doses. Adverse reactions monitored by a questionnaire were mild. After two vaccine doses, the geometric mean concentration of antibodies to H influenzae type b polysaccharide increased from 0.07 micrograms/mL in the prevaccination samples to 0.63 micrograms/mL in the PRP-D group and to 4.32 micrograms/mL in the HbOC group. In the following 7 months, the geometric mean concentrations declined to 0.38 and 1.12 micrograms/mL, respectively. The booster dose given at 14 months elicited a strong antibody response in both groups (to geometric mean concentrations of 29.7 and 58.3 micrograms/mL, respectively). Both vaccines appear to be capable of immunologic priming by immunization in infancy.

Risk factors of invasive Haemophilus influenzae type b disease among children in Finland.

A population-based matched case-control analysis of risk factors of invasive Haemophilus influenzae type b (Hib) disease was conducted in Finland in 1985 and 1986 before large-scale Hib vaccinations; 117 consecutive child patients with invasive Hib disease and 225 control subjects matched for age, sex, and residence were studied. In the multivariate analysis, day care outside the home was found to increase the risk of invasive Hib disease (odds ratio 5, 95% confidence interval 2.3 to 11), with the highest risk among children less than 2 years of age; this risk was significantly higher within the first month of attendance than later on (p = 0.02). The existence of siblings less than 7 years of age was found to be a risk factor, especially for the younger children (odds ratio 8.6, 95% confidence interval 2.6 to 52 for children less than 1 year of age), and the odds ratio increased approximately twofold with each additional sibling. A history of otitis media and previous hospitalizations were further risk factors for invasive Hib disease (odds ratio 2.2, 95% confidence interval 1.2 to 3.9, and odds ratio 1.9, 95% confidence interval 1.0 to 3.4, respectively). Breast-feeding for longer than 6 months was found to be protective (odds ratio 0.47, 95% confidence interval 0.3 to 0.9). The amount of Hib disease in different populations will vary with the incidence of these risk factors.

Simultaneous administration of Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine with routine diphtheria-tetanus-pertussis and inactivated poliovirus vaccinations of childhood.

A Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine (PRP-D) is capable of protecting infants against invasive H. influenzae diseases. Therefore it is very likely that it will be incorporated in routine vaccination schedules during the next few years. In order to test the suitability of simultaneous administration of PRP-D and other vaccines we administered it to 25 infants mixed with diphtheria-tetanus-pertussis vaccine at 3, 4 and 6 months and simultaneously, but in a separate syringe, with inactivated polio vaccine at 12 months. A comparison group of equal size received only diphtheria-tetanus-pertussis and inactivated poliovirus vaccines. The concentration of postvaccination antibodies to diphtheria toxoid was 0.411 IU/ml in the group that received PRP-D vs. 0.352 IU/ml in the comparison group, to tetanus toxoid 3.666 vs. 3.668 IU/ml and the neutralization titer to poliovirus type 1 was 370 vs. 320 units in the comparison group, to type 2 titer values were 230 vs. 270 units and to type 3, respectively, 210 vs. 290 units. Thus the seroresponse to antigens in routine vaccines was not affected by the presence of PRP-D in the vaccination schedule, and PRP-D can safely and effectively be included in the vaccination schedule of infancy.

Efficacy of Haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine in infancy.

Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine has recently been shown to be capable of inducing antibodies to H. influenzae in infants. In an evaluation of its clinical efficacy, 60,000 children were enrolled in an open trial in Finland. Children born on odd-numbered days between October 1, 1985, and September 30, 1986, received the vaccine at 3, 4, 6, and 14 months; those born on even-numbered days served as controls. The geometric mean antibody titer measured in a cohort of 99 children rose from a prevaccination level of 0.08 microgram per milliliter at three months of age to 0.42 microgram per milliliter at seven months. Only minor adverse reactions were reported. Up to February 1987, two cases of invasive H. influenzae infection had occurred among the children who had received three doses of vaccine, whereas 12 cases had occurred among the controls (P = 0.0005 by Poisson one-tailed test). The rate of short-term (average follow-up time, five months) protection provided by this conjugate vaccine in infancy was thus 83 percent.