Spectrum of invasive Haemophilus influenzae type b disease in adults.

A prospective nationwide surveillance of invasive Haemophilus influenzae type b disease among adults (greater than or equal to 16 years old) was conducted in Finland during 1985 through 1988. Thirty-one cases were identified (annual incidence, 0.22/100,000). Of these infections, 71% occurred in patients with severe underlying conditions. The overall case fatality rate was 26%. Septicemia (13 patients) and pneumonia (seven patients) were the most common clinical manifestations of H influenzae type b infection; the others were epiglottitis (six patients), meningitis (three patients), and arthritis (two patients). Epiglottitis occurred in significantly younger patients, all of whom were women and four of whom were previously healthy. Subtyping of the H influenzae type b isolates according to the major outer membrane protein subtype, biotype, and lipopolysaccharide serotype showed that patterns that were uncommon (14%) among children were more common (27%) in the adults.

Clinical experience with Haemophilus influenzae type b conjugate vaccines.

The importance of Haemophilus influenzae type b as the main cause of serious bacteremic infections in young children and the consequent need for preventive measures have been widely appreciated since the 1970s. The knowledge that serum antibodies to the polysaccharide capsule of H influenzae type b increase with age and correlate with resistance to this infection encouraged work toward a vaccine based on the H influenzae type b polysaccharide. Such a vaccine was used in 1974 in a field trial in Finland. Two important lessons were learned. First, vaccine-induced antibodies to the polyribosylribitol-phosphate (PRP) polysaccharide correlated with protection from disease caused by H influenzae type b, so that the serum anti-PRP concentration predicting protection could be estimated as 1 microgram/mL. Second, the vaccine was not effective in infancy; protection and serum antibody concentrations above 1 microgram/mL were not observed before 18 to 24 months of age. The poor immunogenicity of PRP in infancy has been observed in a large number of studies and is shared by other bacterial polysaccharides. Although the reason for this is not known, the most likely hypothesis associates poor immunizing ability in infancy with the "T-independent" nature of these polysaccharide antigens. Such antigens would be unable to stimulate T lymphocytes; therefore, immunity to them would depend exclusively on B cells and antibodies produced by them. If infants, by and large, lack B cells that could be stimulated directly by a polysaccharide antigen, they cannot respond to the polysaccharide vaccine. This hypothesis immediately suggests possibilities for improvement of the vaccine.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacteriology of acute otitis media in a cohort of Finnish children followed for the first two years of life.

BACKGROUND: Timely information on the bacteriology of primary, noncomplicated acute otitis media (AOM) may today be needed more than ever, because of the increasing antimicrobial resistance of its major bacterial causes and because of the potential of new pneumococcal and other bacterial vaccines for prevention of AOM. METHODS: The study followed 329 children from 2 to 24 months of age at scheduled healthy visits and sick visits at the study clinic. Whenever AOM was diagnosed during the follow-up, myringotomy was performed and middle ear fluid was aspirated for bacterial culture. RESULTS: At least one middle ear fluid sample was available from 772 AOM events; Streptococcus pneumoniae (Pnc) was isolated in 201 (26%), Moraxella catarrhalis (Mc) in 177 (23%) and Haemophilus influenzae (Hi) in 174 events (23%). The incidence of Pnc AOM peaked at 12 months of age, whereas the incidence of Mc AOM showed the first peak at 6 months and Hi AOM at 20 months. Pnc AOM showed less prominent seasonality in occurrence than Mc and Hi AOM. Hi was a rare cause of the first 2 AOM episodes (13%) but became increasingly common from the third episode on (32% on average). CONCLUSIONS: Pnc, Mc and Hi were almost equally common findings in AOM. Pnc seems to be the most pathogenic of these three, the role of Mc is increasing and Hi is clearly associated with recurrent AOM.

Epidemiology of invasive Haemophilus influenzae type b disease among children in Finland before vaccination with Haemophilus influenzae type b conjugate vaccine.

On the basis of intensified surveillance in Finland we report the epidemiology of invasive Haemophilus influenzae type b disease based on 333 consecutive culture-proved cases recorded during 1985 and 1986. The annual incidence rate among children younger than 5 years of age was 52/100,000; 46% of patients had meningitis, 29% had epiglottitis and 25% had other forms of invasive disease. The median age of patients was 27 months, with 45% younger than 2 years of age. Meningitis and epiglottitis were found more often among boys than among girls, whereas the opposite was found among patients with other types of invasive disease (P = 0.015). Among the latter 68% of children with pneumonia or septicemia were 2 years or older compared with 32% of patients with arthritis, cellulitis or pyelonephritis (P = 0.009). These background data are essential for correct interpretation and application of results from trials with H. influenzae type b conjugate vaccines that are currently ongoing in Finland.

Neonatal group B streptococcal disease in Finland: a ten-year nationwide study.

BACKGROUND: Group B Streptococcus (GBS) is the most common cause of invasive infections in newborns. GBS bacteria are typed on the basis of capsular polysaccharides or surface-localized proteins. Both polysaccharides and protein antigens have been suggested as potential vaccine candidates. METHODS: A prospective nationwide laboratory-based study of invasive GBS infections in children younger than 3 months of age was conducted in 1985 through 1994. Isolates were serotyped by immunodiffusion in agar gel with HCl extracts and rabbit antisera. Clinical diagnoses and case fatalities were verified from the patient records or the national hospital discharge register. RESULTS: There were 485 cases registered during the 10-year period. The incidence of disease was 0.76/1000 live births. The case fatality rate was 8.0%. Of the 485 cases 398 (83%) were early onset and 87 (17%) late onset infections. The most common clinical diagnosis was bacteremia (77%) without an identified focus of infection. Other diagnoses included meningitis (17%), pneumonia (3%), osteomyelitis or septic arthritis (2%), pyelonephritis or cellulitis. Serotyping of 395 isolates revealed that 47% were of serotype III or III/R, 23% of Ia/c, 11% of Ib, 6% of II/R, 8% of IV, 1% of V and 7% were nontypable. CONCLUSIONS: The clinical picture of GBS disease and serotype distribution are similar to what has been reported from other countries. Serotypes III and III/R dominated (47% of all infections), especially in late onset disease. On the basis of these results a GBS vaccine including at least the Ia, Ib, II and III components would provide coverage against 88% of GBS serotypes causing neonatal disease in Finland.

Pneumococcal carriage in children during their first two years: important role of family exposure.

BACKGROUND: Close family and day-care contacts have been identified as risk factors for pneumococcal (Pnc) carriage. This study addresses the risk of Pnc carriage by infants 2 to 24 months of age in terms of simultaneous carriage of pneumococcus by family members. METHODS: Nasopharyngeal swabs were collected from 100 Finnish infants and their family members on 10 scheduled visits (when infant was 2, 3, 4, 5, 6, 9, 12, 15, 18 and 24 months of age). The 7 most common pneumococcal serogroups (4, 6, 9, 14, 18, 19, 23), also represented in the new heptavalent Pnc conjugate vaccine, were analyzed. Marginal logistic regression analyses were performed to assess the relative importance of different predictors for carriage. RESULTS: The carriage of the studied Pnc serogroups increased with age, being highest at the age of 18 months (28%). Among children older than 6 months of age, the strongest predictor of carriage was simultaneous carriage of the same serogroup by another family member (odds ratio, 3.8; 95% confidence interval, 2.1 to 6.9). At the age of 6 months or younger, carriage was rare and was not significantly associated with a family carriage. CONCLUSIONS: Young infants (< or =6 months old) were largely protected from pneumococcal carriage. After this age family transmission seemed very important despite the small family size. Contrary to some earlier studies communal day care was not associated with an increased risk of Pnc carriage. This could be partly because of the long parental leave in Finland and thus the late age of starting organized day care.

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.

Vaccination with Haemophilus influenzae type b meningococcal protein conjugate vaccine reduces oropharyngeal carriage of Haemophilus influenzae type b among American Indian children.

The effect of Haemophilus influenzae type b (Hib) meningococcal protein conjugate vaccine (Hib-OMPC; Merck, Sharp & Dohme) on oropharyngeal (OP) carriage of Hib was evaluated in Navajo and Apache Indian children, who are known to be at high risk for invasive Hib disease. We obtained 1423 OP swabs at well child visits from 1321 children 3 months to 4 years of age: 293 of the swabs were obtained from children before the administration of any Hib-OMPC; 1119 were taken after the primary vaccination series; and 11 after the booster dose. Swabs were tested for the presence of Hib capsular polysaccharide antigen by enzyme-linked immunosorbent assay. Forty of 1423 swabs were positive for Hib. Among the 40 positive swabs 5 (13%) were obtained from children who had received Hib-OMPC vaccine appropriate for age at swabbing, compared with 500 of 1383 (36%) of negative swabs. Children who were OP carriers of Hib were older than noncarriers (mean age, 13 and 9 months, respectively) and a greater proportion of carriers (48%) had symptoms of respiratory infection at the time of swabbing than noncarriers (30%). These variables were significantly related to increased risk of OP carriage of Hib when incorporated jointly in a logistic regression model: not vaccinated according to age (odds ratio 2.7, 95% confidence interval 1.00 to 7.05); increase of age in months (odds ratio 1.1, 95% confidence interval 1.02-1.10); and respiratory infection symptoms present (odds ratio 2.0, 95% confidence interval 1.06-3.77). Thus besides preventing invasive Hib disease, appropriate vaccination with Hib-OMPC appears to reduce OP carriage of Hib.

Clinical comparison of the Haemophilus influenzae type B polysaccharide-diphtheria toxoid and the oligosaccharide-CRM197 protein vaccines in infancy.

OBJECTIVE: To compare two Haemophilus influenzae type B (HiB) conjugate vaccines, a polysaccharide-diphtheria toxoid conjugate (PRP-D) vaccine and an oligosaccharide-CRM197 protein conjugate (HBOC [PRP-CRM]) vaccine, in the same population. DESIGN: One hundred twenty-five thousand infants were randomized to receive the PRP-D or HBOC vaccine. Primary immunization consisted of two doses of either vaccine administered at 4 and 6 months and a booster dose was given at 14 to 18 months. Protection was assessed by recording episodes of invasive disease with HiB isolated from the blood or another normally sterile body site. SETTING: One thousand thirty-six child health care centers in Finland. PARTICIPANTS: Infants born in Finland during the 24-month period from 1987 to 1989. INTERVENTION: Each vaccine dose was injected intramuscularly in a volume of 0.5 mL. At the same time, a separate site was injected with the diphtheria and tetanus toxoids and pertussis vaccine at 4 months of age, with inactivated poliovirus vaccine at 6 months of age, and with measles-mumps-rubella vaccine at 14 to 18 months of age. MAIN RESULTS: The mean anticapsular antibody concentration 1 month after the second dose was 0.63 micrograms/mL and 4.32 micrograms/mL in the PRP-D and HBOC vaccine recipients, respectively. The booster dose resulted in a high antibody concentration: 33.3 micrograms/mL and 58.3 micrograms/mL for PRP-D and HBOC vaccine recipients, respectively. At 36 months of age, the antibody concentration declined to 2.5 micrograms/mL and 5.6 micrograms/mL for PRP-D and HBOC vaccine recipients, respectively. After two doses of the vaccine, there were five episodes (39 were expected based on historical controls) of invasive HiB disease in the PRP-D group and two episodes (35 were expected) in the HBOC group. Hence, an 87% (95% confidence limit [CL], 69, 96) protection rate in the PRP-D group and a 95% (95% CL, 76, 99) protection rate in the HBOC group were achieved. No episodes occurred after the booster dose in either group. CONCLUSIONS: Both the PRP-D and HBOC vaccines are safe and effective. A two-dose primary vaccination schedule seems appropriate, at least in circumstances prevailing in Finland and probably in other areas with similar epidemiological effects of HiB disease.

Pneumococcal capsular antigen detection after enrichment culture: an alternative to culture methods in epidemiologic research.

Bacterial culture of Streptococcus pneumoniae followed by serotyping is not always feasible under field conditions. Antigen detection methods could be an alternative, but they are associated with sensitivity problems. In an effort to improve their sensitivity, we introduced an enrichment phase before antigen detection and compared the results with direct bacterial culture, using nasopharyngeal swabs from 95 children with symptoms of acute respiratory infection. Antigen detection was performed by latex agglutination and counterimmunoelectrophoresis. Streptococcus pneumoniae was found in 29 (30%) of the samples by culture, and in 42 (44%) by antigen detection after enrichment, an excess of 45% over culture findings. This excess was shown to represent true positive samples since pneumococcal DNA could be detected by polymerase chain reaction in all 15 antigen-positive, culture-negative samples. Two culture-positive samples were antigen-negative; in one of these the bacteria were nonencapsulated. We conclude that for type-specific demonstration of S. pneumoniae, detection of pneumococcal antigen after an enrichment step is a sensitive method that can be applied for epidemiologic study purposes, e.g., in vaccine trials, in areas without ready access to a good microbiology laboratory.

Disappearance of epiglottitis during large-scale vaccination with Haemophilus influenzae type B conjugate vaccine among children in Finland.

Surveillance of blood-culture-proven epiglottitis was conducted in Finland from 1985 through 1992. Among children (< 16 years), all bacteria causing epiglottitis, and among adults, Haemophilus influenzae were included. H influenzae type b (Hib) caused 226 (97%) of cases among children. Among adults with H influenzae epiglottitis (total of 20), 19 were caused by Hib. In 1986, vaccine trials with Hib-conjugate vaccines started in Finland, with vaccination coverage of 94% to 98% of infants. Vaccinations did not yet have an effect on the occurrence of epiglottitis in 1985 or 1986 when the annual incidence among children was 5.3/100,000, among those less than 5 years of age was 13.2/100,000, and among adults was 0.08/100,000. In 1987 through 1992 the proportion of vaccinated children increased steadily while the incidence of Hib epiglottitis decreased from 50 to 60 cases seen annually in 1985 and 1986 to 2 cases in 1992. There was no increase in the occurrence of epiglottitis caused by other pathogens. In conclusion, there is now a safe and efficient way to prevent the majority of epiglottitis cases among children with the new Hib-conjugate vaccines.

Diagnostic value of tympanometry in infants in clinical practice.

One hundred and twenty-one visits of 58 infants (2-11 months of age) were evaluated in the Finnish Otitis Media Vaccine Trial. Infants were examined with tympanometry (Grason-Stadler GSI 38 Autotymp) and pneumatic otoscopy by one study doctor. Diagnosis of otitis media was verified by myringotomy in 74% of cases. Tympanometry was technically successful in 94% of ears. The success rate was statistically significantly higher (P < 0.05) among infants less than 7 months of age than those above 7 months. The sensitivity of tympanometry (type B) to detect ears with middle ear fluid was 0.70 and the specificity 0.98 with a positive predictive value of 0.93 and negative predictive value of 0.94. The sensitivity was somewhat lower in the younger age group (0.61); specificity and positive and negative predictive values were good in both age groups. The high success rate and high negative and positive predictive values of tympanometry make it a useful aid for assuring the correct diagnosis of otitis media in infants in routine clinical practice.

Socioeconomic risk factors for invasive Haemophilus influenzae type b disease.

Socioeconomic risk factors for primary invasive Haemophilus influenzae type b (Hib) disease include factors that increase exposure to Hib (day care attendance, presence of siblings, and crowded households) and factors that increase an individual's susceptibility to Hib infections (short duration of breast feeding, parental smoking, and frequent infections in general). These factors are consistently found to be associated with risk of Hib disease in studies conducted in populations that differ in their Hib disease epidemiology. However, there are large differences in the prevalence of these risk factors among populations. According to present knowledge, variations in the prevalence of socioeconomic risk factors may explain most of the differences in the epidemiology of Hib disease and may also contribute to the differences in Hib vaccine efficacy in different populations.

Interrater agreement on tympanometry in infants.

Two-hundred and forty-two tympanograms of infants were interpreted according to a standard operating procedure independently by an audiologist and ten study doctors from the Finnish Otitis Media Vaccine Trial. The interrater agreement among the study doctors according to Kappa index was excellent (kappa = 0.80). The agreement was significantly better on curves taken during pre-scheduled healthy visits than during sick visits due to respiratory infection (p < 0.001). In addition concurrent knowledge of the clinical ear status significantly improved the agreement on abnormal curves (flat B-curves and failed F-curves, p < 0.001). The clinical differences between the groups were minor. The age of the infant had no effect on interpretation. The agreement between the audiologist and the study doctors was also excellent (kappa = 0.77). Excellent agreement can be achieved in infant tympanometry through adequate instruction and training.

Haemophilus influenzae type b polysaccharide-protein conjugate vaccines in children.

Prevention of invasive infections caused by Haemophilus influenzae type b (Hib) bacteria has become possible with new vaccines. Covalent coupling to a protein carrier increases the immunogenicity of Hib capsular polysaccharide, and changes it to a T-cell dependent antigen. In clinical use, the conjugate vaccines are immunogenic in infancy, induce immunologic memory, and protect efficiently from invasive infections. They even seem to reduce oropharyngeal carriage of Hib bacteria. Wide-scale use of Hib conjugate vaccines has demonstrated their safety and low reactogenicity. Studies to combine them with other childhood vaccines are in progress. First signs of reduction of severe Hib infections can already be seen in countries where Hib conjugate vaccines are in wide use.