Invasive Haemophilus influenzae type B infections: A continuing challenge Hillel Janai, MD Harris R. Stutman, MD Melvin I. Marks, MD Long Beach and Irvine, California
Invasive Haemophilus influenzae type b infections are a major cause of severe infections in children between 2 months and 5 years of age. Meningitis, arthritis, pneumonia, cellulitis, osteomyelitis, and epiglottitis affect approximately 25,000 patients annually and are a major cause of mortality and morbidity in children. H. irzfluenzae type b clinical syndromes, diagnostic methods, epidemiology, immunity, and treatment are discussed in this review. Although potent antibiotics have long been available for treatment, mortality and morbidity rates have not declined substantially in the last 15 years. Prevention of disease is therefore a continuous medical challenge. Secondary cases can be prevented by identification of the high-risk groups and the application of appropriate techniques, including antimicrobial prophylaxis. Primary prevention is the major goal of current research. H. influenzae type b vaccines currently are available for protection of infants 18 months of age and older. Prevention of primary and secondary disease and future developments, including new vaccine strategies, are stressed. (AM J INFECTCONTROL 1990;18:160-6)
Haemophilus influenzae type b (Hib) is the major cause of invasive bacterial infections in the pediatric age group, particularly in children younger than 5 years of age. Twelve thousand cases of H. influenzae meningitis are reported annually; however, the total number of patients affected by systemic infections approximates 25,000, which includes nonmeningitic infections such as bacteremia, epiglottitis, arthritis, pneumonia, and cellulitis.‘~* Clinical manifestations of Hib infection differ according to the patient’s age. Infection is uncommon before 2 months of age, probably as a result of protection by maternal antibodies. From the Memorial Miller Children’s Hospital, Long Beach, and the University of California, Irvine. Reprint requests: Harris R. Stutman, MD, Pediatric Infectious Diseases, Miller Children’s Hospital, 2801 Atlantic Ave., Long Beach, CA 90801-l 428. 17/46/15166
160
Subsequently, infants between 4 months and 4 years of age are at highest risk for meningitis, with most cases occurring before 1 year of age.3 Pneumonia, cellulitis (particularly periorbital), and arthritis, each commonly associated with bacteremia, usually occur before 2 years of age. Most cases of epiglottitis occur in the third and fourth year of life ,4 Older pediatric patients, however, especially those with debilitating disease, are still at risk for Hib infections3 Furthermore, systemic Hib infection occasionally occurs in newborns and adults. Although not the topic of this review, nontypeable strains of H. influenzae, often found on mucosal surfaces, are also occasional pathogens in neonates. An adequate bacteriologic response in Hib meningitis usually is achieved with antibiotics, although morbidity and mortality rates have not declined appreciably in the past 20 years. Late diagnosis and toxic and inflammatory injuries are important factors in determining out-
Volume 18 Number 3
come. Therefore prevention of disease is a priority in approach. We focus on current and future strategies for prevention of Hib infection. CLINICAL
Haemophilus influenzae type b infections
Invasive
June 1990
SYNDROMES
AND
DIAGNOSIS
The most common life-threatening disease caused by Hib is meningitis. The pathogenesis is believed to result from disruption of the upper respiratory mucosa (usually by a respiratory viral infection), passage of the organism into the bloodstream (bacteremia), and meningeal seeding. Children usually have nonspecific findings such as fever, lethargy, and vomiting. Physical findings, especially meningeal irritation, may be difficult to evaluate in young infants. Therefore a lumbar puncture is indicated in most children with suspected Hib bacteremia who are younger than 2 years of age. The mortality rate from invasive Hib infections varies from 1% to 4%, and morbidity from meningitis includes hearing loss or neurologic deficiency in as many as 10% and 30% of survivors, respectively.4S6 Epiglottitis is the second most common lifethreatening disease caused by Hib. This is a medical emergency because an inflamed epiglottis may produce sudden respiratory obstruction. Thus intubation is initiated in most children to maintain airway patency until inflammation subsides. In epiglottitis, bacteremia is common (>75%) and is thought to result from local infection,7 in contrast to meningitis, septic arthritis, and cellulitis, which occur as a consequence of bacteremia. Although these latter two may be cured with antimicrobial agents alone, the risk of concomitant meningeal infection is about 5% to 15%, and therefore a careful diagnostic approach (e.g., lumbar puncture) is recommended.‘, 9 Hib also can cause pneumonia and osteomyelitis. Diagnosis can be difficult because positive bacterial cultures are not easy to obtain. Rapid Hib antigen detection methods, however, are available and should be applied to urine and other body fluids when feasible. A summary of clinical syndromes and specimens likely to yield a definitive diagnosis of Haemophihs disease is given in Table 1.
Table 1. Diagnostic approach suspected Hib disease
161
for
All patients Blood culture* o Urine antigen detection assay l
In addition, in other suspected
clinical entities:
Meningitis l Gram stain and culture of cerebrospinal fluid o Antigen detection assay of cerebrospinal fluid Pneumonia l Gram stain and culture of sputum o Bronchial lavage (bronchoscopy) for culture, in selected cases Arthritis Joint aspirate for Gram stain and culture l Joint fluid for antigen detection assay
l
Cellulifis o Needle aspirate for Gram stain and culture Osteomyelitis Gram stain and culture of bone biopsy (directed by results of radiographs or 99Tc bone scan)
l
*Chocolate (or other supplemented) growth of Haemophilus species.
EPIDEMIOLOGIC
agar must be used to support
FACTORS
Hib infections occur throughout the year with two seasonal peaks, an autumn peak (October to December) and a spring peak in May and June.” There are racial differences in the incidence of Hib, with discrepant risks between white and black populations.” American Indians and Alaskan Eskimos are at increased risk specifically for meningitis caused by Hib. There is no clear association between nasopharyngeal carriage and the incidence of Hib invasive disease, which indicates that decreased host immunity and/or enhanced bacterial virulence is the cause of high-frequency Hib diseases.‘l Epiglottitis is rare among these patient populations, presumably because of different pathogenic mechanisms and different host immunity patterns. MICROBIOLOGIC
FACTORS
AND
IMMUNITY
Hib is a gram-negative pleomorphic bacillus (rod) that can be detected directly from clinical specimens and cultured on appropriate media. Hib does not grow on blood, MacConkey’s, or
162
American Journal of INFECTIONCONTROL
Janai et al.
eosin-methylene blue agars. Chocolate, horse blood, or other media that satisfy the organism’s requirement for factor X (hemin) and factor V (nicotinamide-adenine dinucleotide) must be included in specimen processing. Presumptive isolates are identified by antisera directed against its polysaccharide capsule, a five-carbon sugar base, polyribosylribitol phosphate (PRP). Antibodies against this antigen confer immunity.12 Although various outer membrane proteins also induce an immunologic response, their role in preventing Hib disease is in question. For example, in one study of natural immunity to Hib disease, antibody responses to both capsular polysaccharide (CPS) and outer membrane (OM) proteins were measured during the acute and convalescent phases of Hib disease. Concentrations of anti-CPS antibodies were undetected in the acute phase, but an antibody response later developed in 13 of 2 1 children, mainly those older than 2 years of age. In contrast, all children had detectable antibodies against O M in the acute phase, which suggests that these antibodies have little protective value.13 TREATMENT
Antibiotic therapy has been the mainstay of treatment and prevention of Hib disease. Hib was uniformly sensitive to ampicillin until 1974. Since then, resistance has emerged and up to 30% of isolates are currently ampicillinresistant, mostly as a result of the production of S-lactamase.14*l5 Therefore all Hib isolates from blood or other normally sterile body fluids should be evaluated by one of the rapid tests for P-lactamase production. Moreover, antimicrobial susceptibility of these isolates should be confirmed by standard methods inasmuch as ampicillin-resistant, non-plactamase-producing organisms rarely have been identified. The likelihood of isolating a resistant organism is particularly high among infants previously treated with antibiotics (especially the p-lactams) and greater among type b than noncapsulated types.16,l7 Although the third-generation cephalosporins remain uniformly active against Hib, strains of Hib re-
sistant to both ampicillin and chloramphenicol18 currently are prevalent in Barcelona, Spain, and new resistance patterns may be a problem in the future. Current recommendations for empiric therapy include either a combination of ampicillin and chloramphenicol or one of the third-generation cephalosporins (cefotaxime and ceftriaxone). In Hib infections that do not involve the central nervous system, the second-generation cephalosporin cefuroxime can be equally effective. CARRIER
STATE
The pathogenesis of Hib infection suggests that spread of the organism to the blood stream occurs after nasopharyngeal colonization and subsequent disruption of the mucosal nasopharyngeal protective layer. Hib nasopharyngeal carriage, and thus infection, can be transmitted from person to person, and secondary cases have been reported among household (2% to 4%) day-care (0% to 1.3%), and nosocomial contacts.lga2o Two recent studies to determine nasopharyngeal carriage of H. influenzae in healthy children up to 6 years of age revealed an isolation rate of 30% to 60% for H. influenzae. Of these, 7% to 15% were type b. Subject location (daycare center, outpatient clinic) and season influenced isolation rates, as did culture techniques.“, 21 For example, carriage rates were higher among children who attended day-care centers for more than 6 months or during the autumn and late spring. The use of selective media (antibiotic-supplemented chocolate agar) enhanced the recovery of Hib organisms. Studies in families with an index case of invasive Hib infection revealed a higher rate of carriage (70% to SO%).12, 22These data suggest that higher carriage rates and prolonged contact with the organism may increase the rate of secondary disease acquisition. Two major target groups for prevention and prophylaxis exist. The first is children at increased risk-estimated as high as 4%because of contact with an index case. The second is all infant subjects, aged 2 months to 4 years, the age of maximum disease prevalence.
Volume 18 Number 3 June 1990
Invasive Haemophilus
H. influenzae age and not given rifampin prophylaxis
Table 2. Rates of secondary
Band et aLz6
Location
disease in day-care
Fleming
et al.*’
Osterholm
et aL2*
Seattle Atlanta Oklahoma
Minnesota
12179 to 6161
1183 - 2184 to 7183 - 2184
8182 to 7184
No. of contacts
91
755
1086
Secondary disease n Rate (%)
1 1.1
10 1.3 0.9 - 1.7
95% Cl for secondary
0.0 - 3.3
163
center contacts younger than 4 years of
Multicenter
Time interval
influenzae type b infections
Murphy
et aivz9
Dallas
ioh
to 10184
Makintubee et ai.30
Oklahoma
1184 to 3186
587
486
0 0
1 0.2
6 1.2
0.0 - 0.3
0.0 - 0.4
0.7 - 1.7
disease rate From Marks MI, Dorchester WL. J Pediatr 1987;lli :306. Cl, Confidence interval.
PREVENTION Nosocomial spread
A recent study employed selective media to evaluate the dynamics of nasopharyngeal colonization with Hib during antibiotic therapy. There was no growth of Hib on nasopharyngeal specimens 24 hours after initiation of antimicrobial chemotherapy23 in all 27 patients. Therefore nosocomial spread should be largely preventable by respiratory isolation for the first 24 hours, combined with careful handwashing and specimen handling. It should be mentioned that this risk is largely theoretic, that is, nosocomial spread in acute care settings is not described. Previous studies, however, showed that colonization with Hib may persist or recur after discontinuation of antibiotic therapy in children with invasive Hib diseaseF4 Bacterial persistence and recolonization with contacts are possible mechanisms. A current approach is to add oral rifampin to the last 4 days of systemic treatment. Others prefer to add rifampin after the last dose of systemic therapy to avoid confusion created by adverse effects (e.g., nausea, rash, or fever). Rifampin is effective (90% to 95%) in eradicating nasopharyngeal carriage and thus in decreasing secondary disease.25Currently, rifampin prophylaxis is recommended for all household contacts if there is a sibling
at home younger than 4 years of age (and presumably at risk for invasive disease). Day care
Table 2 lists the rates of secondary Hib disease among day-care contacts as noted in five recent reports.26*30The rate of secondary Hib disease was defined as the number of Hib disease cases that occurred among day-care contacts within 60 days of diagnosis of an index case. The incidence ranged between 0% to 1.3%. Different methods of patient enrollment, diverse day-care center settings, and disparate pathogenicity of Hib subtypes are possible explanations for this variability. A pooled secondary disease rate of 0.6% may provide the best current estimate of the true rate of secondary Hib disease in day-care exposures. With this estimate of high risk, rifampin chemoprophyZuxis, combined with careful surveillance and community education, is recommended by the American Academy of Pediatrics for day-care contacts of a single index case,31under certain circumstances. These include day-care settings in which most children are younger than 2 years of age and contact is 25 hours per week or more. A second case in a single center should prompt prophylaxis for all attendees and supervisory personnel. Previously vaccinated children also
American
164
Janai et al.
should receive prophylaxis, when indicated, because successful immunization does not affect nasopharyngeal carriage. Vaccine
Although many cases of secondary disease can be prevented by antibiotic chemoprophylaxis, this amounts to less than 10% of the total number of Hib infections. Prevention of primary disease is a logical step and is the major goal of researchers around the world. As discussed previously and as shown in many animal studies, anti-CPS antibodies are protective against Hib disease. The immune response to this antigen is weak in younger infants (
Invasive Haemophilus influenzae type b infections are a major cause of severe infections in children between 2 months and 5 years of age. Meningitis, arthritis, pneumonia, cellulitis, osteomyelitis, and epiglottitis affect approximately 25,000 patients annually and are a major cause of mortality and morbidity in children. H. irzfluenzae type b clinical syndromes, diagnostic methods, epidemiology, immunity, and treatment are discussed in this review. Although potent antibiotics have long been available for treatment, mortality and morbidity rates have not declined substantially in the last 15 years. Prevention of disease is therefore a continuous medical challenge. Secondary cases can be prevented by identification of the high-risk groups and the application of appropriate techniques, including antimicrobial prophylaxis. Primary prevention is the major goal of current research. H. influenzae type b vaccines currently are available for protection of infants 18 months of age and older. Prevention of primary and secondary disease and future developments, including new vaccine strategies, are stressed. (AM J INFECTCONTROL 1990;18:160-6)
Haemophilus influenzae type b (Hib) is the major cause of invasive bacterial infections in the pediatric age group, particularly in children younger than 5 years of age. Twelve thousand cases of H. influenzae meningitis are reported annually; however, the total number of patients affected by systemic infections approximates 25,000, which includes nonmeningitic infections such as bacteremia, epiglottitis, arthritis, pneumonia, and cellulitis.‘~* Clinical manifestations of Hib infection differ according to the patient’s age. Infection is uncommon before 2 months of age, probably as a result of protection by maternal antibodies. From the Memorial Miller Children’s Hospital, Long Beach, and the University of California, Irvine. Reprint requests: Harris R. Stutman, MD, Pediatric Infectious Diseases, Miller Children’s Hospital, 2801 Atlantic Ave., Long Beach, CA 90801-l 428. 17/46/15166
160
Subsequently, infants between 4 months and 4 years of age are at highest risk for meningitis, with most cases occurring before 1 year of age.3 Pneumonia, cellulitis (particularly periorbital), and arthritis, each commonly associated with bacteremia, usually occur before 2 years of age. Most cases of epiglottitis occur in the third and fourth year of life ,4 Older pediatric patients, however, especially those with debilitating disease, are still at risk for Hib infections3 Furthermore, systemic Hib infection occasionally occurs in newborns and adults. Although not the topic of this review, nontypeable strains of H. influenzae, often found on mucosal surfaces, are also occasional pathogens in neonates. An adequate bacteriologic response in Hib meningitis usually is achieved with antibiotics, although morbidity and mortality rates have not declined appreciably in the past 20 years. Late diagnosis and toxic and inflammatory injuries are important factors in determining out-
Volume 18 Number 3
come. Therefore prevention of disease is a priority in approach. We focus on current and future strategies for prevention of Hib infection. CLINICAL
Haemophilus influenzae type b infections
Invasive
June 1990
SYNDROMES
AND
DIAGNOSIS
The most common life-threatening disease caused by Hib is meningitis. The pathogenesis is believed to result from disruption of the upper respiratory mucosa (usually by a respiratory viral infection), passage of the organism into the bloodstream (bacteremia), and meningeal seeding. Children usually have nonspecific findings such as fever, lethargy, and vomiting. Physical findings, especially meningeal irritation, may be difficult to evaluate in young infants. Therefore a lumbar puncture is indicated in most children with suspected Hib bacteremia who are younger than 2 years of age. The mortality rate from invasive Hib infections varies from 1% to 4%, and morbidity from meningitis includes hearing loss or neurologic deficiency in as many as 10% and 30% of survivors, respectively.4S6 Epiglottitis is the second most common lifethreatening disease caused by Hib. This is a medical emergency because an inflamed epiglottis may produce sudden respiratory obstruction. Thus intubation is initiated in most children to maintain airway patency until inflammation subsides. In epiglottitis, bacteremia is common (>75%) and is thought to result from local infection,7 in contrast to meningitis, septic arthritis, and cellulitis, which occur as a consequence of bacteremia. Although these latter two may be cured with antimicrobial agents alone, the risk of concomitant meningeal infection is about 5% to 15%, and therefore a careful diagnostic approach (e.g., lumbar puncture) is recommended.‘, 9 Hib also can cause pneumonia and osteomyelitis. Diagnosis can be difficult because positive bacterial cultures are not easy to obtain. Rapid Hib antigen detection methods, however, are available and should be applied to urine and other body fluids when feasible. A summary of clinical syndromes and specimens likely to yield a definitive diagnosis of Haemophihs disease is given in Table 1.
Table 1. Diagnostic approach suspected Hib disease
161
for
All patients Blood culture* o Urine antigen detection assay l
In addition, in other suspected
clinical entities:
Meningitis l Gram stain and culture of cerebrospinal fluid o Antigen detection assay of cerebrospinal fluid Pneumonia l Gram stain and culture of sputum o Bronchial lavage (bronchoscopy) for culture, in selected cases Arthritis Joint aspirate for Gram stain and culture l Joint fluid for antigen detection assay
l
Cellulifis o Needle aspirate for Gram stain and culture Osteomyelitis Gram stain and culture of bone biopsy (directed by results of radiographs or 99Tc bone scan)
l
*Chocolate (or other supplemented) growth of Haemophilus species.
EPIDEMIOLOGIC
agar must be used to support
FACTORS
Hib infections occur throughout the year with two seasonal peaks, an autumn peak (October to December) and a spring peak in May and June.” There are racial differences in the incidence of Hib, with discrepant risks between white and black populations.” American Indians and Alaskan Eskimos are at increased risk specifically for meningitis caused by Hib. There is no clear association between nasopharyngeal carriage and the incidence of Hib invasive disease, which indicates that decreased host immunity and/or enhanced bacterial virulence is the cause of high-frequency Hib diseases.‘l Epiglottitis is rare among these patient populations, presumably because of different pathogenic mechanisms and different host immunity patterns. MICROBIOLOGIC
FACTORS
AND
IMMUNITY
Hib is a gram-negative pleomorphic bacillus (rod) that can be detected directly from clinical specimens and cultured on appropriate media. Hib does not grow on blood, MacConkey’s, or
162
American Journal of INFECTIONCONTROL
Janai et al.
eosin-methylene blue agars. Chocolate, horse blood, or other media that satisfy the organism’s requirement for factor X (hemin) and factor V (nicotinamide-adenine dinucleotide) must be included in specimen processing. Presumptive isolates are identified by antisera directed against its polysaccharide capsule, a five-carbon sugar base, polyribosylribitol phosphate (PRP). Antibodies against this antigen confer immunity.12 Although various outer membrane proteins also induce an immunologic response, their role in preventing Hib disease is in question. For example, in one study of natural immunity to Hib disease, antibody responses to both capsular polysaccharide (CPS) and outer membrane (OM) proteins were measured during the acute and convalescent phases of Hib disease. Concentrations of anti-CPS antibodies were undetected in the acute phase, but an antibody response later developed in 13 of 2 1 children, mainly those older than 2 years of age. In contrast, all children had detectable antibodies against O M in the acute phase, which suggests that these antibodies have little protective value.13 TREATMENT
Antibiotic therapy has been the mainstay of treatment and prevention of Hib disease. Hib was uniformly sensitive to ampicillin until 1974. Since then, resistance has emerged and up to 30% of isolates are currently ampicillinresistant, mostly as a result of the production of S-lactamase.14*l5 Therefore all Hib isolates from blood or other normally sterile body fluids should be evaluated by one of the rapid tests for P-lactamase production. Moreover, antimicrobial susceptibility of these isolates should be confirmed by standard methods inasmuch as ampicillin-resistant, non-plactamase-producing organisms rarely have been identified. The likelihood of isolating a resistant organism is particularly high among infants previously treated with antibiotics (especially the p-lactams) and greater among type b than noncapsulated types.16,l7 Although the third-generation cephalosporins remain uniformly active against Hib, strains of Hib re-
sistant to both ampicillin and chloramphenicol18 currently are prevalent in Barcelona, Spain, and new resistance patterns may be a problem in the future. Current recommendations for empiric therapy include either a combination of ampicillin and chloramphenicol or one of the third-generation cephalosporins (cefotaxime and ceftriaxone). In Hib infections that do not involve the central nervous system, the second-generation cephalosporin cefuroxime can be equally effective. CARRIER
STATE
The pathogenesis of Hib infection suggests that spread of the organism to the blood stream occurs after nasopharyngeal colonization and subsequent disruption of the mucosal nasopharyngeal protective layer. Hib nasopharyngeal carriage, and thus infection, can be transmitted from person to person, and secondary cases have been reported among household (2% to 4%) day-care (0% to 1.3%), and nosocomial contacts.lga2o Two recent studies to determine nasopharyngeal carriage of H. influenzae in healthy children up to 6 years of age revealed an isolation rate of 30% to 60% for H. influenzae. Of these, 7% to 15% were type b. Subject location (daycare center, outpatient clinic) and season influenced isolation rates, as did culture techniques.“, 21 For example, carriage rates were higher among children who attended day-care centers for more than 6 months or during the autumn and late spring. The use of selective media (antibiotic-supplemented chocolate agar) enhanced the recovery of Hib organisms. Studies in families with an index case of invasive Hib infection revealed a higher rate of carriage (70% to SO%).12, 22These data suggest that higher carriage rates and prolonged contact with the organism may increase the rate of secondary disease acquisition. Two major target groups for prevention and prophylaxis exist. The first is children at increased risk-estimated as high as 4%because of contact with an index case. The second is all infant subjects, aged 2 months to 4 years, the age of maximum disease prevalence.
Volume 18 Number 3 June 1990
Invasive Haemophilus
H. influenzae age and not given rifampin prophylaxis
Table 2. Rates of secondary
Band et aLz6
Location
disease in day-care
Fleming
et al.*’
Osterholm
et aL2*
Seattle Atlanta Oklahoma
Minnesota
12179 to 6161
1183 - 2184 to 7183 - 2184
8182 to 7184
No. of contacts
91
755
1086
Secondary disease n Rate (%)
1 1.1
10 1.3 0.9 - 1.7
95% Cl for secondary
0.0 - 3.3
163
center contacts younger than 4 years of
Multicenter
Time interval
influenzae type b infections
Murphy
et aivz9
Dallas
ioh
to 10184
Makintubee et ai.30
Oklahoma
1184 to 3186
587
486
0 0
1 0.2
6 1.2
0.0 - 0.3
0.0 - 0.4
0.7 - 1.7
disease rate From Marks MI, Dorchester WL. J Pediatr 1987;lli :306. Cl, Confidence interval.
PREVENTION Nosocomial spread
A recent study employed selective media to evaluate the dynamics of nasopharyngeal colonization with Hib during antibiotic therapy. There was no growth of Hib on nasopharyngeal specimens 24 hours after initiation of antimicrobial chemotherapy23 in all 27 patients. Therefore nosocomial spread should be largely preventable by respiratory isolation for the first 24 hours, combined with careful handwashing and specimen handling. It should be mentioned that this risk is largely theoretic, that is, nosocomial spread in acute care settings is not described. Previous studies, however, showed that colonization with Hib may persist or recur after discontinuation of antibiotic therapy in children with invasive Hib diseaseF4 Bacterial persistence and recolonization with contacts are possible mechanisms. A current approach is to add oral rifampin to the last 4 days of systemic treatment. Others prefer to add rifampin after the last dose of systemic therapy to avoid confusion created by adverse effects (e.g., nausea, rash, or fever). Rifampin is effective (90% to 95%) in eradicating nasopharyngeal carriage and thus in decreasing secondary disease.25Currently, rifampin prophylaxis is recommended for all household contacts if there is a sibling
at home younger than 4 years of age (and presumably at risk for invasive disease). Day care
Table 2 lists the rates of secondary Hib disease among day-care contacts as noted in five recent reports.26*30The rate of secondary Hib disease was defined as the number of Hib disease cases that occurred among day-care contacts within 60 days of diagnosis of an index case. The incidence ranged between 0% to 1.3%. Different methods of patient enrollment, diverse day-care center settings, and disparate pathogenicity of Hib subtypes are possible explanations for this variability. A pooled secondary disease rate of 0.6% may provide the best current estimate of the true rate of secondary Hib disease in day-care exposures. With this estimate of high risk, rifampin chemoprophyZuxis, combined with careful surveillance and community education, is recommended by the American Academy of Pediatrics for day-care contacts of a single index case,31under certain circumstances. These include day-care settings in which most children are younger than 2 years of age and contact is 25 hours per week or more. A second case in a single center should prompt prophylaxis for all attendees and supervisory personnel. Previously vaccinated children also
American
164
Janai et al.
should receive prophylaxis, when indicated, because successful immunization does not affect nasopharyngeal carriage. Vaccine
Although many cases of secondary disease can be prevented by antibiotic chemoprophylaxis, this amounts to less than 10% of the total number of Hib infections. Prevention of primary disease is a logical step and is the major goal of researchers around the world. As discussed previously and as shown in many animal studies, anti-CPS antibodies are protective against Hib disease. The immune response to this antigen is weak in younger infants (
