Haemophilus influenzae

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Chapter 186 Haemophilus influenzae

Robert S. Daum

An effective vaccine to prevent Haemophilus influenzae type b disease introduced in the USA and many other countries has resulted in a dramatic decrease in the incidence of infections caused by this organism. However, mortality and morbidity from H. influenzae type b infection remain a problem worldwide, primarily in developing countries. Occasional cases of invasive disease caused by non–type b organisms continue to occur but infrequently. Nontypable members of the species are important causes of otitis media and sinusitis.

Etiology

H. influenzae is a fastidious, gram-negative, pleomorphic coccobacillus that requires factor X (hematin) and factor V (phosphopyridine nucleotide) for growth. Some H. influenzae isolates are surrounded by a polysaccharide capsule and can be serotyped into 6 antigenically and biochemically distinct types designated by letters a-f.

Epidemiology

Before the advent of an effective type b conjugate vaccine in 1988, H. influenzae type b was a major cause of serious disease among children in all countries. There was a striking age distribution of cases, with >90% in children <5 yr of age and the majority in children <2 yr of age. The annual attack rate of invasive disease was 64-129 cases/100,000 children <5 yr of age per year. Invasive disease caused by other capsular serotypes has been much less frequent but continues to occur. The incidence of invasive disease caused by b and non–type b serotypes has been estimated at about 0.08 and 1.02 cases/100,000 children <5 yr of age per year, respectively, in the USA. Nonencapsulated (nontypable) H. influenzae organisms also occasionally cause invasive disease, especially in neonates, immunocompromised children, and children in developing countries. The estimated rate of invasive disease due to nontypable H. influenzae in the USA is 1.88/100,000 children <5 yr of age per year. Nontypable isolates are common etiologic agents in otitis media, sinusitis, and chronic bronchitis.

Humans are the only natural hosts for H. influenzae, which is part of the normal respiratory flora in 60-90% of healthy children. Most isolates are nontypable. Before the advent of conjugate vaccine immunization, H. influenzae type b could be isolated from the pharynx of 2-5% of healthy preschool and school-aged children, with lower rates among infants and adults. Asymptomatic colonization with H. influenzae type b occurs at a much lower rate in immunized populations.

The continued circulation of the type b organism despite current vaccine coverage levels suggests that elimination of type b disease may be a formidable task. The few cases of type b invasive disease in the USA now occur in both unvaccinated and fully vaccinated children. Approximately one half of cases occur in young infants too young to have received a complete primary vaccine series. Among the cases in patients who are old enough to have received a complete vaccine series, the majority are underimmunized. To highlight this point, during a recent shortage of H. influenzae type b vaccine, invasive disease developed in five children in Minnesota, all of whom were incompletely immunized. Continued efforts will be necessary to provide currently available conjugate vaccines to children in developing countries, where affordability remains an important issue.

In the pre-vaccine era, certain groups and individuals had an increased incidence of invasive type b disease, including Alaskan Eskimos, Apaches, Navajos, and African-Americans. Persons with certain chronic medical conditions were also known to be at increased risk for invasive disease, including those with sickle cell disease, asplenia, congenital and acquired immunodeficiencies, and malignancies. Unvaccinated infants with invasive H. influenzae type b infection are also at increased risk for recurrence, reflecting the fact that they typically do not develop a protective immune response to H. influenzae.

Socioeconomic risk factors for invasive H. influenzae type b disease included child care outside the home, the presence of siblings of elementary school age or younger, short duration of breast-feeding, and parental smoking. A history of otitis media was associated with an increased risk for invasive disease. Much less is known about the epidemiology of invasive disease due to non–type b strains, and it is not clear whether the epidemiologic features of type b disease apply to disease caused by non–type b isolates.

Among age-susceptible household contacts who have been exposed to a case of invasive H. influenzae type b disease, there is increased risk for secondary cases of invasive disease in the first 30 days, especially in susceptible children <24 mo of age. Whether a similar increased risk occurs for contacts of individuals with non–type b disease is unknown.

The mode of transmission is most commonly direct contact or inhalation of respiratory tract droplets containing H. influenzae. The incubation period for invasive disease is variable, and the exact period of communicability is unknown. Most children with invasive H. influenzae type b disease are colonized in the nasopharynx before initiation of antimicrobial therapy; 25-40% may remain colonized during the first 24 hr of therapy.

With the decline of disease caused by type b organisms, disease caused by other serotypes (a, c-f) and nontypable organisms has been recognized more clearly. There is no evidence that these non–type b infections have increased in frequency. However, clusters of type a and, less often, type f and type e infections have occurred.

Pathogenesis

The pathogenesis of disease begins with adherence to respiratory epithelium and colonization of the nasopharynx, which is mediated by pilus and non-pilus adherence factors. The mechanism of entry into the intravascular compartment is unclear but appears to be influenced by cytotoxic factors. Once in the bloodstream, H. influenzae type b and perhaps other encapsulated strains resist intravascular clearance mechanisms at least in part via the presence of a polysaccharide capsule. In the case of H. influenzae type b, the magnitude and duration of bacteremia influence the likelihood of dissemination of bacteria to sites such as the meninges and joints.

Noninvasive H. influenzae infections such as otitis media, sinusitis, and bronchitis are usually caused by nontypable strains. These organisms gain access to sites such as the middle ear and sinus cavities by direct extension from the nasopharynx. Factors facilitating spread from the pharynx include eustachian tube dysfunction and antecedent viral infections of the upper respiratory tract.

Antibiotic Resistance

Most H. influenzae isolates are susceptible to ampicillin or amoxicillin, but about a third produce a β-lactamase and are therefore resistant. β-Lactamase–negative ampicillin-resistant (BLNAR) isolates have been identified that manifest resistance by production of a β-lactam–insensitive cell wall synthesis enzyme called PBP3.

Amoxicillin-clavulanate is uniformly active against H. influenzae clinical isolates except for the rare BLNAR isolates. Among macrolides, azithromycin is active against about 99% of H. influenzae isolates; in contrast, the activity of erythromycin and clarithromycin against H. influenzae clinical isolates is poor. H. influenzae resistance to 3rd-generation cephalosporins has not been documented. Resistance to trimethoprim-sulfamethoxazole is infrequent (≈10%), and resistance to quinolones is believed to be rare.

Immunity

In the pre-vaccine era, the most important known element of host defense was antibody directed against the type b capsular polysaccharide polyribosylribitol phosphate (PRP). Anti-PRP antibody is acquired in an age-related fashion and facilitates clearance of H. influenzae type b from blood, in part related to opsonic activity. Antibodies directed against antigens such as outer membrane proteins or lipopolysaccharides may also have a role in opsonization. Both the classic and alternative complement pathways are important in defense against H. influenzae type b.

Before the introduction of vaccination, protection from H. influenzae type b infection was presumed to correlate with the concentration of circulating anti-PRP antibody at the time of exposure. A serum antibody concentration of 0.15-1.0 µg/mL was considered protective against invasive infection. Unimmunized infants >6 mo of age and young children usually lacked an anti-PRP antibody concentration of this magnitude and were susceptible to disease after encountering H. influenzae type b. This lack of antibody in infants and young children may have reflected a maturational delay in the immunologic response to thymus-independent type 2 (TI-2) antigens such as unconjugated PRP, presumably explaining the high incidence of type b infections in infants and young children in the pre-vaccine era.

The conjugate vaccines (Table 186-1) act as thymus-dependent antigens and elicit serum antibody responses in infants and young children. These vaccines are believed to prime memory antibody responses on subsequent encounters with PRP. The concentration of circulating anti-PRP antibody in a child primed by a conjugate vaccine may not correlate precisely with protection, presumably because a memory response may occur rapidly on exposure to PRP and provide protection.

Table 186-1 HAEMOPHILUS INFLUENZAE TYPE B CONJUGATE VACCINES AVAILABLE IN THE USA

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Much less is known about immunity to other H. influenzae serotypes or to nontypable isolates. For nontypable isolates, evidence suggests that antibodies directed against 1 or more outer membrane proteins are bactericidal and protect against experimental challenge. A variety of antigens have been evaluated in an attempt to identify vaccine candidates for nontypable H. influenzae, including outer membrane proteins (P1, P2, P4, P5, P6, D15, and Tbp A/B), lipopolysaccharide, various adhesins, and lipoprotein D.

Diagnosis

Presumptive identification of H. influenzae is established by direct examination of the collected specimen after staining with Gram reagents. Because of its small size, pleomorphism, and occasional poor uptake of stain as well as the tendency for proteinaceous fluids to have a red background, H. influenzae

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