Haemophilus influenzae

Etiology

Haemophilus 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 1 of 6 antigenically and biochemically distinct types designated a, b, c, d, e, and f.

Epidemiology

Before the advent of an effective Hib conjugate vaccine in 1988, H. influenzae type b was a major cause of serious disease among children. There was a striking age distribution of cases, with >90% in children <5 yr old and the majority in children <2 yr old. The annual attack rate of invasive disease was 64-129 cases per 100,000 children <5 yr old. Invasive disease caused by other capsular serotypes has been much less frequent but continues to occur. The incidence of invasive disease caused by type b and non–type b serotypes has been estimated at approximately 0.08 and 1.02 cases, respectively, per 100,000 children <5 yr old per year in the United States. Nonencapsulated (nontypeable) H. influenzae strains also occasionally cause invasive disease, especially in neonates, immunocompromised children, and children in developing countries. The estimated rate of invasive disease caused by nontypeable H. influenzae in the United States is 1.88 per 100,000 children <5 yr old per year. Nontypeable 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 nontypeable. 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-age children, with lower rates among infants and adults. Asymptomatic colonization with Hib 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 Hib disease may be a formidable task. The few cases of Hib invasive disease in the United States now occur in both unvaccinated and fully vaccinated children. Approximately 50% of cases occur in young infants who are 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 shortage of Hib vaccine, invasive disease developed in 5 children in Minnesota, all of whom were incompletely immunized. Continued efforts are necessary to provide currently available Hib conjugate vaccines to children in developing countries, where affordability remains an important issue.

In the prevaccine era, certain groups and individuals had an increased incidence of invasive Hib disease, including Alaskan Natives, American Indians (Apache, Navajo), 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 Hib infection are also at increased risk for recurrence, reflecting that they typically do not develop a protective immune response to H . influenzae.

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

Among age-susceptible household contacts who have been exposed to a case of invasive Hib disease, there is increased risk for secondary cases of invasive disease in the 1st 30 days, especially in susceptible children <24 mo old. Whether a similar increased risk occurs for contacts of individuals with non-Hib disease is unknown.

The mode of transmission is usually 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 Hib disease are colonized in the nasopharynx before initiation of antimicrobial therapy; 25–40% may remain colonized during the 1st 24 hr of therapy.

With the decline of disease caused by type b organisms, disease caused by other serotypes (a, c-f) and nontypeable 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. Data from Israel suggest that nontypeable H. influenzae is the most common case of invasive H. influenzae disease in that country.

Pathogenesis

The pathogenesis of Hib disease begins with adherence to respiratory epithelium and colonization of the nasopharynx, which is mediated by pilus and nonpilus 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 because of a polysaccharide capsule. In the case of Hib, 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 nontypeable 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.

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 is sometimes difficult to visualize. Furthermore, given that identification of microorganisms on smear by either technique requires at least 10 ⁵ bacteria/mL, failure to visualize them does not preclude their presence.

Culture of H. influenzae requires prompt transport and processing of specimens because the organism is fastidious. Specimens should not be exposed to drying or temperature extremes. Primary isolation of H. influenzae can be accomplished on chocolate agar or on blood agar plates using the staphylococcus streak technique.

Serotyping of H. influenzae is accomplished by slide agglutination with type-specific antisera. Accurate serotyping is essential to monitor progress toward elimination of type b invasive disease. Timely reporting of cases to public health authorities should be ensured.

Clinical Manifestations and Treatment

The initial antibiotic therapy of invasive infections possibly caused by H. influenzae should be a parenterally administered antimicrobial agent effective in sterilizing all foci of infection and effective against ampicillin-resistant strains, usually an extended-spectrum cephalosporin such as ceftriaxone. These antibiotics have achieved popularity because of their relative lack of serious adverse effects and ease of administration. After the antimicrobial susceptibility of the isolate has been determined, an appropriate agent can be selected to complete the therapy. Ampicillin remains the drug of choice for the therapy of infections caused by susceptible isolates. If the isolate is resistant to ampicillin, ceftriaxone can be administered once daily in selected circumstances for outpatient therapy.

Oral antimicrobial agents are sometimes used to complete a course of therapy initiated by the parenteral route and are typically initial therapy for noninvasive infections such as otitis media and sinusitis. If the organism is susceptible, amoxicillin is the drug of choice. An oral second- or third-generation cephalosporin or amoxicillin-clavulanate may be used when the isolate is resistant to ampicillin.