Haemophilus influenzae was first recognized in 1892 by Pfeiffer, who erroneously concluded that the bacterium was the cause of influenza. H. influenzae is a small (1- × 0.3-μm) gram-negative organism of variable shape; thus, it is often described as a pleomorphic coccobacillus. In clinical specimens such as cerebrospinal fluid (CSF) and sputum, H. influenzae frequently stains only faintly with safranin and therefore can easily be overlooked.
H. influenzae grows both aerobically and anaerobically. Its aerobic growth requires two factors: hemin (X factor) and nicotinamide adenine dinucleotide (V factor). These requirements are used in the clinical laboratory to identify the bacterium. Caution must be used to distinguish H. influenzae from H. haemolyticus, a respiratory tract commensal that has identical growth requirements. H. haemolyticus has classically been distinguished from H. influenzae by the hemolysis of the former species on horse blood agar. However, a significant proportion of isolates of H. haemolyticus have now been recognized as nonhemolytic. Analysis of various genotypic and phenotypic markers, including 16S ribosomal sequences, superoxide dismutase, outer-membrane protein P6, protein D, and fuculose kinase, can be used to distinguish these two species.
Six major serotypes of H. influenzae have been identified; designated a through f, they are based on antigenically distinct polysaccharide capsules. In addition, some strains lack a polysaccharide capsule and are referred to as nontypable strains. Type b and nontypable strains are the most relevant strains clinically (Table 54-1), although encapsulated strains other than type b can cause disease. H. influenzae was the first free-living organism to have its entire genome sequenced.
TABLE 54-1CHARACTERISTICS OF TYPE B AND NONTYPABLE STRAINS OF HAEMOPHILUS INFLUENZAE ||Download (.pdf) TABLE 54-1 CHARACTERISTICS OF TYPE B AND NONTYPABLE STRAINS OF HAEMOPHILUS INFLUENZAE
|FEATURE ||TYPE B STRAINS ||NONTYPABLE STRAINS |
|Capsule ||Ribosyl-ribitol phosphate ||Unencapsulated |
|Pathogenesis ||Invasive infections due to hematogenous spread ||Mucosal infections due to contiguous spread |
|Clinical manifestations ||Meningitis and invasive infections in incompletely immunized infants and children ||Otitis media in infants and children; lower respiratory tract infections in adults with chronic bronchitis |
|Evolutionary history ||Basically clonal ||Genetically diverse |
|Vaccine ||Highly effective conjugate vaccines ||None available; under development |
The antigenically distinct type b capsule is a linear polymer composed of ribosyl-ribitol phosphate. Strains of H. influenzae type b (Hib) cause disease primarily in infants and children <6 years of age. Nontypable strains are primarily mucosal pathogens but occasionally cause invasive disease.
EPIDEMIOLOGY AND TRANSMISSION
H. influenzae, an exclusively human pathogen, is spread by airborne droplets or by direct contact with secretions or fomites. Colonization with nontypable H. influenzae is a dynamic process; new strains are acquired and other strains are replaced periodically.
The widespread use of Hib conjugate vaccines in many industrialized countries has resulted in striking decreases in the rate of nasopharyngeal colonization by Hib and in the incidence of Hib infection (Fig. 54-1). However, the majority of the world’s children remain unimmunized. Worldwide, invasive Hib disease occurs predominantly in unimmunized children and in those who have not completed the primary immunization series. Certain groups have a higher incidence of invasive Hib disease than the general population, including African-American children and Native American groups. Although this increased incidence has not yet been accounted for, several factors may be relevant, including age at exposure to the bacterium, socioeconomic conditions, and genetic differences.
Estimated incidence (rate per 100,000) of invasive disease due to Haemophilus influenzae type b among children <5 years of age: 1987–2000. Fewer than 40 cases per year have been reported since 2000. (Data from the Centers for Disease Control and Prevention.)
Hib strains cause systemic disease by invasion and hematogenous spread from the respiratory tract to distant sites such as the meninges, bones, and joints. The type b polysaccharide capsule is an important virulence factor affecting the bacterium’s ability to avoid opsonization and cause systemic disease.
Nontypable strains cause disease by local invasion of mucosal surfaces. Otitis media results when bacteria reach the middle ear by way of the eustachian tube. Adults with chronic bronchitis experience recurrent lower respiratory tract infection due to nontypable strains. In addition, persistent nontypable H. influenzae colonization of the lower airways of adults with chronic obstructive pulmonary disease (COPD) contributes to the airway inflammation that is a hallmark of the disease. Nontypable strains that cause infection in adults with COPD differ in pathogenic potential and genome content from strains that cause otitis media. In the middle ear, nontypable strains form biofilms. More resistant to host clearance mechanisms and to antibiotics than are planktonic bacteria, biofilms are associated with chronic and recurrent otitis media. The incidence of invasive disease caused by nontypable strains is low. Strains that cause invasive disease are genetically and phenotypically diverse.
Antibody to the capsule is important in protection from infection by Hib strains. The level of (maternally acquired) serum antibody to the capsular polysaccharide, which is a polymer of polyribitol ribose phosphate (PRP), declines from birth to 6 months of age and, in the absence of vaccination, remains low until ~2 or 3 years of age. The age at the antibody nadir correlates with that of the peak incidence of type b disease. Antibody to PRP then appears partly as a result of exposure to Hib or cross-reacting antigens. Systemic Hib disease is unusual after the age of 6 years because of the presence of protective antibody. Vaccines in which PRP is conjugated to protein carrier molecules have been developed and are now used widely. These vaccines generate an antibody response to PRP in infants and effectively prevent invasive infections in infants and children.
Since nontypable strains lack a capsule, the immune response to infection is directed at noncapsular antigens. These antigens have generated considerable interest as immune targets and potential vaccine components. The human immune response to nontypable strains appears to be strain-specific, a characteristic that accounts in part for the propensity of these strains to cause recurrent otitis media and recurrent exacerbations of chronic bronchitis in immunocompetent hosts.
The most serious manifestation of infection with Hib is meningitis (Chap. 36), which primarily affects children <2 years of age. The clinical manifestations of Hib meningitis are similar to those of meningitis caused by other bacterial pathogens. Fever and altered central nervous system function are the most common features at presentation. Nuchal rigidity may or may not be evident. Subdural effusion, the most common complication, is suspected when, despite 2 or 3 days of appropriate antibiotic therapy, the infant has seizures, hemiparesis, or continued obtundation. The overall mortality rate from Hib meningitis is ~5%, and the morbidity rate is high. Of survivors, 6% have permanent sensorineural hearing loss, and about one-fourth have a significant handicap of some type. If more subtle handicaps are sought, up to half of survivors are found to have some neurologic sequelae, such as partial hearing loss and delayed language development.
Epiglottitis (Chap. 20) is a life-threatening Hib infection involving cellulitis of the epiglottis and supraglottic tissues. It can lead to acute upper airway obstruction. Its unique epidemiologic features are its occurrence in an older age group (2–7 years old) than other Hib infections and its absence among Navajo Indians and Alaskan Eskimos. Sore throat and fever rapidly progress to dysphagia, drooling, and airway obstruction. Epiglottitis also occurs in adults.
Cellulitis (Chap. 26) due to Hib occurs in young children. The most common location is on the head or neck, and the involved area sometimes takes on a characteristic bluish-red color. Most patients have bacteremia, and 10% have an additional focus of infection.
Hib causes pneumonia in infants. The infection is clinically indistinguishable from other types of bacterial pneumonia (e.g., pneumococcal pneumonia) except that Hib is more likely to involve the pleura. Several less common invasive conditions can be important clinical manifestations of Hib infection in children. These include osteomyelitis, septic arthritis, pericarditis, orbital cellulitis, endoph-thalmitis, urinary tract infection, abscesses, and bacteremia without an identifiable focus.
Non–type b encapsulated strains of H. influenzae (types a, c, d, e, and f) are unusual causes of invasive infection manifested predominantly by bacteremia and pneumonia. Most such infections occur in the setting of underlying conditions.
Nontypable H. influenzae is the most common bacterial cause of exacerbations of COPD; these exacerbations are characterized by increased cough, sputum production, and shortness of breath. Fever is low-grade, and no infiltrates are evident on chest x-ray. Nontypable strains also cause community-acquired bacterial pneumonia in adults, especially among patients with COPD or AIDS. The clinical features of H. influenzae pneumonia are similar to those of other types of bacterial pneumonia, including pneumococcal pneumonia.
Nontypable H. influenzae is one of the three most common causes of childhood otitis media (the other two being Streptococcus pneumoniae and Moraxella catarrhalis) (Chap. 20). Infants are febrile and irritable, while older children report ear pain. Symptoms of viral upper respiratory infection often precede otitis media. The diagnosis is made by pneumatic otoscopy. An etiologic diagnosis, although not routinely sought, can be established by tympanocentesis and culture of middle-ear fluid. Clinical features associated with H. influenzae otitis media include a history of recurrent episodes, treatment failure, concomitant conjunctivitis, bilateral otitis media, and recent antimicrobial therapy. The increasing use of pneumococcal polysaccharide conjugate vaccines in infants is resulting in a relative increase in the proportion of otitis media cases that are caused by H. influenzae.
Nontypable H. influenzae also causes puerperal sepsis and is an important cause of neonatal bacteremia. These nontypable strains, which are closely related to H. haemolyticus, tend to be of biotype IV and cause invasive disease after colonizing the female genital tract.
Nontypable H. influenzae causes sinusitis (Chap. 20) in adults and children. In addition, the bacterium is a less common cause of various invasive infections. These infections include empyema, adult epiglottitis, pericarditis, cellulitis, septic arthritis, osteomyelitis, endocarditis, cholecystitis, intraabdominal infections, urinary tract infections, mastoiditis, aortic graft infection, and bacteremia without a detectable focus. While most H. influenzae invasive infections in countries where Hib vaccines are used widely are caused by nontypable strains, there is no convincing evidence of an increased incidence of infection by nontypable H. influenzae as a result of use of Hib vaccines. Continued monitoring will be important. Many patients with H. influenzae bacteremia have an underlying condition, such as HIV infection, cardiopulmonary disease, alcoholism, or cancer.
The most reliable method for establishing a diagnosis of Hib infection is recovery of the organism in culture. The presence of gram-negative coccobacilli in Gram-stained CSF is strong evidence for Hib meningitis. Recovery of the organism from CSF confirms the diagnosis. Cultures of other normally sterile body fluids, such as blood, joint fluid, pleural fluid, pericardial fluid, and subdural effusion, are confirmatory in other infections.
Detection of PRP is an important adjunct to culture in rapid diagnosis of Hib meningitis. Immunoelectrophoresis, latex agglutination, coagglutination, and enzyme-linked immunosorbent assay are effective in detecting PRP. These assays are particularly helpful when patients have received prior antimicrobial therapy and thus are especially likely to have negative cultures.
Because nontypable H. influenzae is primarily a mucosal pathogen, it is a component of a mixed flora; thus etiologic diagnosis is challenging. Nontypable H. influenzae infection is strongly suggested by the predominance of gram-negative coccobacilli among abundant polymorphonuclear leukocytes in a Gram-stained sputum specimen from a patient in whom pneumonia is suspected. Although bacteremia is detectable in a small proportion of patients with pneumonia due to nontypable H. influenzae, most such patients have negative blood cultures.
A diagnosis of otitis media is based on the detection by pneumatic otoscopy of fluid in the middle ear. An etiologic diagnosis requires tympanocentesis but is not routinely sought. An invasive procedure is also required to determine the etiology of sinusitis; thus, treatment is often empirical once the diagnosis is suspected in light of clinical symptoms and sinus radiographs.
TREATMENT Haemophilus influenzae
Initial therapy for meningitis due to Hib should consist of a cephalosporin such as ceftriaxone or cefotaxime. For children, the dosage of ceftriaxone is 75–100 mg/kg daily given in two doses 12 h apart. The pediatric dosage of cefotaxime is 200 mg/kg daily given in four doses 6 h apart. Adult dosages are 2 g every 12 h for ceftriaxone and 2 g every 4–6 h for cefotaxime. An alternative regimen for initial therapy is ampicillin (200–300 mg/kg daily in four divided doses) plus chloramphenicol (75–100 mg/kg daily in four divided doses). Therapy should continue for a total of 1–2 weeks.
Administration of glucocorticoids to patients with Hib meningitis reduces the incidence of neurologic sequelae. The presumed mechanism is reduction of the inflammation induced by bacterial cell-wall mediators of inflammation when cells are killed by antimicrobial agents. Dexamethasone (0.6 mg/kg per day intravenously in four divided doses for 2 days) is recommended for the treatment of Hib meningitis in children >2 months of age.
Invasive infections other than meningitis are treated with the same antimicrobial agents. For epiglottitis, the dosage of ceftriaxone is 50 mg/kg daily, and the dosage of cefotaxime is 150 mg/kg daily, given in three divided doses 8 h apart. Epiglottitis constitutes a medical emergency, and maintenance of an airway is critical. The duration of therapy is determined by the clinical response. A course of 1–2 weeks is usually appropriate.
Many infections caused by nontypable strains of H. influenzae, such as otitis media, sinusitis, and exacerbations of COPD, can be treated with oral antimicrobial agents. Approximately 20–35% of nontypable strains produce β-lactamase (with the exact proportion depending on geographic location), and these strains are resistant to ampicillin. Several agents have excellent activity against nontypable H. influenzae, including amoxicillin/clavulanic acid, various extended-spectrum cephalosporins, and the macrolides azithromycin and clarithromycin. Fluoroquinolones are highly active against H. influenzae and are useful in adults with exacerbations of COPD. However, fluoroquinolones are not currently recommended for the treatment of children or pregnant women because of possible effects on articular cartilage.
In addition to β-lactamase production, alteration of penicillin-binding proteins—a second mechanism of ampicillin resistance—has been detected in isolates of H. influenzae. Although rare in the United States, these β-lactamase-negative ampicillin-resistant strains are common in Japan and are increasing in prevalence in Europe. Continued monitoring of the evolving antimicrobial susceptibility patterns of H. influenzae will be important.
(See also Chap. 5) Two conjugate vaccines that prevent invasive infections with Hib in infants and children are licensed in the United States. In addition to eliciting protective antibody, these vaccines prevent disease by reducing rates of pharyngeal colonization with Hib. The widespread use of conjugate vaccines has dramatically reduced the incidence of Hib disease in developed countries. Even though the manufacture of Hib vaccines is costly, vaccination is cost-effective. The Global Alliance for Vaccines and Immunizations has recognized the underuse of Hib conjugate vaccines.
The disease burden has been reduced in developing countries that have implemented routine vaccination (e.g., The Gambia, Chile). An important obstacle to more widespread vaccination is the lack of data on the epidemiology and burden of Hib disease in many developing countries.
All children should be immunized with an Hib conjugate vaccine, receiving the first dose at ~2 months of age, the rest of the primary series at 2–6 months of age, and a booster dose at 12–15 months of age. Specific recommendations vary for the different conjugate vaccines. The reader is referred to the recommendations of the American Academy of Pediatrics (Chap. 5 and www.cispimmunize.org).
Currently, no vaccines are available specifically for the prevention of disease caused by nontypable H. influenzae. However, a vaccine that contains protein D—a surface protein of H. influenzae—conjugated to pneumococcal polysaccharides is licensed in other countries and is used widely in Europe. The vaccine has shown partial efficacy in preventing H. influenzae otitis media in clinical trials. Additional progress in the development of vaccines against nontypable H. influenzae is anticipated.
The risk of secondary disease is greater than normal among household contacts of patients with Hib disease. Therefore, all children and adults (except pregnant women) in households with an index case and at least one incompletely immunized contact <4 years of age should receive prophylaxis with oral rifampin. When two or more cases of invasive Hib disease have occurred within 60 days at a child-care facility attended by incompletely vaccinated children, administration of rifampin to all attendees and personnel is indicated, as is recommended for household contacts. Chemoprophylaxis is not indicated in nursery and child-care contacts of a single index case. The reader is referred to the recommendations of the American Academy of Pediatrics.