Haemophilus and Moraxella Infections

Haemophilus Influenzae

Definition

Haemophilus refers to the bacteria’s requirement for specific blood components for growth. In the respiratory tract, which is the primary site of colonization for most Haemophilus species, the most common infections include otitis media, sinusitis, bronchitis, and pneumonia. Serious invasive diseases (e.g., epiglottitis, bacteremia, endocarditis, meningitis, septic arthritis) may occur, particularly in susceptible older adults and infants ( Table 277-1 ).

TABLE 277-1

SITES OF COLONIZATION AND INFECTIONS BY HAEMOPHILUS INFLUENZAE

SPECIES	NORMAL FLORA	ASSOCIATED DISEASES
H. influenzae	Nasopharynx Upper respiratory tract	Meningitis Epiglottitis Sinusitis Otitis media Pneumonia Cellulitis Septic arthritis Osteomyelitis Obstetric infections Endocarditis
H. influenzae , biogroup aegyptius		Purulent conjunctivitis Brazilian purpuric fever

The Pathogen

Haemophilus species are small, nonmotile, pleomorphic, gram-negative bacteria that can grow aerobically or anaerobically. H. influenzae are classified or typed based on the presence or absence of serologically unique capsule polysaccharides—including six capsule serotypes (a to f) as well as nonencapsulated (nontypeable) forms. Encapsulated types are relatively clonal, whereas nonencapsulated types are very heterogeneous. Isolation of Haemophilus species in the laboratory is best accomplished on chocolate agar medium, which supplies the hemin and nicotinamide adenine dinucleotide required for its growth, in a carbon dioxide–enriched atmosphere.

Epidemiology

H. influenzae can colonize the nasopharynx of both children and adults. Current vaccination rates for H. influenzae type b are about 70% worldwide, but the organism still causes an estimated 3 million cases of serious disease and 400,000 deaths annually.

Prior to the introduction of H. influenzae type b conjugate vaccines in the United States, between 3 and 5% of infants harbored H. influenzae type b in their nasopharynx, and about 1 in 200 children less than 5 years of age experienced invasive disease. In unvaccinated populations, H. influenzae type b is still the most common cause of meningitis in young children, but vaccines reduce invasive H. influenzae type b disease by more than 99%. Furthermore, the risk of secondary invasive infections among nonimmune household contacts of a patient with invasive H. influenzae type b disease is increased about 600-fold.

With immunization with a protein conjugate H. influenzae type b vaccine, both colonization and infection with H. influenzae type b are greatly reduced. Although nasopharyngeal colonization with nontypeable H. influenzae is very common in both children and adults, infection occurs in only a small proportion of colonized individuals.

In the United States, the overall annual incidence of invasive H. influenzae infections is now 1.70 cases per 100,000 population, with cases increasing for H. influenzae types a, e, and f and nontypeable species even as cases of type b have remained low. From 1998 to 2007, H. influenzae caused 6% of meningitis cases in U.S. adults, the majority of which were nontypeable strains. Similar data are reported from other countries where conjugate H. influenzae vaccines are routinely used.

The risk of invasive H. influenzae disease is highest in infants less than 1 year of age and adults ages 65 years and older. People living with human immunodeficiency virus (HIV) infection also have increased risk for H. influenzae infection. Other underlying conditions that increase the risk for H. influenzae infection include immunoglobulin deficiencies ( Chapter 231 ), sickle cell disease ( Chapter 149 ), anatomic or functional asplenia ( Chapter 154 ), malignant disease, pregnancy, cerebrospinal fluid (CSF) leaks, head trauma ( Chapter 368 ), alcohol use disorders ( Chapter 364 ), and chronic obstructive pulmonary disease (COPD; Chapter 76 ).

Disproportionately high rates of invasive H. influenzae disease also are noted in Indigenous populations. The incidence of invasive H. influenzae serotype a disease is currently 17 times higher in American Indian/Alaska native children below age 5 years than among children of all other races combined. In nonvaccinated populations, daycare attendance, crowding, other siblings in the household, prior hospitalizations, and prior otitis media increase the risk for H. influenzae type b disease in young children, whereas breast-feeding decreases the risk.

Pathobiology

H. influenzae have six unique polysaccharide capsular serotypes (a through f) that are key factors in virulence by inhibiting opsonization, clearance, and intracellular killing of the organisms. Nontypeable strains lack this capsular polysaccharide. The H. influenzae type b capsule contains pentose polysaccharides, specifically polyribosyl ribitol phosphate, whereas the other serotypes contain hexose polysaccharides. H. influenzae type b capsule is more virulent than the other capsulated types, and the amount of polyribosyl ribitol phosphate produced is related to its resistance to complement.

Structurally and antigenically distinct encapsulated isolates (types a to f) are responsible for most of the invasive infections in unvaccinated children and of acute epiglottitis in both children and adults, whereas the nonencapsulated (nontypeable) isolates are associated with localized respiratory mucosal infections, conjunctivitis, female genital tract infections, and invasive disease in older adults and in patients who have underlying conditions such as COPD. Nontypeable H. influenzae is one of the most common causes of acute otitis media in children. Among non-b capsule serotypes, serotype a capsule is most similar to the type b capsule, and type a isolates can cause severe invasive disease that is similar to H. influenzae type b in young children. In vaccinated populations, most infections are now caused by nontypeable strains and somewhat less often by non-b serotypes (particularly H. influenzae serotypes a, e, and f).

Fimbriae are present in both typeable and nontypeable isolates and are important virulence factors that facilitate adherence of H. influenzae to mucosal surfaces. The lipooligosaccharides of H. influenzae also contribute to their virulence. Phase-variable modifications to the H. influenzae surface lipooligosaccharide alter receptor tropism and evasion of innate immune defenses. Nontypeable H. influenzae , with lipopolysaccharides containing more phosphorylcholine, more efficiently colonize the upper respiratory tract by binding to platelet-activating factor receptors on epithelial cells. In contrast, isolates that invade the blood stream have lipopolysaccharides that contain less phosphorylcholine to avoid complement activation and enhance their intravascular survival.

A variety of outer membrane proteins also serve as virulence factors in H. influenzae disease by inhibiting complement killing and facilitating mucosal adhesion. Effective activation of complement is an essential component of the host defense against some H. influenzae diseases, and congenital complement component deficiencies (e.g., in C2, C3, and factor I; see Chapter 37 ) increase the risk of serious infection. Efficient scavenging of iron within the human host is crucial for H. influenzae to multiply. To evade the local mucosal immune response, H. influenzae produces immunoglobulin A1 protease, which specifically cleaves human immunoglobulin A1 (IgA1).

Serum bactericidal antibodies directed against the polysaccharide capsule are critical to protection against encapsulated H. influenzae , particularly type b infection. Capsule-specific antibodies facilitate opsonization and complement-mediated killing. Neonates acquire transplacental maternal antibodies that protect against invasive Hib disease for the first 3 to 6 months of life. As maternal antibodies wane, susceptibility to H. influenzae type b infections increases during infancy. In unvaccinated populations, most cases of H. influenzae type b meningitis occur in infants after they lose passively acquired maternal antibodies and before they develop active humoral immunity. Not surprisingly, patients who have functional asplenia (e.g., sickle cell disease) or who have undergone splenectomy also have an increased risk of developing severe disease with H. influenzae type b and, rarely, serotype a.

Clinical Manifestations and Diagnosis

Meningitis

H. influenzae meningitis now more commonly occurs in unvaccinated or undervaccinated young children, immunocompromised children and adults, and patients who have a history of skull fractures or CSF leaks. As with other bacterial meningitides ( Chapter 381 ), patients typically present with fever, headache, and mental status changes, including lethargy, confusion, somnolence, and sometimes seizures.

The CSF white blood cell count is usually greater than 1000/µL, with an elevated protein level and low glucose level. The CSF Gram stain is neither sensitive for detecting nor specific for excluding H. influenzae , and the diagnosis is established by CSF culture or a multiplex polymerase chain reaction (PCR) panel that detects H. influenzae nucleic acid, even in patients who have had prior antibiotic treatment, before culture results are available.

Epiglottitis

H. influenzae type b is the most common cause of acute epiglottitis in unvaccinated children, especially before age 5 years, but is rare after vaccination. Symptoms in children include the rapid onset of fever, drooling, dysphagia, respiratory distress, stridor, and life-threatening airway obstruction. In adults, symptoms may be more insidious and include fever, sore throat, dysphagia, and odynophagia. Tender cervical lymphadenopathy is common in all ages. A swollen, cherry-red epiglottis (see Fig. 331-2B ) can be visualized on laryngoscopy, which should be performed only by experts who can perform emergency tracheotomy if the procedure precipitates acute airway obstruction. A lateral radiograph (see Figs. 331-2 C and D) or a computed tomographic (CT) scan of the neck may confirm the diagnosis. H. influenzae should be differentiated from parainfluenza virus ( Chapter 331 ), which is the leading cause of epiglottitis in vaccinated populations. Since H. influenzae is often part of the normal respiratory flora, PCR and cultures of the pharynx and other mucosal surfaces may not provide a definitive diagnosis, so the diagnosis is usually established by a positive blood culture for H. influenzae .

Tracheobronchitis

H. influenzae tracheobronchitis ( Chapter 84 ), which is characterized by fever, cough, and purulent sputum without radiographic evidence of pneumonia, occurs especially as an exacerbation of respiratory symptoms in patients with known COPD. For example, H. influenzae explains 10 to 15% of cases of persistent subacute cough after an upper respiratory infection. A sputum Gram stain that demonstrates purulence and a predominance of small, pleomorphic/coccobacillary gram-negative organisms is suggestive of the diagnosis, but definitive bacteriologic diagnosis is often difficult to achieve, and associated bacteremia is rare. A response to treatment for H. influenzae supports the diagnosis.

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