Haemophilus influenza Disease

H . influenza DISEASE

Hib produces acute, life-threatening infections of the central nervous system, epiglottis, and soft tissues, primarily in children. Disease begins with fever and lethargy, and in the case of acute meningitis, can progress to coma and death in less than 1 day. In affluent countries, Hib disease has been controlled by immu-nization. H. influenzaealso produces common but less fulminant infections of the bronchi, respiratory sinuses, and middle ear. The latter are usually associated with nonencapsulated strains.

EPIDEMIOLOGY

H. influenzae can be found in the normal nasopharyngeal flora of 20 to 80% of healthypersons, depending on age, season, and other factors. Most of these are nonencapsulated, but capsulated strains, including Hib, are not rare. Prior to the introduction of effective vaccines, approximately 1 in every 200 children developed invasive Hib disease by the age of 5 years. Meningitis is the most common form and most often attacks those under 2 years of age. Cases of epiglottitis and pneumonia tend to peak in the 2- to 5-year age range. Over 90% of these cases are due to the single serotype, Hib.

By the end of the first decade of universal immunization with the Hib protein conju-gate vaccine in the United States (see Prevention), invasive disease rates have already de-clined by 99%. Now, invasive disease strikes only 1 in 100,000 children, and most of these cases are not caused by the type b serotype. Similar results have been seen in other countries, but Hib disease continues in those unable to afford the vaccine. Under the di-rection of the World Health Organization, government and philanthropic efforts are now underway to make this vaccine available to all children throughout the world.

At one time H. influenzae – caused meningitis was believed to be an isolated endoge-nous infection, but reports of outbreaks in closed populations and careful epidemiologic studies of secondary spread in families have changed this view. The risk of serious infec-tion for unimmunized children under 4 years of age living with an index case is more than 500-fold that for nonexposed children. This risk indicates a need for prophylaxis for contacts in the susceptible age group. Rifampin is currently recommended for this purpose.

PATHOGENESIS

Invasive Disease

For unknown reasons, H. influenzae strains commonly found in the normal flora of the nasopharynx occasionally invade into deeper tissues. Bacteremia then leads to spread to the central nervous system and metastatic infections at distant sites such as bones and joints. These events seem to take place within a short period ( < 3 days) after an encounter with a new virulent strain. Systemic spread is typical only for capsulated H. influenzae strains, and over 90% of invasive strains are type b. Even among Hib strains there are dis-tinct clones, which account for about 80% of all invasive disease worldwide, and other clones, which are rarely associated with invasion.

The pathogenic mechanisms involved in Hib invasiveness remain to be fully under-stood. Attachment to respiratory epithelial cells is mediated by pili and other adhesins. There is some evidence to suggest that this is a complex regulatory cascade, coordinating capsular biosynthesis and adherence factors that act cooperatively in establishing the mi-crobe within susceptible hosts. H. influenzae can be seen to invade between the cells of the respiratory epithelium, and for a time resides between and below them. Once past the mucosal barrier, the antiphagocytic capsule confers resistance to opsonophagocytosis in the same manner as it does with other encapsulated bacteria (Streptococcus pneumoniae,Neisseria meningitidis). Endotoxin in the cell wall is toxic to ciliated respiratory cells, but endotoxemia is not a prominent feature ofHaemophilus infection to the extent that it is with N. meningitidis. H. influenzae produces no known exotoxins.

Localized Disease

Nonencapsulated H. influenzae produce disease under circumstances in which they are entrapped at a luminal site adjacent to the normal respiratory flora such as the middle ear, sinuses, or bronchi. This is usually associated with some compromise of normal clearing mechanisms, which is caused by a viral infection or structural damage. Consistent with their relative prevalence in the respiratory tract, nontypeable organisms account for more than 90% of localized H. influenzae disease, particularly otitis media, sinusitis, and exac-erbations of chronic bronchitis. Nonencapsulated H. influenzae may have pili capable of promoting attachment to host cells, but they are relatively uncommon. However, a family of nonpilus, surface-exposed, high-molecular-weight proteins (eg, HMW1, HMW2) has been identified in nonencapsulated strains and have not been found in capsulated strains. These proteins also mediate adherence to epithelial cells, and some of them show homol-ogy with the filamentous hemagglutinin that plays an essential role in adherence of Bor-detella pertussis to ciliated epithelial cells.

IMMUNITY

Immunity to Hib infections has long been associated with the presence of anticapsular (PRP) antibodies, which are bactericidal in the presence of complement. The infant is usually protected by passively acquired maternal antibody for the first few months of life. Thereafter the presence of actively acquired antibody increases with age; it is present in the serum of most children by 10 years of age. The peak incidence of Hib infections in unimmunized populations is 6 to 18 months of age, when serum antibody is least likely to be present. This inverse relationship between infection and serum antibody is similar to that for N. meningitidis (see Fig 20 – 2). The major difference is that substantial immunity is provided by antibody directed against a single type (Hib) rather than the multiple im-munotypes of other bacteria. Thus, systemic H. influenzaeinfections (meningitis, epiglottitis, cellulitis) are rare in adults. When such infections develop, the immunologic deficit is the same as that with meningococci — lack of circulating antibody.

Like many polysaccharides, Hib PRP behaves as a T cell – independent antigen. B cells mount the primary response without significant involvement of helper T cells. Antibody re-sponses from immunization with PRP are variable and typically poor at less than 18 months of age. Significant secondary responses from boosters are not elicited. Conjugation of PRP to protein dramatically improves the immunogenicity by eliciting the T-cell responses typi-cal of protein antigens while preserving the specificity for PRP, even in infants.