These three bacteria have accounted, prior to the development of effective immunizations, for more than 80% of all cases of meningitis in industrialized nations.

Prior to effective immunizations, the world experienced as many as 2.2 million cases of Hib disease and 300,000-400,000 deaths each year as consequences of Hib infection. Hib has been the most important cause of meningitis in children younger than 5 years, with estimated incidence rates in various nations ranging 4-34 or more per 100,000 per year. Children younger than 1 year have manifested incidence rates of 30-66 cases of meningitis per 100,000 per year. Selected populations manifested much higher rates of incidence of meningitis, particularly among American Eskimos younger than 5 years, whose incidence of 409 meningitis cases per 100,000 per year was documented in 1981 (Ward, 1981).

Fortunately, effective immunization for Hib has diminished the incidence of Hib-related meningitis and of other serious Hib-related diseases, such as pneumonia or sepsis, by as much as 87-90% or more in countries where such immunizations have been provided to children. Unfortunately, the important goal of global immunization of children against Hib has not yet been realized.

Between 46% and 60% of all serious Hib-related diseases present as meningitis. Other serious Hib diseases, also most likely to arise in early childhood, are epiglottitis, sepsis, cellulitis, pneumonia, and pyelonephritis. Hib's medical importance has included the role that it has played in the experimental and pathological study of infectious diseases in a wide variety of organ systems. The bacterium has provided particularly valuable information concerning the understanding of the pathophysiology of meningitis.

Transmissibility of Hib infection and the capacity of this organism to cause purulent meningitis was first demonstrated by Wollstein in 1911. She first drew attention to the marked tendency for Hib meningitis to occur in infants and young children. Pittman distinguished 6 serotypes (A through F) of H influenzae in 1931 and demonstrated that the B serotype accounted for almost all cases of meningitis. Fothergill and Wright enlarged the epidemiologic understanding of Hib meningitis, the protective role of passively transmitted maternal antibodies, and the inadequacy of host immune response from infancy to age 3 years in an important series of studies published in 1933.

Of the encapsulated strains, Hib is the most virulent, and prior to vaccination, accounting for more than 95% of all cases of H influenzae meningitis in the prevaccination era.

Transmission probably occurs by inhalation of aerosolized respiratory droplets, although nose-finger-finger-nose routes may play a role in transmission between 2 individuals. Humans are the only known host for H influenzae, and colonization is common in both children and adults. However, most isolates are unencapsulated, and encapsulated strains are only rarely detected. Hib colonization occurs in 2-5% of children but is much less frequently found in adults and children younger than 1 year. Rates of carriage are even lower in immunized populations. However, rates of carriage are much higher among household contacts of an index case. Twenty to 25% of all those exposed to the index case become colonized. Among children younger than 5 years, carriage rates are as high as 50%. Carriage is generally asymptomatic and may occur despite circulating antibodies or effective eradication of meningitis. It may persist for weeks to months.

To become infected, individuals must first acquire a state of nasopharyngeal Haemophilus colonization, a fairly common event of early life. In North America, nearly 5% of young children are colonized with Hib, the most important cause of Haemophilus infections. Over time, this colonized state resolves because less than 1% of adults are colonized with Hib strains. The rather low rate of carriage in children is likely caused by lack of exposure because only approximately 50-55% of children younger than 6 years who are household contacts of children with Hib meningitis are also found to be colonized. Interestingly, the rate of nasopharyngeal colonization is lower for the household contacts of a child that has Hib epiglottitis than those of a child who has Hib meningitis.

The infection that can occur in a colonized individual is either invasive or noninvasive. Epiglottitis is an example of noninvasive infection that occurs in the upper airways of susceptible individuals. Why the individuals with highest risk for this disease (ie, boys aged 3-6 y) have a particular susceptibility for that form of infection and why that susceptibility is found in children at an older age than susceptibility for Hib meningitis, for which somewhat younger boys are also particularly prone, is unknown. Invasive infection requires that Hib organisms from the nasopharyngeal colony become locally invasive and enter the blood stream. The mechanisms of this invasiveness are not as yet understood, but it likely involves both bacterial and host factors that result in incapacity of that individual for bacterial Hib containment.

The particular susceptibility of children who no longer have passively transferred antibodies is likely due to the fact that they do not develop adequate immune-mediated bactericidal capacity for Hib until several additional years of life have passed. This may be due, in part, to the fact that more than 90% of 2- to 12-month-old infants have very low titers of antibodies to the alpha-PRP capsular constituent of Hib as compared to resistant adults. These antibodies likely play a role, together with complement, in opsonization and bactericidal effects that may prevent colonization, invasion, or persistence in circulation of Hib organisms.

Persistent Hib-related PRP antigenemia due to failure of these containment and killing activities may in turn delay the development of a type-specific antibody response to Hib. An interval as long as 3 months is required for infants and young children who develop Hib meningitis to mount a type-specific response to the causative Hib strain. In older children, the relative freedom from risk of Hib meningitis is likely due to the fact that immune system maturity results in full development and deployment of these various important immune mechanisms, possibly including sensitization to Hib epitopes due to noninfectious exposure to Hib or to other organisms that have similar capsular epitopes.

To varying degrees, the development of these protective immune responses is more delayed and less robust in children who have immune system compromise, such as agammaglobulinemia, immunoglobulin G (IgG2) subclass deficiency, or various degrees of asplenia due to sickle cell anemia or other causes, as well as those with cancer, HIV infection, chronic pulmonary or renal disease, or immunosuppression due to organ transplant or other causes. Hib meningitis is more common in such infants. Young children with these immunocompromising conditions may continue to be vulnerable to Hib meningitis longer than children who experience the normal course of immune development that renders Hib meningitis unlikely in children older than 5 years. Some diseases that otherwise interfere with normal immune function, such as CSF fistulae or other abnormalities of BBB function may also predispose to Hib meningitis.

The capacity to mount resistance to invasive Hib disease rises rapidly after age 3 years and, once acquired, tends to be permanent. This resistance is likely due to maturation of immune responses designed to prevent colonization, contain organisms that colonize, eliminate organisms from circulation, and prevent invasion into and persistence within target tissues. In support of this view is the fact that most older children and adults who develop Hib meningitis have underlying medical conditions that interfere with immune function. The predisposing conditions include malignancies, asplenia, chronic obstructive pulmonary disease, alcoholism, and HIV infection. Haemophilus is also a common cause of infection in patients with cystic fibrosis. Some evidence suggests enhanced susceptibility because of alcoholism, which may in turn represent risk enhancement due to poor nutrition or other factors.
 

• In the US: Prior to the implementation of effective vaccination, Hib accounted for 40-60% of all cases of meningitis in children aged 0.1-15 years in the United States and fully 90% of all cases of meningitis arising in children aged 0.1-5 years. Hib meningitis was rare in individuals older than 5 years. However, because it was the chief cause of meningitis in children younger than 5 years and because children of such young age have a much higher rate of meningitis than any other age group, Hib was the cause of nearly half of the 25,000 or so cases of meningitis occurring annually in patients of any age in the United States.

  In the prevaccine era, the incidence of serious Hib disease was 60-100 cases per 100,000 children younger than 5 years in the United States. To some extent, this may reflect the inclusion of populations at higher risk such as is apparently true of Native Americans such as the Eskimos. Quite recently, the use of effective conjugated vaccines has dramatically reduced the risk that Hib has posed for young children, lowering the annual prevalence of Hib meningitis in well-immunized populations by 76-90%.

  Moreover, cases of Hib meningitis still occur in countries with well-vaccinated populations. That the individual risk for Hib meningitis is dependent not only on individual vaccination history but also on the degree to which the entire population has been vaccinated suggests that herd immunity has an effect on the prevalence of particular meningogenic bacterial strains. Vaccination appears to reduce the prevalence of carriage of Hib within the general population, presumably including colonization and carriage by household contacts.

  In the prevaccine era, from year to year, a considerable amount of variation occurred in annual prevalence of Hib meningitis in the United States. Some well-defined regions exhibited year-to-year variations of as much as 67%. Considerable additional variation was observed in comparison of a given region to some other region. Thus, in the United States, higher prevalences were observed in certain regions, such as Alaska.

  Far less evidence exists in favor of epidemics of Hib meningitis than has been found for N meningitidis meningitis, although some evidence indicates variation in the virulence or invasiveness of prevalent meningitis-associated Hib strains from year to year. With opportunity, Hib colonization is readily achieved in small children. In prevaccine era studies of households containing a child who developed Hib meningitis, as many as 20-25% of family contacts and more than 50% of siblings younger than 10 years developed encapsulated Hib carriage.

  Of exposed contacts, the rate of disease is 4% for children younger than 2 years, 2-3% for children aged 2-3 years, and 0.1% for children aged 4-5 years. Thus, the risk for disease is about 600-fold greater than the age-adjusted risk for the population at large.
  
   

  Day care attendance appears to enhance risk in children younger than 2 years. That risk enhancement is greatest in the first month of daycare attendance. A twin sibling is at greater risk for the development of Hib meningitis than are other siblings of an index case, risk that may be due to proximity in combination with the fact that a twin is in exactly the same vulnerable age bracket for Hib meningitis risk, while other siblings are likely to fall outside that most vulnerable age group (ie, they tend to be >4-5 y or <2-3 mo).
  
   

  Some evidence suggests that crowded urban living, especially as experienced by children of comparatively low socioeconomic status may enhance risk for invasive Hib disease, although these observations have not carefully excluded potential confounding variables. Some of the potential confounding variables include the possibility of genetically enhanced risk, possibly among blacks or especially American Indians/Eskimos. These studies, in turn, have not excluded the possible contribution of crowding, low socioeconomic status, or other variables (eg, dietary factors, alcohol consumption) in explaining the higher risk discerned in these more or less genetically homogeneous populations.
  
   

  The peak incidence of Hib meningitis in the United States, as in other Northern Hemisphere temperate countries, occurs in a bimodal distribution with the first peak in June and the second in September to October. This seasonal prevalence differs significantly from potential differential considerations such as the other two major causes of human meningitis, N meningitidis and S pneumoniae, both of which have greatest prevalence in the winter months. It differs from conditions such as sporadic herpes I encephalitis or epidemic conditions such as mumps encephalitis that occur year-round, although this difference is of little help in determining the differential diagnosis.
  
   

  The increased Hib prevalence in summertime corresponds somewhat, but not exactly, to the period of highest prevalence of arboviral encephalitis, aseptic meningitis, enteric encephalitides such as poliomyelitis or coxsackie encephalitis, and tick-borne encephalitides such as Lyme disease or Rocky Mountain spotted fever. Many of these differential considerations have their highest prevalence in July to August.