Haemophilus Meningitis

Throughout the modern era of bacteriology, Haemophilus influenzae type b (Hib) has been identified as one of the three most common causes of bacterial meningitis in adolescents. It is an uncommon cause of adult bacterial meningitis, mainly causing disease in those with predisposing factors. ^[1] The other two causes of bacterial meningitis in adolescents are Neisseria meningitidis and Streptococcus pneumoniae. Before the development of effective immunizations, these three bacteria accounted for more than 80% of all cases of meningitis in industrialized nations. (See Pathophysiology and Etiology.)

Initial manifestations of meningitis, seen in more than half of all cases of Hib meningitis, include altered cry, change in mentation, nausea or vomiting, fever, headache, photophobia, meningismus, irritability, anorexia, and seizures. The possibility of Hib meningitis is suggested by the presence of risk factors (eg, time of year, patient age, vaccination status), as well as clinical features. (See Clinical Presentation and Diagnosis.)

Lumbar puncture is critical in the evaluation of patients with suspected meningitis and should be performed unless some specific contraindication exists. In the absence of focal neurologic findings, the risk of herniation in cases of Hib meningitis is low and one can safely proceed to lumbar puncture without imaging. Brain imaging is also helpful in certain cases. (See Workup.)

The most critical aspect of initial treatment is prompt initiation of antimicrobial therapy, because any delay in treatment is associated with increased morbidity and mortality. Either cefotaxime or ceftriaxone should be initially provided to children who present with meningitis and who are older than 6 weeks and younger than 6 years. Adjunctive anti-inflammatory therapy continues to be controversial. (See Treatment and Management.)

In countries where effective immunization against Hib has been provided to children, the incidence of Hib meningitis—as well as other serious Hib-related diseases, such as pneumonia or sepsis—has diminished by as much as 87–90% or more. Unfortunately, the important goal of global immunization of children against Hib has not yet been realized. (See Prevention of Haemophilus Meningitis.)

Go to Meningitis, Meningococcal Meningitis, Staphylococcal Meningitis, Tuberculous Meningitis, Viral Meningitis, and Aseptic Meningitis for more complete information on these topics.

Haemophilus species are small oxidase-positive pleomorphic gram-negative aerobic or facultative anaerobic coccobacilli. Humans are the only known host for Haemophilus influenzae.

Haemophilus strains may be encapsulated or unencapsulated. Encapsulated strains (also known as typeable) are surrounded by a polysaccharide capsule that plays an important role in the determination of virulence of the organism. The outer membrane lipo-oligosaccharides also contribute to the degree of virulence. Encapsulated strains are divided, on the basis of capsular antigens, into 6 serotypes designated a through f. Unencapsulated strains lack the polysaccharide capsule and are designated untypable strains.

Transmissibility of H influenzae infection and the capacity of this organism to cause purulent meningitis were first demonstrated by Wollstein in 1911. She also drew attention to the marked tendency for Haemophilus meningitis to occur in infants and young children. In 1931, Pittman demonstrated that H influenzae type b (Hib) accounted for almost all cases of meningitis.

In an important series of studies published in 1933, 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. They demonstrated that this maternally conferred protection largely dissipates by age 4 months.

Between 46 and 60% of all serious Hib-related diseases present as meningitis. 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.

Haemophilus colonization

To become infected with Haemophilus, individuals must first acquire a state of nasopharyngeal colonization, a fairly common event of early life. Acquisition of Haemophilus probably occurs by inhalation of aerosolized respiratory droplets, although nose-finger-finger-nose routes may play a role in person-to-person transmission.

Haemophilus colonization occurs mostly with unencapsulated strains; encapsulated strains are only rarely detected. In North America, 2-5% of young children are colonized with Hib, the most important cause of Haemophilus infections. Hib colonization is much less frequently found in adults and in 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 6 years who are exposed, carriage rates are as high as 50%. Interestingly, the rate of nasopharyngeal colonization is lower in household contacts of a child with Hib epiglottitis than those of a child with Hib meningitis.

Carriage is generally asymptomatic and may occur despite circulating antibodies or effective eradication of meningitis. It may persist for weeks to months. Over time, colonization rates decline, dropping to below 1% by adulthood.

Hib infection in a colonized individual may be either invasive or noninvasive. Epiglottitis is an example of noninvasive infection that occurs in the upper airways of susceptible individuals. Invasive infection requires that Haemophilus organisms from the nasopharyngeal colony become locally invasive and enter the bloodstream, resulting in bacteremia. The mechanisms of this invasiveness are not as yet understood, but both bacterial and host factors are likely involved (see below).

Haemophilus bacteremia

Infection of distant sites appears to require the achievement of a degree of bacteremia sufficient to overcome the bacterial defense systems of the particular host. Clearance of bacteria from circulating blood is possibly more difficult for host defenses than containment of colonized bacteria. The capacity to eliminate Haemophilus from the circulation clearly entails normal function of the spleen as well as humoral and cellular arms of the immune system, because infections are more common in individuals who have defects in these systems.

In addition, preceding viral infections are possibly permissive of Haemophilus invasiveness (from colonized site to bloodstream or from bloodstream to target tissues) either because they disrupt barriers or they interfere with critical aspects of the host immune response. Upper respiratory infections or otitis media, presumably viral, often precede Haemophilus meningitis.

Once a sufficient degree of bacteremia is achieved, one or more sites may become infected. Predilection for a given site may be determined by proximity, blood flow characteristics, affinity of organisms for particular endothelial receptors, and the ability of organisms to pass through various barrier systems of the body.

Invasion of the central nervous system (CNS) may involve patterns of venous drainage from sites of nasopharyngeal colonization to vulnerable nearby CNS sites (eg, cribriform plate, thin sinus walls) or, more likely, high blood flow to sites of reduced blood-brain barrier (BBB) function (eg, choroid plexus).

Bacterial factors conducing to invasiveness

Passage into both the blood circulation and the immunologically privileged CNS appears to involve not only capsular epitopes that do not arouse an effective host immune response but also epitopes that may facilitate bacterial attachment to given endothelial receptors and subsequent invasiveness in target sites. Invasiveness likely also involves the capacity to develop and then shed such attachment-related devices as bacterial fimbriae.

Encapsulated strains of H influenzae, in particular the type b serotype, are responsible for most invasive infections. The polysaccharide capsule of these organisms not only confers virulence and invasiveness but also provides resistance to opsonization and complement-mediated bactericidal activities and inhibits neutrophil phagocytosis.

Host factors conducive to invasiveness

Hib meningitis is quite rare in the first 2 months of life, accounting for 0-0.3% of all meningitis cases in this age group. Children of this age group are likely protected from infection by passively transferred maternal antibodies. Levels of these antibodies are considerably diminished by 2 months of life and they are often completely gone by 4 months of life. This period of protection appears to be prolonged in breastfed infants, likely because of continued passive transfer of antibodies.

After the loss of passively transferred antibodies, children do not develop adequate immune-mediated bactericidal capacity for Hib until several additional years of life have passed. This is the period of highest risk for Hib meningitis.

In immunocompetent children, the capacity to mount resistance to invasive Hib disease rises rapidly after age 3 years and, once acquired, tends to be permanent. Most older children and adults who develop Hib meningitis have underlying medical conditions that interfere with immune function.

The development of resistance to Hib infection appears to be due to gradual acquisition of antibodies directed at capsular determinants of Hib and possibly to other aspects of immune system maturation. More than 90% of 2- to 12-month-old infants have very low titers of antibodies to the alpha–polyribosyl-ribitol-phosphate (PRP) capsular constituent of Hib, compared with resistant adults. These antibodies likely play a role, with complement, in opsonization and bactericidal effects that may prevent colonization, invasion, or persistence in circulation of Hib.

Exposure to Hib and colonization with it is the only possible cause of a rise in specific antibody titers. Possibly, pertinent antibodies develop as the result of exposure to other genera of encapsulated bacteria that express cross-reactive epitopes in their capsules. Among the most important of the likely causes of such cross-reactive protection are enteric bacteria.

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. Infants and young children who develop Hib meningitis take as long as 3 months to mount a type-specific response to the causative Hib strain.

To varying degrees, the development of these protective immune responses is delayed and less robust in children who have immune system compromise, such as those with 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 cerebrospinal fluid (CSF) fistulae or other abnormalities of BBB function, may also predispose to Hib meningitis.

Of the encapsulated H influenzae strains, serotype b is the most virulent. Most invasive Haemophilus infections are caused by encapsulated strains, in particular Hib. Unencapsulated strains rarely cause bacteremia; these species are more likely to produce noninvasive infections (eg, sinusitis, otitis media).

In the prevaccination era, Hib accounted for more than 95% of all cases of H influenzae meningitis. Most human diseases are caused by a limited clone complex of Hib strains that appear to have achieved worldwide distribution as the result of historical migrations of human hosts. These clones express in their capsules a repeating polymer of PRP that has been shown to be a particularly important virulence factor.

It remains important to recognize and treat unencapsulated and therefore nontypeable H influenzae (NT-HI) infections, against which Hib vaccine provides no protection. Factors that predispose to systemic infection with NT-HI include the presence of cerebrospinal fluid shunts, posttraumatic compromise of the blood-brain barrier (as with post-traumatic encephalocele), and central nervous system implants. ^[2]

Risk factors

An individual’s risk for Hib meningitis depends not only on that person’s vaccination history but also on the degree to which the entire population has been vaccinated. This 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.

Day care attendance appears to enhance risk in children younger than 2 years. That risk enhancement is greatest in the first month of day care 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, whereas other siblings are likely to fall outside that most vulnerable age group.

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.

Before 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. In unimmunized populations, Hib has been the most important cause of meningitis in children younger than 5 years, with estimated incidence rates in various nations ranging from 0.9-94.6 cases per 100,000 per year. ^[3]

United States statistics

In the prevaccine era, the annual rate of Hib meningitis in the United States varied considerably. Some well-defined regions exhibited year-to-year variations of as much as 67%. Considerable additional variation was observed in comparisons among regions; higher rates were observed in certain regions (eg, Alaska). This variation was presumably due to year-to-year changes in the virulence or invasiveness of prevalent meningitis-associated Hib strains. Far less evidence exists in favor of Hib meningitis epidemics than has been found for Neisseria meningitidis meningitis.

In the United States, before effective vaccination, Hib accounted for 40–60% of all cases of meningitis in children aged 0.1–15 years 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 the incidence of meningitis is much higher in this age group than in any other, Hib was the cause of nearly half of the approximately 25,000 cases of meningitis occurring annually in patients of any age.

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 for Hib meningitis (eg, Eskimos, Apaches, and Navajos). The use of effective conjugated vaccines has dramatically reduced the risk of Hib meningitis in young children, lowering the annual incidence in well-immunized populations by 76–90%.

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. Among 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.

International statistics

Current Northern European experience with Hib meningitis resembles that of North America, as does that of most industrialized nations that have had the resources to devote to immunization programs. Some data suggest, however, that in the prevaccine era, the incidence of Hib meningitis was lower in some parts of Europe than in the United States. As compared to 60-100 cases per 100,000 per year in children younger than 5 years in the United States, Finland reported 26–43 cases per 100,000 children of the same age group, as did most other Northern European countries.

Some of this variation may have been due to differences in methods of assessment (ie, voluntary reporting versus active centralized surveillance). However, to some degree, this variation may be due to genetic factors, ecological niches in which certain predisposing viruses maintain a local annual presence, regional early childhood experiences pertinent to immune system function, or other unknown influences.

Some authorities have proposed that the variation occurs because more Northern European mothers breastfeed their infants and that they tend to do so for longer periods than North American mothers, thereby prolonging the period of protection afforded by passively transmitted antibodies.

Annual incidence of Hib meningitis in children younger than 5 years in various years have been reported as 9 cases per 100,000 in Austria, 6 cases per 100,000 in Spain, ^[4] 8 cases per 100,000 in Romania, ^[5] and 8 cases per 100,000 in Greece. Interestingly, the Romanian data show a very high rate for meningococcal meningitis (22 cases per 100,000 per year for children younger than 5 years. ^[5] ) At the time of publication of the Romanian data, no immunization program was in place for Hib.

The annual incidence for Hib meningitis in Western Australia in the preimmunization era was reported as 150 cases per 100,000 children younger than 5 years. ^[6] This high incidence may reflect increased vulnerability among the regionally prevalent indigenous peoples of Australia. Striking improvement in this incidence was observed after institution of immunization.

Unfortunately, in many areas of the world, Hib meningitis continues to be the enormous threat to public health that it once was in the United States and Northern Europe. The incidence remains high in developing countries—including many or perhaps most tropical and many Asian nations and those currently experiencing the disruption produced by warfare—where lack of resources has resulted in the virtual absence or delayed initiation of anti-Hib vaccination programs.

Establishing the exact degree of risk has been difficult because in many countries, inadequate resources have been devoted to establishing the epidemiology of Hib diseases. Nevertheless, researchers have calculated rates of more than 50 cases per 100,000 per year in Ghana and Uganda. ^[7] Internationally, the spectrum of serious Hib illnesses, including meningitis, may account for as many as 1.9 million deaths per year in children younger than 5 years. ^[8]

On the other hand, some Middle Eastern and Asian nations have recently reported low rates of Hib meningitis in children younger than 5 years, such as 3.8 cases per 100,000 in Thailand, ^[9] 6 cases per 100,000 in South Korea, and 1-10 cases per 100,000 (varying by region) in China. ^[10] Curiously, the survey of bacterial meningitis among young children in Guangxi, China by Dong et al found a much higher incidence of staphylococcal meningitis than of Hib meningitis. In Japan, the annual incidence of Hib has significantly decreased in the last decade from 0.66 to 0.01. ^[11]

Annual incidences of less than 15 cases per 100,000 per year in children younger than 5 years have been recently reported for Iran, Jordan, and Uzbekistan. The annual incidence of Hib meningitis in Saudi Arabia has been estimated to be 17 cases per 100,000 per year in children younger than 5 years. ^[12]

The reports showing low rates of Hib meningitis in Asia stand in contrast to data from other Southeast Asian locations demonstrating much higher annual incidence, such as 2 studies in the Philippines showing an annual incidence of 18-95 cases per 100,000 per year in children younger than 5 years. ^{[13, 14]}

To some extent, the high variability from country to country may reflect disparities in data-gathering methodology. However, the data of Rerks-Ngarm et al from Thailand ^[9] appear to have been diligently and carefully obtained, although questions have been raised about possible methodological flaws. ^[8]

Thus, data on the incidence of meningitis and other serious Hib illnesses among children younger than 5 years in Southeast Asia and various other tropical regions remain controversial, particularly where the incidence of these diseases appears low even in the absence of immunization. The problem of interpreting results of blood and CSF cultures in the large number of children who have previously received antibiotics has been particularly significant, as has the problem of knowing how carefully all avenues of healthcare-seeking by the local population have been investigated.

Particularly heartening is the report that 14 years after the introduction of Hib vaccination in Gambia, the annual incidence remains below 5 cases per 100,000 children. ^{[15, 16]} Given the incomplete coverage achieved by Gambian children (estimated to be less than 70%), this result is strongly supportive of the concept of herd immunity as an important determinant of risk. Moreover, this effect was achieved with either 2 or 3 vaccinations for children who received vaccine.

Similarly positive information has been reported for Hib vaccination programs instituted in Chile and the Dominican Republic, where, before immunization, the annual incidence of Hib meningitis in children younger than 5 years had been higher than 20 cases per 100,000.

Significant declines in incidence of Hib meningitis are reported for hospitals in Argentina and South Africa, as well as declines in percentage of positive CSF indicators of bacterial meningitis, such as elevated white blood cell count, low glucose, elevated protein, or turbidity. These are possible surrogate markers for assessment of efficacy of Hib immunization in developing countries. ^[17]

Age distribution for Hib meningitis

Virtually all studies conducted in the prevaccine era on children from North America or Northern Europe showed that the great majority of Hib meningitis cases occur within a fairly narrow age range. In 1933, Fothergill and Wright showed that children younger than 2 months accounted for less than 0.004% of all cases of Hib meningitis.

More recent studies have suggested that children younger than 2 months account for 0.3% of cases. The risk to neonates may have increased in the late 20th century because of a decrease in maternal transmission of Hib antibodies, possibly as the result of diminished maternal exposure.

In prevaccination studies, infants younger than 6 months accounted for only about 10% of Northern European Hib meningitis cases, as compared to 16-38% of North American cases. For unclear reasons, a profile similar to the North American prevalence figures was found for Australian Aborigines. The tendency toward later onset of Hib meningitis in Northern Europe may be due to more widespread and prolonged breastfeeding by Northern European mothers.

The peak Hib meningitis risk for unvaccinated North American children was from age 6-9 months, with a continued very high risk until approximately 24 months of life. Prevalence for Hib meningitis among children aged 6-17 months during the prevaccine era was approximately 122 cases per 100,000 population per year, as compared with 65 cases per 100,000 population per year for infants aged 18-23 years. After 23 months, a rapid decline in prevalence was observed.

In Northern European studies, the peak risk for Hib meningitis in unvaccinated populations occurs in older children than in North America. The mean age at presentation of Hib meningitis in Northern Europe is approximately 1.5 years of age. Although approximately 80% of North American cases occur in children prior to their second birthday, only 60% of Northern European cases occur in such young children.

Throughout the world, children younger than 1 year account for approximately 59% of all Hib meningitis cases, while another 24% of all cases occur in the second year of life. ^[3] Children in their first year of life have manifested incidence rates of 30-66 cases of Hib meningitis per 100,000 per year.

Risk for Hib meningitis declines rapidly after the second birthday and becomes quite low after the fourth. After age 15 years in unvaccinated populations, Hib is responsible for only 1-3% of all infectious meningitis cases.

Adults may be rendered vulnerable to Hib meningitis by chronic diseases such as alcoholism, nephrosis, diabetes mellitus, CSF fistula, asplenia, agammaglobulinemia, neoplasms (eg, chronic lymphocytic leukemia, multiple myeloma, Hodgkin disease), and AIDS, as well as by chemotherapy or radiotherapy. However, cases of Hib meningitis have occurred in adults who have no clearly identified risk factors.

Sex distribution for Hib meningitis

Reasonably well-conducted studies have demonstrated that 59-70% of Hib meningitis cases occur in boys. At least one prevalence study, performed prior to the availability of an effective vaccine, showed the annual prevalence of Hib meningitis among boys younger than 5 years to be 89 cases per 100,000 population, versus 37 cases per 100,000 population for girls in that age group. However, other studies have not confirmed a sex-related predilection for Hib meningitis.

Prevalence of Hib meningitis by race

Conflicting data and conclusions have been reported regarding the influence of race on susceptibility to Hib meningitis. To some extent, these conflicts derive from the artificiality of the demographic construct termed race and the lack of available scientific measures of the genetic contribution, giving rise to the superficially expressed characteristics upon which a racial assignment is based. These studies are further compromised by adverse socioeconomic factors that may be associated with race. However, the available data do suggest certain correlations.

Several studies have found a significantly higher rate of disease among blacks than many other nonwhites. According to some authorities, the risk that Hispanics have for Hib meningitis falls into an intermediate level between the higher risk that some studies have reported for blacks and the lower risk that some have reported for whites.

Data suggest even higher risk for Native Americans than for black populations. One prevaccination-era study from Washington State showed that annual case rates per 100,000 children were 2.2 in whites, 3.4 in blacks, and 13.5 in Native Americans.

Among American Eskimos younger than 5 years, an incidence of 409 meningitis cases per 100,000 per year was documented in 1981. ^[18] However, more recent study documents that the annual incidence of meningitis among all North American Arctic residents has decreased to 0.6 per 100000 cases annually. ^[19]

Other high-risk populations include Australian Aboriginals, Canadian Keewatins, and the Apaches and Navajos of the American Southwest. The overall risk for Hib meningitis in unimmunized individuals from these kindreds range from 35-530 cases per 100,000 annually in children younger than 5 years, with mean risk of 418 cases per 100,000 annually.

Some studies reporting race-related predilection have found that enhanced risk is defined not only by race but also by age. Some data suggest that enhanced risk in blacks is found only in children older than 1 year but not in children younger than 1 year.

On the other hand, some studies have found no racial predilection for Hib meningitis. Some authorities think that racial incidence studies are confounded by other risk factors (including socioeconomic factors such as poverty, crowding, poor healthcare, and poor nutrition) and that this may account for perceived race-related determination of risk.

For example, urban crowding may enhance the risk for Hib infection, and therefore the population risk for Hib meningitis, and may even enhance the risk for serious consequences of Hib infection. This has been demonstrated for whites living in urban as compared to rural environments in Minnesota; however, this enhanced risk was found to be true only for nonmeningitic invasive Hib disease. Some studies have suggested that low socioeconomic status may also increase the risk of contracting invasive Hib disease.

Seasonal variation in incidence of Hib meningitis

In the temperate countries in the Northern Hemisphere, including the United States, the seasonal incidence of Hib meningitis follows a bimodal distribution, with the first peak in June and the second in September to October.

This seasonal pattern differs significantly from that of the other 2 major causes of human meningitis, N meningitidis and S pneumoniae, both of which occur most frequently in the winter months. It differs from that of conditions such as sporadic herpes encephalitis or epidemic conditions such as mumps encephalitis, which occur year-round, although this difference is of little help in determining the differential diagnosis.

The mortality rate of Hib meningitis is 15–20% overall and is higher in very young infants (ie, < 2 mo), in individuals who have immunodeficiencies, and in children who present with fulminant meningitis.

Analysis of 127 studies carried out in a wide variety of international locations has shown an overall international mean case-fatality rate of 13.8% (median, 10%; range, 0-65%). The overall mean case-fatality rate in industrialized nations was found to be 3.2%, while in developing nations this mean rate was 17%. The European mean rate was 4.1%, as compared with 27.6% in Africa. ^[3]

Approximately 45% of children who have had Hib meningitis recover without sequelae. From 15–25% are left with mild neurologic impairment, 20–40% have significant neurologic impairment, and 10% experience severely handicapping neurologic sequelae. Other long-term problems that are experienced by children who have had Hib meningitis include epilepsy, hemiparesis, and hearing loss.

Delays in diagnosis and treatment likely increase both morbidity and mortality. It remains unclear whether the success of immunization programs will blunt sensitivity to the diagnosis of Hib meningitis and delay initiation of appropriate therapies, thus secondarily enhancing both morbidity and mortality in the small residual population of children that develop Hib meningitis despite population or personal vaccination. For obvious reasons, delay in diagnosis and treatment may be much greater in countries with inadequate infrastructure.

Population-based mortality and morbidity rates remain very high in some developing countries because of lower rates of vaccination and because of decreased accessibility to early standard treatment for Hib meningitis and its various complications. Other factors (eg, nutrition) may also play roles in very high morbidity and mortality rates in such regions.

The emergence of resistant organisms also increases morbidity and mortality where such agents are the cause of meningitis, perhaps by as much as 3-fold. ^[20] This too is a problem faced more commonly in developing nations that have inadequate immunization programs.