Throughout the modern era of bacteriology, Haemophilus influenzae type b (Hib) has been identified as 1 of the 3 most common causes of bacterial meningitis in adolescents. The other 2 are Neisseria meningitidis and Streptococcus pneumoniae. Before the development of effective immunizations, these 3 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.
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).
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).
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.
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.[1]
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.[2]
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.
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,[3] 8 cases per 100,000 in Romania,[4] 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.[4] ) 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.[5] 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.[6] 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.[7]
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,[8] 6 cases per 100,000 in South Korea, and 1-10 cases per 100,000 (varying by region) in China.[9] 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.[10]
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.[11]
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.[12, 13]
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[8] appear to have been diligently and carefully obtained, although questions have been raised about possible methodological flaws.[7]
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.[14, 15] 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.[16]
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.[2] 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.
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.
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.[17] 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.[18]
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.
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.[2]
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.[19] This too is a problem faced more commonly in developing nations that have inadequate immunization programs.
Initial manifestations of meningitis, seen in more than half of all cases of Haemophilus influenzae type b (Hib) meningitis, include the following:
An altered cry is an important and statistically significant indicator of meningitis or other severe illness, especially in children younger than 2 years; it is noted in as many as 80% of young children with meningitis. Alterations of importance include high-pitched cry, inconsolable crying, weak cry, moaning, or severe reduction or absence of cry. Cry may suggest discomfort or severe distress for which no source outside of the nervous system can be identified.
Lethargy is an early sign in at least half of all cases of bacterial meningitis, versus approximately one third of all viral meningitis cases. Increasing lethargy or the occurrence of convulsive seizures is the usual reason for parents to bring such children to medical attention. These patients should be carefully examined for any evidence of meningismus.
Vomiting is reported as an early manifestation in nearly 50% of Hib meningitis cases. Some data suggest that in individuals with suspected meningitis who have associated vomiting, the lumbar puncture discloses evidence for either bacterial or viral meningitis in 15% of cases. If vomiting occurs, it generally does so within hours to days after the onset of fever.
The presentation of Hib meningitis may be considerably less fulminant than either meningococcal or pneumococcal meningitis, leading to misinterpretation of the initial symptoms or discounting of the significance of the somewhat more leisurely progression of illness. In such subacute cases, fever, irritability, and drowsiness may be the only reported initial signs and symptoms. These subtle manifestations may be mistakenly attributed to a preceding bout of otitis media or other form of upper respiratory illness.
Seizures occur in 23-44% of Hib meningitis cases. They tend to appear during the acute phase, usually within the first 3 days of illness. They are often focal but may secondarily generalize. If this focality is overlooked, seizures due to Hib meningitis may be mistakenly designated as febrile seizures.
Obtaining a history in children younger than 16 months (ie, those at greatest risk for Hib meningitis) may pose particular challenges. The absence of clinical evidence of severe illness cannot be relied upon to exclude the diagnosis of Hib meningitis, particularly in infants and toddlers, whose personal histories cannot readily be obtained. Irritability may be the only presenting sign of Hib meningitis in these young children, and meningismus may be difficult to demonstrate.
Some elements of the history are helpful in establishing the possibility that a patient with possible meningitis has Hib meningitis. These risk factors are pertinent to children older than 2 months and younger than 5 years.
Time of year is a factor. Presentation between June and November is suggestive of Hib meningitis (in the temperate or sub-Arctic latitudes of the Northern hemisphere).
Vaccination status—both group and individual—is important. With a child who is a member of an unvaccinated population, the likelihood of meningitis being caused by Hib is as high as 95%. A child presenting with meningitis who has not been vaccinated against Hib has a considerably greater chance for Hib diagnosis. Hib remains the most common cause of meningitis in unvaccinated children aged 2 months to 5 years even in a vaccinated population.
Although Hib vaccines have considerably reduced the likelihood that Hib is the cause of meningitis in children in this age group, they have not eliminated Hib meningitis in this naturally susceptible population, especially those children with compromised immune function. Remember that Hib-immunized children may develop Haemophilus meningitis because of unrecognized immunodeficiency or vaccine failure or because they are infected with an untypable or non-B Haemophilus strain.
A history of a presumed viral upper respiratory illness or otitis media preceding the onset with an intervening period of improvement or recovery is fairly characteristic of Hib meningitis. From 60-80% of children who develop Hib meningitis have had otitis media or an upper respiratory illness (presumably viral) immediately before the onset of meningitis; others develop Hib meningitis after a presumably viral gastrointestinal (GI) illness. A meningitic presentation in the wake of epiglottitis may be particularly suggestive of Hib etiology, although this presentation is uncommon.
Conditions that predispose individuals to Hib meningitis include the following:
Although meningitis in a child older than 5 years is much more likely to be due to meningococcus or pneumococcus than to Hib, some cases of Hib meningitis occur in older children and adolescents, particularly those with the above conditions. Hib meningitis does occur in adults, albeit rarely. Predisposing conditions for Hib meningitis infection in adults are the same as those in children and adolescents. It is unclear whether diabetes mellitus or alcoholism, which may also predispose to Hib meningitis in adults, predisposes adolescents to Hib meningitis as well.
The patient’s race should be considered. The risk for Hib is greater in blacks than in whites and greater in Native Americans than in blacks. (See Epidemiology.)
Occasionally, children present with the report of fulminant deterioration in mental status, with or without seizures, sometimes after cardiopulmonary arrest. In fulminant cases, medical attention is often sought because of medical emergencies such as coma or status epilepticus.
Infants younger than 2 months very seldom develop Hib meningitis, justifying in part the current vaccination schedule for children. In the rare instances when these very young infants do develop Hib meningitis, their manifestations tend to be fulminant, even if no contemporary evidence exists for an epidemic due to a particularly virulent Hib strain.
Presentations in these cases suggest sepsis because the infants tend to be moribund with high fever. Meningismus may or may not be found. Pneumonia with pneumatocele formation, pericarditis, or osteomyelitis may further complicate the diagnosis and management of these severely ill infants.
Findings on general physical examination of children with Hib meningitis are helpful in arriving at the diagnosis, although they may be subtle or equivocal.
Temperature higher than 38.5°C is found in at least 94% of individuals with meningitis. The temperature tends to be higher in bacterial meningitis than in viral. Studies wherein most cases of childhood meningitis were due to Hib have shown that approximately 80% of children with meningitis have temperatures higher than 38.8°C on presentation, compared with 40% of children with viral meningitis. The fever may exert protective effects, reducing bacterial replication; hence, aggressive treatment of fever may be counterproductive.
The combination of fever with either change in behavior/mental status or new seizures compels consideration of meningitis in children, especially those younger than 1 year.
Occasionally, children with Hib meningitis are hypothermic. These patients tend to be severely ill at presentation, and the hypothermia portends a worse prognosis. In part, the poorer outcome may be due to enhanced bacterial replication at lower temperatures.
The combination of anorexia or vomiting with fever may cause an infant to appear dehydrated (ie, dry oral mucous membranes, diminishment of the usual glabrous appearance of the skin, altered skin texture to finger stroke). These findings are especially important indicators of meningitis in patients without associated diarrhea.
Skin color may be abnormal; the skin may appear pale, cyanotic, ashen, or pasty. These skin-color changes and associated dehydration are statistically significant indicators of meningitis in children younger than 2 years with fever and no clear alternative diagnosis.
In more severe cases, the infant or child may appear cachectic, with loss of skin turgor or capillary refill. Very ill children may have tachycardia and thready pulse in addition to high fever.
Changes in mental status have been shown to be important indicators of enhanced risk for serious infectious illnesses (ie, meningitis, sepsis, pneumonia, urinary tract infection) in children younger than 2 years. Most children with meningitis show changes in mental status, and at least 40% of patients exhibit other neurologic deficits at or shortly after presentation. Special care must be taken to exclude meningitis in such cases because it is has the greatest potential to produce devastating consequences if it is not recognized and treated swiftly.
An altered level of consciousness ranging from drowsiness to stupor or coma is common. This can have an effect on cry. In young children, consciousness may be assessed with reference to their reaction to parent stimulation/smile/holding or their reaction to brightly colored interesting toys, presentation of their bottle, or an approach from the examiner. The eyes may appear glazed over. Marked changes in their reaction, to which parents can attest, are statistically significant indicators of serious infectious disease in children younger than 2 years.
Irritability is common in meningitis and is often associated with loss of interest in surroundings or various forms of visual or auditory stimulation. Photophobia may also be found.
The combination of abnormalities in cry, skin color, hydration, and mental status as measured by response to parental or social stimulation has 88% specificity and 77% sensitivity for the diagnosis of meningitis in small children. If a suggestive history and examination findings are also found, the sensitivity rises to 92%.
Meningeal signs that may be found in children include nuchal rigidity to passive flexion and the signs of Kernig or Brudzinski. Sometimes the presence of these signs may be difficult to judge in irritable infants. Although resistance to passive neck flexion is found in most cases of childhood meningitis at presentation, Kernig and Brudzinski signs are found in approximately half.
In order to test for Kernig sign, the hip of a recumbent patient is passively flexed to 90 degrees, permitting the knee to be fully flexed. The attempt is then made to passively extend the knee joint. If significant pain or involuntary resistance to the knee extension is encountered, the Kernig sign is present.
Three Brudzinski signs exist: the nape of the neck sign, the identical contralateral hip sign, and the reciprocal contralateral hip sign. All are elicited in the recumbent patient.
The nape of the neck sign is elicited by passive neck flexion, and a positive result is indicated if the hips and knees flex in response. The identical contralateral hip sign is elicited by passive flexion of the hip and knee on one side, and a positive result is indicated if the other leg responds by assuming flexion of the hip and knee. The reciprocal contralateral sign is found if a patient who has manifested an identical contralateral hip sign immediately follows it by a small kick due to sudden partial extension at the knee.
Meningeal signs are found in 77-98% of children older than 12 months presenting with meningitis, in as many as 98% of those aged 12-18 months, and in nearly all of those older than 18 months when properly examined by an experienced individual. Kernig and Brudzinski signs may be difficult to judge in irritable infants.
Meningismus may be universal in fulminant cases or once a child has entered a moderate-to-severe stage of illness. The absence of meningismus does not exclude the diagnosis of meningitis, however, especially in children younger than 8 months. Absence of meningismus at the onset of meningitis is reported in rare instances in children who are older than 2 years. In all such cases of bacterial meningitis, other indicators are present, such as fever, mental status changes, seizures, or elevation of the circulating white blood cell count to greater than 10,000/µL.
Evidence for elevation of intracranial pressure (ICP) must be sought on physical examination, both because it supports the diagnosis of meningitis in febrile infants or children and because it raises important questions about the advisability of performing lumbar puncture.
Signs of increased ICP are especially likely to be found in children with a fulminant history and those who are moribund on presentation. In addition to meningismus and diminished mental status, these patients may have dilated and poorly reactive pupils, as well as loss of lateral eye movements or abnormal convergence of gaze. Reflexes may be increased in the lower extremities, and clonus may be present. The Cushing reflex (hypertension with bradycardia) may be detected. Papilledema may be found.
Unilateral pupillary dilatation, a unilateral field cut, or unilateral loss of lateral eye movement suggests the possibility of a lateralized mass lesion such as empyema or brain abscess and may contraindicate lumbar puncture, at least until a diagnostic scan is obtained.
Generally, papilledema is not found in the early stages of meningitis. Therefore, absence of papilledema cannot exclude the possibility of elevated ICP. Moreover, correct interpretation of funduscopic findings in infants or even young children who present acutely with fever and serious illness exceeds the competence of most physicians.
Detection of papilledema at presentation with mental status changes after a brief course of illness is more suggestive of brain abscess or some other focal process, especially if unilateral papilledema, lateral gaze palsy, or other focal signs are found.
Acute complications of Hib meningitis are as follows:
Repeat blood cultures or lumbar puncture or other testing may be indicated in patients who develop these complications. However, lumbar puncture may sometimes be contraindicated or must be deferred until after brain imaging is performed.
Prolonged primary fevers are found in about 10-15% of all Hib meningitis cases and necessitate reconsideration of the antibiotic regimen. Additional considerations include the exclusion of pneumonia, urinary tract infection, intravenous line sepsis, or the development of subdural effusions or empyema.[20] The differential diagnosis should also be revisited; for example, the patient may have a brain abscess rather than meningitis.
Subdural effusions may develop in as many as half of all cases of Hib meningitis, but few are clinically significant. They are the putative cause of approximately 25% of all instances of prolonged primary fevers after initiation of appropriate antibiotic therapy in Hib meningitis. Along with nosocomial infections (eg, intravenous line infections), infected subdural effusions are the most commonly identified causes for secondary fevers.
Prolonged coma or progressive deterioration in function raises the possibility of increased ICP. The presence of bulging fontanelle, papilledema, sunsetting or convergence of the eyes, pupillary dilatation, Cushing reflex, or other brainstem signs of herniation suggests potential elevation of ICP, which may be due to brain edema or hydrocephalus.
Brain edema may develop because of hypoxia, ischemia, hypoglycemia, prolonged seizures, inflammatory vasculitis, or other derangements of brain during the initial or subsequent stages of fulminant Hib meningitis. It may also result from brain infarction or from the development of either communicating or noncommunicating hydrocephalus. Management of brain edema entails careful attention to metabolic parameters and avoidance of excessive hypotonic fluids. On the other hand, sufficient fluids must be provided to maintain cerebral perfusion.
Management of this combination of cytotoxic and vasogenic edema by hyperventilation and administration of mannitol is a complex subject, the review of which falls beyond the scope of this article. Suffice it to say that generalizations accepted several years ago concerning the potential efficacy of hyperventilation to achieve carbon dioxide concentrations in the range of 25-30 mm Hg are no longer widely accepted and that evidence suggests such manipulations may be deleterious. Mannitol, in some instances, may prove useful if used over a short term.
Hydrocephalus of either the communicating or the noncommunicating variety responds to interventions much more reliably than brain edema does. Urgent consultation with a neurosurgeon is indicated for the alleviation of pressure. If communicating hydrocephalus develops in Hib meningitis, it is probably because inflammatory exudate across the vertices impaired the resorptive function of arachnoid granulations. Noncommunicating hydrocephalus usually develops because of exudative blockage of the foramina of Magendie and Luschka.
Focal deficits or seizures can be the result of focal processes that should be identified by computed tomography (CT) of the brain. Brain edema or hydrocephalus may produce focal brainstem signs through compression or herniation. Subdural effusions or empyemas may grow large enough to compress the cortex and produce hemiparesis. Other processes that may be identified include cerebral infarctions, cerebritis, or brain abscess. Generally speaking, magnetic resonance imaging (MRI) is far superior to CT scanning in identifying these processes.
Laboratory tests should be performed as appropriate. Lumbar puncture should be strongly considered in all infants aged 2-12 months with a history suggestive of Haemophilusinfluenzae meningitis and the finding of meningismus on physical examination. Brain imaging studies may be of importance. Electroencephalography (EEG) is indicated in some situations. All patients should undergo brainstem auditory evoked response (BAER) testing either during hospitalization or soon thereafter.
Go to Meningitis for more complete information on this topic.
At presentation, the majority of patients with H influenzae type b (Hib) meningitis have an elevated white blood cell (WBC) count, with a left shift. As with Hib epiglottitis, counts in excess of 20,000/µL may be found.
Serum glucose values should be measured, for the sake of comparison with cerebrospinal fluid (CSF) glucose levels (see below). Serum glucose values are often abnormal (low or high) in cases of acute bacterial meningitis.
Serum and urine chemistry, in particular sodium values, should be ascertained immediately and monitored at intervals throughout treatment. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) develops in approximately half of all cases of Hib meningitis. It may cause stupor or seizure and may contribute to the elevation of intracranial pressure.
Diagnostic criteria for SIADH are as follows:
In some instances, low serum sodium is due to cerebral salt wasting rather than SIADH. Unlike SIADH, cerebral salt wasting is associated with a decline rather than an increase in patient mass. In other instances, hyponatremia is produced by the excessive intravenous administration of hyposmolar fluids.
Hib may be grown from blood cultures in at least 50-80% of cases if the patient has received no prior treatment with antibiotics. Accurate etiologic diagnosis of meningitis may be more complicated in developing countries, where often there is widespread use of antibiotics before blood or CSF cultures can be obtained. This approach is understandable if one considers the delay that may be encountered in some nations in rapidly obtaining access to healthcare facilities capable of performing such studies.
Lumbar puncture is critical in the evaluation of patients with suspected meningitis. Lumbar puncture results may confirm the diagnosis of meningitis or suggest an alternative diagnosis. In cases of bacterial meningitis, CSF Gram stain and culture may identify the organism causing meningitis, which is advantageous in that treatment and prognostication can be adjusted to the specific organism. Identification of increased pressure by lumbar puncture may also modify the therapy provided.
CSF abnormalities are found in approximately 16-20% of children who are evaluated by lumbar puncture for possible meningitis. Of the children with abnormalities, 60-68% have viral infection, 20-26% have bacterial infection, and the cause remains unclear or unknown in 5-10%.
Lumbar puncture should be performed unless some specific contraindication exists. In young febrile children, lumbar puncture should be performed if meningitis cannot be otherwise excluded (after appropriate consideration of such contraindications as asymmetrical space-occupying lesion).
Lumbar puncture should also be strongly considered if another definite source of infection and fever cannot be found and outpatient antibiotic therapy is to be provided. In such cases, performing puncture avoids the diagnostic difficulties associated with partially treated meningitis in the event that the infant returns within the next few days with clinical worsening.
Care must be taken not to perform lumbar punctures in patients who are at risk for brain herniation or are manifesting signs of impending herniation. Although the scientific underpinnings of allegations that there is a relationship between lumbar puncture and herniation are in many cases weak, they may not appear to be so in the minds of nonmedical personnel called upon to review such an alleged relationship in retrospect in a courtroom.
Findings that may indicate the onset of herniation or impending herniation include focal brainstem signs, especially if present unilaterally (eg, dilation of a pupil, diminution or loss of pupillary reactivity, diminution or loss of abducens function); head tilt; meningismus; deterioration in mental status; visual field defect; focal seizures; vomiting; increased tone in the lower extremities; Cushing reflex (ie, elevated blood pressure with slow heart rate); and hyperventilation or other disturbances of breathing rhythm consistent with brainstem regulatory failure.
Papilledema is a very important sign, but it may not develop until after several hours of increased intracranial pressure (ICP), and a large segment of the medical community cannot reliably determine the pertinent early funduscopic changes. Venous pulsation presence may be reassuring, but the absence of pulsations is of greatest value only in cases where they were known to be present prior to the current urgent presentation.
In cases where concern is raised by any of these signs, deferring lumbar puncture until after brain imaging can be obtained is appropriate. However, in all such cases wherein the diagnosis of meningitis is entertained, obtaining a blood culture and initiating appropriate broad-spectrum antibiotic therapy immediately afterward is crucial, so that performance of the brain scan does not delay initiation of treatment.
The authors re-emphasize the point that the performance of brain imaging studies should never delay the initiation of treatment for increased intracranial pressure or seizures. Note that even in cases where intravenous (IV) antibiotics have been administered immediately before a computed tomography (CT) scan, CSF from a lumbar puncture performed after the completion of the scan seldom has been sterilized by the antibiotics.
In the absence of focal neurologic findings (such as those noted above), the risk of herniation in cases of Hib meningitis is low, and one can safely proceed to lumbar puncture without imaging. In general, evidence of raised ICP is not considered a categorical contraindication to lumbar puncture, as long as no signs suggesting focal space-occupying lesions are found. If evidence exists for increased ICP, a small needle (#22 gauge) should be employed by the most skilled available person, and only as much CSF as is needed for essential tests should be collected.
Opening pressure should be recorded. This should be done only when patients are in the lateral recumbent position and are as relaxed and calm as possible.
In bacterial meningitis, opening pressure is frequently elevated, which may have an impact on treatment. In small calm infants, pressures should be less than 160 mm water. Older infants and children should have pressures less than 180 mm water. In some obese individuals, normal pressures are as high as 250 mm water. In fulminant cases of Hib meningitis, pressures as high as 300 mm water to more than 500 mm water may be recorded.
CSF should be collected in a sterile manner in sufficient quantity and immediately submitted to the laboratory. If extra CSF is available, freeze it and store it for possible future evaluation.
The appearance of the CSF should be noted. Normal CSF is clear. In bacterial meningitis, however, the presence of greater than 200 WBCs/µL, greater than 400 red blood cells (RBCs)/µL, greater than 100 mg/dL protein, or greater than 105 colony-forming units (CFU) of bacteria may cause the CSF to appear cloudy. This change may be subtle and is best appreciated by flicking the bottom of the firmly held tube and observing for a shimmer of iridescence. In severe cases, the CSF may appear purulent. Protein values of greater than 150 mg/dL cause the fluid to appear xanthochromic.
Gram staining of the CSF may reveal the Hib pleomorphic gram-negative coccobacilli. If the CSF is cloudy, the stain should be performed on fresh uncentrifuged CSF. If the CSF is clear, it should be performed on the pellet of centrifuged CSF.
The probability of visualizing bacteria depends on the concentration of bacteria in CSF. Bacteria are identifiable in 60-90% of all cases of acute bacterial meningitis, particularly in cases where more than 105 CFU/mL are present. The specificity of a positive Gram stain for bacterial meningitis is approximately 95%. Gram staining does not provide a definitive identification of the bacteria and does not, of course, provide information concerning antibiotic sensitivities.
Oral or IV pretreatment with antibiotics may disable the identification of organisms by Gram stain. Indeed, the presence of organisms on Gram stain 24 hours after IV treatment has been initiated may be an important indicator of treatment failure.
CSF should be examined promptly for WBCs because these cells generally begin to disintegrate within about 90 minutes of the lumbar puncture. WBC levels greater than 10/µL are usually considered abnormal, as is the presence of even 1 polymorphonuclear (PMN) leukocyte.
WBC differential counts from cytocentrifuged CSF may falsely elevate the PMN leukocyte count. The occurrence of a preceding convulsive seizure may elevate the WBC count, particularly the PMN leukocyte count. When modest CSF pleocytosis is due to seizure and not meningitis, opening pressure is usually normal, CSF is clear, fewer than 80 WBC/µL are found, and CSF glucose is normal.
The typical finding in Hib meningitis is PMN leukocyte–predominant pleocytosis, as is the case in most other forms of bacterial meningitis. CSF WBC counts in Hib meningitis are greater than 100/µL in more than 90% of cases and greater than 1000 in 65-70% of cases. The mean CSF WBC counts for Hib meningitis approach 1100/µL.
Note, however, that although lymphocytes typically predominate in the fully developed CSF pleocytosis of viral meningitis, PMN leukocytes may predominate in as many as 20-75% of lumbar puncture samples obtained in the early phases of viral encephalitis, and they may be found in 5-8% of viral encephalitides even after fully developed pleocytosis has been achieved. On the other hand, approximately 10-30% of bacterial meningitis cases have early lymphocytic predominance, especially in cases where the CSF WBC count is fewer than 1000/µL.
In at least half of all patients who receive appropriate antibiotic therapy for bacterial meningitis, the CSF WBC count remains elevated for at least 1 week after initiation of therapy. In some cases, the elevation persists for several weeks. However, falling CSF WBC counts on repeat lumbar punctures should be considered a reassuring indication of response to appropriate treatment.
Relatively low CSF WBC counts in a very ill child with Hib meningitis may indicate a poor prognosis, especially if large numbers of nonengulfed Hib organisms are observed on the CSF Gram stain.
CSF glucose concentrations lower than 40 mg/dL are found in approximately two thirds of all cases of acute bacterial meningitis. Comparison must always be made to serum glucose concentrations measured at the time of the lumbar puncture. The CSF-to-serum-glucose ratios should be approximately 2:3 (ie, 0.6).
In the presence of an elevated serum glucose concentration, a CSF glucose concentration within the reference range may not actually be normal, because the CSF value must be interpreted with respect to the serum value. A CSF-to-serum-glucose ratio of less than 0.31 is observed in 70% of patients with bacterial meningitis. Low CSF-to-serum glucose ratios are also found in fungal and carcinomatous meningitides.
In as many as 80% of patients who receive appropriate IV antibiotic treatment for bacterial meningitis, CSF glucose concentration returns to the reference range by day 3 of that treatment. Even with appropriate treatment, however, some patients continue to exhibit low CSF glucose concentrations for 7-10 days.
As happens with any process that disturbs the function of the blood-brain barrier, CSF protein concentrations increase in bacterial meningitis. In Hib meningitis, this value for lumbar CSF is typically greater than 50 mg/dL, with a typical range of 100-500 mg/dL. If ventricular CSF is available for analysis, note that protein values greater than 15 mg/dL are abnormal. In the event of a traumatic tap, protein values may be grossly estimated by subtracting 1 mg/dL of protein for every 1000 RBCs/µL.
In the setting of bacterial meningitis, CSF lactate is frequently elevated. Values in excess of 3.5-3.8 mmol/L are sensitive indicators of acute bacterial meningitis, found in as many as 92% of cases. The specificity of this finding is comparatively low, although elevation of lactate to the concentrations noted above is more strongly indicative of bacterial than viral meningitis. However, elevation of lactate does not exclude the diagnosis of viral meningitis.
Whether CSF lactate as a diagnostic test adds information that cannot be obtained from CSF cell counts, glucose, and protein is not clear. Moreover, elevated CSF lactate may be due to other potential alternative diagnoses (eg, closed head injury, smothering and other causes of hypoxic-ischemic brain injury, neoplasia, or prolonged seizures from any of a wide variety of causes).
Elevation of CSF lactate in Hib meningitis may be due to cerebral edema or changes in cell membranes or cellular energy metabolism leading to anaerobic glycolysis. CSF lactate may remain elevated for a fairly long time after effective antimicrobial therapy has resulted in amelioration of brain edema and restoration of ICP to the reference range.
Repeated lactate estimation (by lumbar CSF analysis or magnetic resonance imaging [MRI] spectroscopically) may provide a method for estimating possible deleterious effects of fluid restriction in cases of Hib meningitis–induced brain swelling. Inadequate systemic volume may be deleterious in such cases because of the high ICP and pressure-passive nature of dysregulation of cerebral circulation in meningitis.
Culture of the CSF yields the most specific information; unfortunately, that information is not immediately available. CSF cultures are positive within 48 hours in approximately 75-80% of cases, with a sensitivity of 95% and a specificity of 99%. Hib in culture can be considered the cause of meningitis most confidently when the organism was found on Gram stain of the initial CSF.
A positive culture is the most valuable single test in confirming the diagnosis of bacterial meningitis. Although in some instances a false-positive CSF culture is obtained, these cultures tend to contain skin commensals such as Staphylococcus alba, and a false-positive CSF culture containing Hib is likely very rare. Moreover, ascribing such a positive culture to contamination is so risky that the physician rarely has any choice other than to complete the usual course of therapy for meningitis.
A positive CSF culture provides the additional benefit of permitting the determination of antimicrobial sensitivity in subcultures of recovered organisms and thus allowing the adjustment of antibiotic selection. However, several additional days after recovery of the organism may be necessary to obtain such results.
Although CSF assays may be less sensitive or specific than positive cultures and Gram stains (unless the CSF findings are very abnormal), the results of CSF analysis are critical for the initial management of Hib meningitis. Evidence suggests that in cases where the clinical picture is consistent, any of the following CSF results predict bacterial meningitis with 99% certainty:
Moreover, in cases where individuals have been treated with antibiotics within the week before the lumbar puncture, the less-irrefutable approach of diagnosing meningitis by CSF cell counts and chemistries must nonetheless be relied upon for decisions concerning initiation and continuation of therapy. Two careful prospective studies indicate that as many as one third of children with Hib meningitis have received recent antibiotic treatment, usually for suspected otitis media.
Previous treatment with oral antibiotics may significantly reduce the yield of CSF culture and Gram stain; indeed, these may be rendered negative within 24 hours of such treatment. CSF protein concentration and neutrophil percentage are also decreased. On the other hand, previous treatment has not been shown to significantly decrease the yield of blood culture, total CSF WBC count, CSF glucose concentration, or CSF-to-serum-glucose ratio.
The reduced significance of some of these indicators of bacterial meningitis was thought to be due to the fact that oral antibiotics, while not preventing the development of meningitis, had attenuated the severity of illness. This concept is supported by the finding that among children whose Hib meningitis was preceded by otitis media or upper respiratory illness, the interval between the preceding illness and the development of meningitis was several days longer in children who received antibiotic treatment than in untreated children.
Studies of the effects of IV antibiotic administration on CSF characteristics of children with meningitis have shown that as many as several days of IV treatment with appropriate antibiotics does not significantly alter CSF protein, glucose, or WBC concentrations, although the yield of Gram stain and culture is lost.
No results of CSF cell counts or chemistries can be used to irrefutably rule out a meningitis diagnosis in a patient who has clinical indications of possible meningitis. This is particularly true because of the possibility of viral meningitis in such cases.
Bacterial antigen tests such as counterimmunoelectrophoresis or latex agglutination immunologically detect the soluble antigens on many bacteria, including those of Hib. The tests are very rapid but detect only the most common meningitis pathogens. The latex particle agglutination antigen tests for Hib have a sensitivity of 97% and a specificity of 95%.
Polymerase chain reaction (PCR) is an emerging technique that may ultimately be useful in identifying the organism when the Gram stain and culture results are negative. However, its application to bacterial meningitis has been limited by a significant number of false-positive results caused by amplification of contaminating DNA and mispriming.
An advantage of both bacterial antigen tests and PCR is that the results are not affected by treatment with oral antibiotics before presentation.
Various studies have been published concerning the utility of testing for fibrin degradation products, lactate dehydrogenase, creatine kinase, or other potential CSF constituents in evaluation of children who may have meningitis. As yet, no compelling evidence indicates that such testing is valuable.
Brain imaging studies may be of importance in patients with Hib meningitis. These studies are appropriately obtained in the acute setting to identify mass lesions that are in the differential diagnosis (eg, focal encephalitis, brain abscess, empyema, parasitism, subdural hemorrhages) not only for diagnostic purposes, but also to evaluate possible risks of lumbar puncture. Hence, evidence of focal neurologic dysfunction (ie, seizures, focal neurologic deficits) or of papilledema should prompt consideration of scanning.
Other indications for scanning during the initial or subsequent phases of hospitalization include persistently depressed or unexplained deterioration in neurologic status and prolonged fever despite treatment.
Scanning should never be performed before other critical management decisions have been made and acted instituted. If lumbar puncture is deferred until after scanning, adequate IV access must be established, blood cultures must be drawn, and broad-spectrum antibiotic coverage pertinent to any suspected meningitic agent should be administered.
If a scan is ordered because of seizures, full IV loading with an anticonvulsant should be considered. The authors regard phenobarbital as the drug of choice for this in young children because its sedative properties may make other forms of sedation unnecessary.
The wide therapeutic window of phenobarbital permits multiple additional doses to be administered if seizures are resistant to treatment, and this agent is easier to manage than phenytoin because of the nonlinear kinetics of phenytoin, if an anticonvulsant is judged necessary at discharge. Phenobarbital may also have beneficial effects in cases of increased ICP by reducing irritability and cerebral metabolic demand.
Brain imaging studies obtained at presentation are usually justified to identify an alternative diagnosis to meningitis (eg, brain abscess, subdural empyema) that may contraindicate a lumbar puncture. Results of imaging studies do not confirm the diagnosis of meningitis, which can only truly be confirmed by the performance of lumbar puncture. In instances where lumbar puncture is contraindicated, the presumption of meningitis may be made when the imaging results or clinical circumstances and other testing do not disclose an alternative diagnosis.
Go to Imaging in Bacterial Meningitis for more complete information on this topic.
Either CT or MRI may provide information concerning the usual space-occupying lesions or other complications that may result from Hib meningitis and either modality provides information concerning some alternative diagnoses. Generally, CT is obtained because it is usually more readily available and requires less time. Patients must be monitored by qualified personnel during imaging because seizures or critical elevation in ICP may develop while the study is being performed.
The most common imaging findings in cases of Hib meningitis at or shortly after presentation are meningeal, ependymal, or choroidal enhancement due to meningitic inflammation. Inflammatory exudate may be demonstrable in the basilar cisterns, especially the foramen magnum. The accumulation of inflammatory exudate tends to widen the basilar cisterns and the cortical sulci (particularly over the convexities of the forebrain hemispheres).
Findings on CT scanning may be fully normal in the acute stage of Hib meningitis. MRI scanning, if performed, may reveal the abnormalities noted above with even greater sensitivity and definition than CT scanning.
Abnormalities indicative of meningitic inflammation and exudate support the diagnosis of meningitis but are not very specific with regard to organism and usually do not modify therapy or prognosis. Thus, for example, the extent of meningeal enhancement is not indicative of prognosis. Rarely, adults may present with Hib meningoventriculitis, evident as ventricular debris, periventricular hyperintense signal, and periventricular ependymal enhancement.[21]
Other important abnormalities that scans may detect tend to develop later in the course of Hib meningitis and constitute complications of the disease. In many cases, these abnormalities are better defined by MRI than by CT scanning. Indications for obtaining such scans, whether CT or MRI, include the following:
On CT scanning performed because of these various indications, abnormalities are found in slightly more than 50% of all such scans. However, in most instances, these abnormalities do not require specific interventions, and their detection may not prove helpful in estimating prognosis.
Transependymal movement of CSF may be detected, especially in instances where noncommunicating hydrocephalus develops. Brain swelling may be found, and on MRI, diffuse increased T2-weighted signal may be found, representing interstitial cerebral edema. These various changes may indicate the need for management of increased ICP.
On CT scanning, brain edema causes loss of differentiation of gray and white matter. Care must be taken not to overinterpret the watery appearance of white matter in the brains of very young infants; this appearance may be normal because of the larger water content of unmyelinated tissue. Loss of sulcal markings and of the usually distinct suprasellar, perimesencephalic, and quadrigeminal cisterns may occur. Ventricular compression imparting a slitlike contour to the frontal horns may occur.
Subdural effusions are common in Hib meningitis and are usually the result of an inflammation-induced increase in the permeability of capillaries and veins of the inner dural surface, permitting leakage of sterile fluid into the subdural space.
On CT imaging, subdural effusions are crescentic extra-axial collections between the outer surface of the brain and the inner surface of the skull, and their density is quite low, appearing similar to CSF. They are often bilateral and, if large, may flatten the anterior portions of the brain and may displace the frontal horns posteriorly. To some extent, the displacement posteriorly may be the artificial result of the recumbent positioning of the patient in the scanner. They do not usually enhance after contrast administration.
Subdural effusions are generally benign and do not cause symptoms and should in general be left alone. Eventually they resorb spontaneously, as the meningitis resolves. On occasion, however, subdural effusions can create local mass effect with involvement of local tissue. They may even result in elevated ICP, herniation, or focal signs. The development of new or progressive deficits, such as hemiparesis, during the course of illness may indicate that a subdural effusion has begun to exert mass effects.
Subdural effusions may become infected. On brain imaging, infection is suggested by the fact that the purulent material within the effusion produces an imaging appearance that is of higher density than CSF. IV contrast administration results in enhancement, especially at the border between cortex and subdural surface.
Hydrocephalus, either communicating or obstructive, may occur in Hib meningitis. Such a process should be suspected if the patient has progressive or prolonged altered consciousness despite appropriate antibiotic treatment. Communicating hydrocephalus probably develops because the inflammatory exudate across the vertices impairs the resorptive function of arachnoid granulations. Noncommunicating hydrocephalus usually develops because of exudative blockage of the foramina of Magendie and Luschka.
In distinction to the changes of edema, communicating hydrocephalus enlarges the entire ventricular system, including the fourth ventricle and, in some instances, the extra-axial spaces. Transependymal movement of CSF may result in periventricular lucency of the frontal ventricular horns.
In obstructive hydrocephalus, these periventricular lucencies are even more pronounced and the ventricular enlargement is limited to the lateral and third ventricles without enlargement of the fourth ventricle or extra-axial spaces. Obviously, the periventricular changes are even more evident on MRI than on CT scanning and consist of bright signal on T2 weighting.
Cerebral infarction as a consequence of meningitic vasculitis may be found. CT scanning may show low-density lesions corresponding to a particular vascular territory. Hib meningitis–associated infarction tends to be found in the subcortical white matter, cerebellum, and brainstem. Administration of contrast results in gyriform, nodular, or ring enhancement of the infracted area. Infarctions may be hemorrhagic, a feature that CT scanning is particularly likely to reveal.
MRI is more likely to demonstrate bland infarction, particularly when sequences designed to demonstrate restricted diffusion are employed. These abnormalities tend to be found in subcortical white matter, cerebellum, and brainstem and resemble the changes that may be found in hypoxic-ischemic encephalopathy. Lesions such as these should be suspected when patients with Hib meningitis manifest focal deficits or seizures.
The low-density changes of cerebritis may be quite difficult to identify by CT scanning, although after contrast administration, the margins of areas of cerebritis are sometimes surrounded by a rather indistinct and nonhomogeneous halo. Occasionally, contrast is also found in the center of such regions. Evolution of brain abscess in such regions results in a ring of low density surrounded by contrast enhancement that is itself contained within a larger low-density area of brain edema. These changes are much more distinct on MRI.
Unlike some other types of meningitis, abscess formation is uncommon in Hib meningitis. Abscess formation may be detected in scans obtained because the patient has developed focal deficits or seizure.
EEG is sometimes indicated to evaluate for seizure activity. Indications include persistent depressed mental status without obvious evidence of seizure activity. Nonconvulsive status epilepticus is common in this population, although altered mental status is more often caused by metabolic disarray.
Hearing impairment is a common complication in Hib meningitis. It is usually permanent. Hearing may be difficult to assess clinically; therefore, all children should have BAER testing at some point during hospitalization or in the early period of posthospitalization recovery.
The results of BAER testing do not influence acute management, and to that extent, the timing of BAER testing is not important. However, the value of BAER testing in predicting permanent sensorineural hearing loss from bacterial meningitis is limited if test results are abnormal before resolution of conductive loss (due to the presence of otitis media, which frequently precedes Hib meningitis) or other possible forms of acute inflammation of neural tissue. Thus, the test should be repeated some weeks or months later if results are initially abnormal.
On the other hand, if the test results are normal during the acute phase of the disease, their predictive value for normal hearing is excellent. Unlike other focal complications of meningitis, sensorineural hearing loss is not a risk factor for epilepsy. However, sensorineural hearing loss is associated with language and learning delays. Thus, if present, children should be referred for further hearing and speech evaluations and therapies.
The first attempts at treatment, which resulted in only modest reductions in the high mortality rate of Haemophilus influenzae type b (Hib) meningitis, involved the administration of antisera generated by intrathecal inoculation of horses. Not infrequently, this form of immunotherapy had untoward immune consequences, including serum sickness, conjunctival edema, and anaphylaxis. Alexander developed much more effective antisera in rabbits in 1939.
Although sulfonamides proved disappointing at first, combining this antibiotic with Alexander’s antisera in 1942 resulted in the first great therapeutic breakthrough, with a reduction of the mortality rate to 26%, although the combination induced untoward immune-mediated reactions in more than 40% of patients.
The year 1944 saw the introduction of streptomycin. The use of this antibiotic—systemic and intrathecal, often in combination with either Alexander’s antisera or sulfadiazine or both—reduced the mortality rate to 3.4% by 1947. Chloramphenicol replaced streptomycin in 1950 because its excellent penetration of the blood-brain barrier eliminated the need for intrathecal treatment. In combination with sulfadiazine, chloramphenicol remained the treatment of choice until this role was assumed by ampicillin.
The most critical aspect of initial treatment of meningitis is prompt initiation of antimicrobial therapy, because any delay in treatment is associated with increased morbidity and mortality. Anti-inflammatory therapy remains controversial, but dexamethasone may help prevent hearing loss. When necessary, increased intracranial pressure (ICP) can be treated with mannitol.
Go to Meningitis, Meningococcal Meningitis, Staphylococcal Meningitis, Tuberculous Meningitis, Viral Meningitis, and Aseptic Meningitis for complete information on these topics.
Currently, the agent of choice for the treatment of Hib meningitis in children who are older than 6 weeks and younger than 6 years is a third-generation cephalosporin (eg, cefotaxime or ceftriaxone), given intravenously (IV). These agents are at least as effective as the older regimen of combination therapy with ampicillin and chloramphenicol and are more effective in children who are infected with microbes that are resistant to ampicillin or chloramphenicol. They are well tolerated, with few adverse effects.
In addition, third-generation cephalosporins can be effectively administered in fewer total daily doses. Thus, although the total daily dose of cefotaxime has usually been divided into 3 doses given at 8-hour intervals, evidence supports administration twice or even once daily. Likewise, the long half-life of ceftriaxone affords the opportunity, in selected cases, for a once-daily antibiotic regimen, enabling patients who have responded well to initial treatment to be discharged home for outpatient IV therapy to complete the course of treatment for Hib meningitis.
Once started, these cephalosporins are generally administered for a total 10-day course, although emerging evidence suggests that 7 days may be adequate for uncomplicated Hib meningitis. The course may be prolonged to a total duration of 14-21 days in complicated cases or in those manifesting prolonged or recurrent fever.
Although older studies suggested that the second-generation cephalosporin cefuroxime might be reliably effective for Hib meningitis, subsequent studies have not confirmed that reliance, and it is no longer recommended. The rejection of this drug as standard therapy is based on evidence that it is slower than third-generation cephalosporins in sterilization of cerebrospinal fluid (CSF) and that treatment may prove ineffective, with more prolonged illness, greater chance for hearing loss and other complications, and risk of recurrence of infection with discontinuation.
Meropenem may be considered a good alternative to the third-generation cephalosporins for the treatment of HiB meningitis.
Ampicillin and gentamicin remain the agents of empiric choice for those younger than 6 weeks because of the importance of gram-negative organisms in that age group and the rarity of Hib meningitis in such very young infants.
With the considerable decline in Hib meningitis among vaccinated children younger than 6 years, the percentage of cases of Streptococcus pneumoniae in that age group has increased. Furthermore, because resistance of S pneumoniae to both penicillin and cephalosporins is increasing in some parts of the world, vancomycin should be included in empiric therapy of children presenting with meningitis.
Previously, ampicillin and chloramphenicol were recommended for the treatment of Hib meningitis. However, resistance to both these antibiotics has emerged. Specifically, strains of Hib produce beta-lactamase and others are resistant through reduced affinity for penicillin-binding proteins. Hib resistance to ampicillin may be found in beta-lactamase negative strains that have shown increasing prevalence in the past few years in Japan and elsewhere.
Alarmingly, some of these strains are also demonstrating resistance to cefotaxime and ceftriaxone. In situations where such beta-lactamase negative/ceftriaxone-resistant Hib strains are encountered, high-dose ceftriaxone (150 mg/kg/d) may be the treatment of choice.[22]
Resistance to chloramphenicol is mediated through bacterial elaboration of chloramphenicol acetyltransferase, which is found in more than half of all Hib isolates from children in some countries.
The emergence of resistant strains of Hib has been especially troublesome in developing nations, where the availability and cost of newer antibiotics may prevent patients infected with these strains from being effectively treated. Between 1994 and 2002, a Kenyan hospital noted that resistance susceptibilities to various antibiotics for H influenzae isolates were amoxicillin (66%), chloramphenicol (66%), and TMP-sulfa (38%). Most of this resistance was found in the Hib strains.[23]
In addition to the growing problem of resistance, chloramphenicol has other disadvantages. Toxic effects (eg, bone marrow suppression, diminished myocardial contractility) render it less desirable for use in children. Myocardial toxicity is more likely to arise in individuals in shock, which may be the case in fulminant Hib sepsis/meningitis.
Serum chloramphenicol levels must be monitored because of the considerable individual variation in pharmacokinetics. In addition, chloramphenicol has several interactions with drugs that are commonly used in the setting of meningitis. Coadministration with phenytoin may increase chloramphenicol concentration, and chloramphenicol may affect serum levels of phenytoin. Coadministration with phenobarbital may decrease chloramphenicol concentration.
These kinds of interactions do not arise with third-generation cephalosporins, whose pharmacokinetic reliability eliminates the necessity for monitoring of antimicrobial levels.
Experimental and pathological evidence strongly suggests that host immune responses to the cell wall constituents of lysed bacteria or other epitopes play roles in the pathogenesis of bacterial meningitis. Further, experimental investigations have produced support for the concept that corticosteroids may significantly reduce the prevalence of neurologic sequelae in individuals with meningitis.
Most clinical studies, including a meta-analysis, show that early use of dexamethasone improves outcomes of treatment, chiefly in preventing hearing loss. Two recent studies have been controversial. One was retrospective and the children in the steroid arm were sicker and more likely to be ventilated. The other study, a prospective study from Malawi, had a high percentage of children with HIV infection and most children seemed to present with severe illness and with a long delay before therapy. These studies emphasize 2 important points: (1) early administration of steroids (prior to or with the first dose of antibiotics) is beneficial and (2) the use of steroids after the development of severe neurological damage may be of limited benefit.
The Infectious Diseases Society of America considers the use of dexamethasone in the treatment of HiB meningitis in infants and children to be an A-I recommendation.[24] European guidelines recommend a total duration of 4 days for Hib meningitis in children whereas American guidelines recommend the use of dexamethasone for 2–4 days in children with Hib meningitis.[25, 26]
The recommended dose is 0.15 mg/kg every 6 hours for the first 2 days after initial diagnosis and treatment. Administering the dexamethasone either before or concomitant with the first dose of antimicrobial therapy is likely of considerable importance if a positive effect is expected.
No evidence indicates that this form of treatment with dexamethasone, administered during the first 2 days of illness, compromises the outcome of appropriate antimicrobial therapy. This may be especially true if such treatment is continued for only 2 days, although data to confirm this point of view are not currently available.
If dexamethasone treatment is elected, care must be exerted to avoid complications such as gastrointestinal hemorrhage.
Patients with Hib meningitis require careful attention to metabolic parameters, close attention to timely replacement and management of IV lines to prevent secondary infections, and management of pulmonary and cardiovascular function as necessary in light of the severity of illness.
Head circumference, fontanelle pressure, funduscopy, and other measures of secondary increases in intracranial volume due to postmeningitic hydrocephalus or the development of extra-axial collections (eg, abscess, empyema, subdural hemorrhage, noninfectious subdural collections) should be monitored as indicated in individual cases. Repeat scans of the intracranial contents should be ordered as needed when unexpected deteriorations of function occur that might be explained by structural processes.
Surgical intervention may occasionally be required in infants or children who develop increased ICP. Intervention in such instances may be limited to the placement of a device to monitor ICP in order to facilitate treatment. In other instances, surgery may be required to alleviate noncommunicating hydrocephalus.
The first vaccines against Hib were produced from the polysaccharide capsule material and were licensed in 1985 for routine use in children older than 2 years. However, these vaccines proved ineffective for children younger than 18 months (who are those most likely to develop Hib meningitis) and had only moderate effectiveness in older children.[27]
Subsequently, new vaccines were developed that conjugated a carrier protein to the polyribosyl-ribitol-phosphate (PRP) molecule. These were first licensed in the United States in 1987 but were not approved for use in children as young as 2 months until 1990. All of these agents have demonstrated a considerable degree of immunogenicity, even in very young children. For more information, see Medication.
The failure rate of Hib conjugate vaccines is exceedingly low. Such failures are related, in slightly less than half of all cases, to defined underlying immunological deficiency or other pertinent risk factors. Immunoglobulin (Ig) deficiency and asplenia are the most commonly encountered impediments to effective vaccination.[28]
IgG3-deficient individuals, who may be infection-prone due to low capacity to generate protective antibody levels have been shown to respond well to immunization with the conjugate ACT-HIB vaccine, achieving sufficient levels of antibodies to provide protection against both Hib infections and tetanus.[29]
Side effects of these vaccines are difficult to assess because Hib vaccination is administered concurrently with other vaccinations. The most commonly reported reactions are local erythema, local induration, and irritability. Fever has also been reported. No serious adverse reactions have as yet been clearly linked to the currently used Hib vaccines.
Several studies have demonstrated a significant reduction in the rate of carriage after vaccination. Carriage of the organism increases the risk of infection in the colonized individual. Reduction in rates of carriage also reduces the exposure to other children who may be at risk. The achievement of reduced nasopharyngeal carriage in older children, who received conjugated vaccines before their approval for use in infants, may account for the fact that many studies showed a decline in incidence of Hib meningitis in infants who were not as yet eligible for vaccination.
Several studies in the United States and abroad have demonstrated a significant reduction in the incidence of invasive Hib infection soon after the introduction of the vaccine. Within the United States, the incidence of invasive Hib diseases has fallen from 85% to 90%. These results have been reproducible in both regional and multistate studies and are not accounted for by interannual variations. The population that received the greatest benefit is that consisting of infants younger than 14 months, a group with the highest incidence of Hib meningitis.
North American immunization recommendations now include as many as 24 vaccines to be administered in an injectable form by 18 months of age. Because of pain as well as compliance, combination vaccines have been recommended where such combinations have been found to be effective.
Among these vaccines, a particularly important combination is that which immunizes against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b (DTaP-IPV/Hib). When instituted in a proper and complete schedule, this combination vaccine has been shown to be safe and effective for primary infant immunization and toddler booster immunization.[30]
Canada, which has had an immunization program since 1992, has discerned a shift in population prevalence for Hib meningitis, with cases occurring more frequently in infants younger than 6 months. Two thirds of cases occur in individuals with no or incomplete vaccination (due to age, parental refusal, or other delaying circumstances). However, some cases occur in individuals who have completed the primary series of immunizations.
It has also been demonstrated in Canada that the conjugate vaccine efficacy is not affected by coadministration of other typical age-indicated vaccinations. Higher case-fatality rates are observed in the postimmunization epoch in Canada and in older individuals, and two thirds of these cases occur in males.[31]
Studies in the Netherlands have detected a disturbing trend toward an increase in the rate of invasive Hib disease in children younger than 5 years. The increased annual incidence is from 0.66 cases per 100,000 in 1998 to 2.96 cases per 100,000 in 2001. The investigators are concerned that this increase is due to the change from the use of whole-cell pertussis vaccine to the conjugate DTaP-Hib vaccine. This newer vaccine has been associated with the achievement of lower levels of anti-Hib antibodies, although in the Netherlands that effect has not been observed.[32]
Unfortunately, even vaccination producing “adequate” Hib antibody levels may in rare instances not prevent the development of severe Hib infection, as has been observed recently in a case of fatal Hib septic purpura fulminans.[28]
Despite effective reduction in the incidence of disease, the case-fatality rate has remained about the same in the United States in the era of effective vaccination as it was prior to the availability of an effective vaccine. However, fewer deaths related to Hib meningitis in vaccinated populations have occurred annually since the number of cases has been so greatly reduced.
On the other hand, in developing nations, the effect of vaccination on case-fatality and case-morbidity rates may be expected to be much higher, since these outcome measures are so much worse in nations where diagnosis and treatment may be delayed due to the inadequacies of transportation and medical infrastructure.
Moreover, in developing nations the rates of antibiotic resistance (which increase morbidity and mortality) is high and steadily increasing. In Pakistan, where 35% of childhood meningitis is Hib, occurring mostly in the first year of life, the rates of Hib resistance to antibiotics is approximately 33% for ampicillin, 22% for chloramphenicol, and 49% for cotrimoxazole.[19]
The increasing role of nontypeable strains of H influenzae, for which no effective immunization is available, has been noted. So has recognition of such typeable strains as H influenzae type f (Hif), suggesting that the place of Hib as the overwhelmingly most common cause of invasive disease due to H influenzae may be taken to some degree by other capsular types. It is troubling that there has been possible clonal expansion of several strains of Haemophilus that are the same in the United States and Denmark.[33]
Some of the current controversies and difficulties concerning establishment of immunization programs in developing nations have been discussed earlier. (See Epidemiology.)
In 2005, the Global Alliance for Vaccines and Immunization (GAVI) created the Hib Initiative, aiming to spend $37 million, over a 4-year period, for the funding of immunization programs in countries where immunization is inadequate. Institution of vaccination programs has been delayed not only by insufficient funding but also by considerations such as establishing current rates of infection and discerning which regions of the country contain children at greatest risk.
The importance of such immunization programs, irrespective of the controversies concerning regional annual incidence of Hib meningitis, is the fact that, in many targeted countries, Hib meningitis has much higher rates of morbidity and mortality than in wealthier nations with superior infrastructure, such as roads and hospitals. Thus, in rural Papua New Guinea, as many as 63% of children surviving meningitis (excluding a rather high rate of children lost to follow up) manifested major neurological sequelae.
The high rates of morbidity and mortality have been ascribed in part to the high rates of resistance to chloramphenicol and the unavailability of third-generation cephalosporins. However, the introduction of greater supplies of third-generation cephalosporins cannot be expected to significantly lower these rates, since nations such as Papua New Guinea, are unavoidably plagued by delayed presentation of sick children to centers capable of administering appropriate antibiotic treatment.
A major issue in Hib immunization is that the expense of vaccination, amounting to more than $2 US per person, is considerable for many nations. Accordingly, those who are on the front lines of this healthcare problem have pleaded for wealthier nations to assist in sponsoring vaccination and encouraging vaccine manufacturers to lower the costs of vaccines.[34]
Another issue is that the risk for severe outcomes from Hib infections may be increasing with the appearance of more examples of antibiotic-resistant strains. Treatment of these strains requires utilization of increasingly expensive antibiotics. In comparison with the growing cost of antimicrobial therapy, the relatively small expense of immunization may come to appear advantageous.
In order both to protect the children of developing countries and to limit the appearance of resistant strains, there seems every reason for the nations of the world to consider underwriting universal childhood immunization as a matter not just of international consideration but also of international self-interest. To date, however, this logical formulation has not resulted in adequate support from wealthier nations for such a program.
GAVI has approved 15 of 75 nations eligible for approval for vaccine introduction. Unfortunately, 26 countries that account in total for most of the world’s children have as yet provided too little data for consideration of approval for vaccine introduction.
Equally unfortunate is the fact that the officials of some countries that have received assistance for the introduction of Hib vaccines have expressed doubt as to whether the vaccine has proven beneficial and provided no practical plan for sustaining the administration of vaccines after introductory financial support was withdrawn, hence, the importance of gathering adequate information before and after the effective introduction of immunization.
No specifically pertinent dietary issues exist. Very ill patients who are unable to receive oral nutrition should, as early as is feasible, receive nutrition as IV hyperalimentation or via the placement of enteric feeding tubes.
The activities of infants and children during the acute phase of illness are dictated by the nature of their disease and necessity of providing various forms of therapy. In some instances, various forms of sedation or restraint are necessary to allow respiratory intervention or other forms of support. Activity should be limited by reduction of stimulation, and in some cases, sedation (eg, in cases where intracranial pressure is elevated). Elevation of the head of the bed is indicated in such cases.
Activities during the phase of recuperation are indicated by the nature and degree of recovery. No generic limitations of activity are associated with the acute or subsequent phases of Hib meningitis.
Consultations may be sought during the acute phase of illness from infectious disease specialists, neurosurgeons, or pediatric intensivists. Hearing testing should be performed at the conclusion of treatment, and posthospitalization interventions for such deficits as are found should be arranged.
Infants and children with prolonged courses or poor outcomes may require consultations from pediatric gastroenterologists. Physical and occupational therapy evaluations and therapy should be initiated as soon as is judged feasible in cases where neurologic abnormalities persist after initial treatment. Children who develop a chronic disability (eg, static encephalopathy), in time, may require the services of pediatric developmental specialists and pediatric orthopedic surgeons.
Patients may require care for the management of deficits resulting from Hib meningitis, including static encephalopathy, seizures, behavioral changes, or epilepsy. In some instances, patients may require anticonvulsants, analgesics, and medications to promote sleep or to attenuate behavioral, attention, or learning problems.
Some sequelae of Hib meningitis are transient; others lead to chronic or even permanent problems. Despite adequate treatment of children with Hib meningitis, approximately 20-40% are left with persistent sequelae. Some studies report that deficits are present in more than 50% of survivors. Permanent deficits are more likely in patients whose diagnosis and treatment is delayed and in those who are treated with less effective antibiotics (eg, ones to which the pathogens are resistant). The general categories are as follows:
Seizures that occur on presentation and during the earliest acute phase of Hib meningitis do so because of transient focal derangements in cortex or because of metabolic disturbances such as hyponatremia or hypoglycemia. Treatment may require the administration of anticonvulsants, the choice of which involves consideration of type of seizures, age of patient, and route of drug administration.
During the acute phase of presentation, care must be taken to diagnose and appropriately treat seizures prior to sedating or paralyzing patients for such procedures as brain imaging. Failure to do so may permit seizures to persist unrecognized for intervals of 40 minutes or more, which may have a very deleterious effect on outcome.
Occasionally, children with meningitis manifest subtle change in mental status in the wake of prolonged generalized seizures. Signs of such a process include poor responsiveness and the presence of widespread irregularly repetitive minipolymyoclonic jerks or twitches. Electroencephalographic assessment may be necessary.
Initial administration of anticonvulsants may precede discernment of the cause of seizure in cases in which seizures are prolonged or may increase ICP or metabolic demand. In such instances, children are generally treated with IV benzodiazepines, phenytoin, or phenobarbital. The decision to continue providing maintenance anticonvulsant treatment during the course of hospitalization depends on the cause and severity of seizures as well as the likelihood of recurrence.
Epilepsy, which may be difficult to control despite multiple antiepileptic medications, is present in less than 10% of survivors. The first seizure after the acute phase usually occurs within the first 2 years, although it may occur much later. Seizures are generally focal or have a focal onset. Most patients with epilepsy had transient focal seizures during the acute phase. However, seizures during the acute phase do not independently predict the occurrence of late seizures.
The presence of a persistent neurologic deficit other than sensorineural hearing loss is a risk factor for late manifestation of seizures (ie, seizures appearing for the first time in the late stages of hospitalization or after a period of weeks to years after discharge). In one study, all patients with a persistent deficit other than sensorineural hearing loss went on to have recurrent seizures after Hib meningitis.
Provision of appropriately selected anticonvulsants with consideration of seizure type and age of patient is necessary in patients with persistent seizures. Generally, patients respond well to treatment and have no recurrence for the ensuing year. In such cases, medications may be discontinued at the end of a year of treatment with small risk for recurrence. A second group continues to have seizures despite the first appropriately chosen drug. Their seizures remain difficult to control despite multiple anticonvulsants.
Occasionally, persistent seizures manifest in children who have had Hib meningitis but who recover fully and without any evidence on examination of focal neurologic deficits. These children are usually found to have structural brain abnormalities on brain imaging. In some of these cases, if seizures are intractable, as well as in cases where persistent deficits are mild or moderate, epilepsy surgery can be considered at an appropriately remote time from acute hospitalization.
Hearing impairment is a common complication of meningitis. It is among the most common sequelae of Hib meningitis, occurring in about 20% of cases, although reports indicate a range of 10-30%. Hearing loss is sensorineural and may be unilateral or bilateral, with deficits ranging from mild hearing loss to deafness in the involved ear. Persistent hearing deficits may be associated with learning disabilities and language delay.
The actual mechanisms of damage to the hearing system are not fully understood. The absence of all waveforms on brainstem auditory evoked response (BAER) testing in these patients suggests a peripheral process. One explanation of injury is that, during the acute phase of illness, the eighth cranial nerve becomes encased by inflammatory exudate within its sleeve in the subarachnoid space.
Another possible mechanism is bacterial invasion of the spiral ganglia or cochlear perilymph via the internal auditory canal or cochlear aqueduct, resulting either in direct damage or in damage secondary to toxins or inflammatory products. Evidence for either of these mechanisms has been found in pathological studies.
Although sensorineural hearing loss is the most common finding, occasional patients with postmeningitic deafness are found to have conductive hearing loss. This type of deficit may result from the otitis media that fairly commonly precedes the development of Hib meningitis. Unlike sensorineural hearing loss, conductive hearing deficits resolve without permanent impairment.
Cranial neuropathies other then the eighth cranial nerve may occur. The involvement of cranial nerves other than the eighth is found in approximately 6% of children who have had Hib meningitis. Nerves most commonly involved are the facial, abducens, and oculomotor, but any of the nerves may be involved.
The mechanisms for these forms of injury include the inflammatory investment of the nerve within the nerve sheath near the brainstem (ie, due to the basilar meningitic inflammatory process), or they may be injured by compression due to elevation in intracranial pressure.
Ataxia is among the less common manifestations of Hib meningitis. It is typically sensory/vestibular in origin. Although it occurs less often than hearing deficits, the presumed mechanism of disease is similar to that of sensorineural hearing loss—namely, inflammatory investment of the vestibular division of the eighth cranial nerve. It is generally a self-limited process, although it is predictive of more permanent hearing loss.
Hemiparesis is found in approximately 6% of children recovering from Hib meningitis. In some instances, it is due to cerebral strokes that occur because of vasculitic inflammation of the brain. In other instances, it is the result of large subdural effusions that are commonly observed in meningitis.
Cognitive and behavioral disturbances are found in as many as 40% of children who have had Hib meningitis. Many studies have been undertaken to evaluate cognitive impairment after meningitis. When compared with siblings closest in age, children who have had meningitis have lower average full-scale intelligence quotients (IQs). The magnitude of difference is greater than one standard deviation in 30% of cases. In one such study, 28% of patients were found to have significant handicaps, including 11% with mental retardation.
In addition, a wide range of neurologic and learning disabilities is found in a large percentage of survivors who are successfully treated with antibiotics and subsequently considered to be normal by parents, teachers, and peers.
However, more recent studies have not demonstrated large differences in intellectual outcomes. No difference was detected in the IQ between index cases and nearest-age siblings. Differences that were significant were mild and of questionable clinical significance.
The most critical aspect of initial treatment of meningitis is prompt initiation of antimicrobial therapy, because any delay in treatment is associated with increased morbidity and mortality. Anti-inflammatory therapy remains controversial, but dexamethasone may help prevent hearing loss. When necessary, increased intracranial pressure (ICP) can be treated with mannitol. Vaccination may help in the prevention of Haemophilus meningitis. Patients may require care for the management of deficits resulting from Hib meningitis, including static encephalopathy, seizures, behavioral changes, or epilepsy.
Clinical Context: Ampicillin is a broad-spectrum penicillin. It interferes with bacterial cell wall synthesis during active replication, causing bactericidal activity against susceptible organisms. Ampicillin could be considered an option if HiB is known to be susceptible to the drug. Nontypable H influenzae strains, which are increasingly being encountered, tend to be susceptible to ampicillin.
Clinical Context: Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity and lower efficacy against gram-positive organisms. It also has higher efficacy against resistant organisms. Bactericidal activity results from inhibiting cell wall synthesis by binding to one or more penicillin-binding proteins. It exerts antimicrobial effect by interfering with the synthesis of peptidoglycan, a major structural component of the bacterial cell wall. Bacteria eventually lyse due to the ongoing activity of cell wall autolytic enzymes, while cell wall assembly is arrested. It is highly stable in the presence of beta-lactamases, both penicillinase and cephalosporinase, of gram-negative and gram-positive bacteria.
Clinical Context: Cefotaxime is a third-generation cephalosporin with a broad gram-negative spectrum, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. It arrests bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins, which, in turn, inhibits bacterial growth. Its safety profile is more favorable than aminoglycosides. It is used to treat suspected or documented bacterial meningitis caused by susceptible organisms such as H influenzae or N meningitidis.
Clinical Context: Meropenem is a carbapenem antibiotic and is considered an alternative to cephalosporins. It exerts its bactericidal activity by inhibiting cell wall synthesis and can be considered an option in patients who are intolerant of cephalosporins.
The most critical aspect of initial treatment for meningitis is prompt initiation of antimicrobial therapy, because any delay in treatment is associated with increased morbidity and mortality. Chloramphenicol was previously used to treat HiB meningitis but has fallen out of favor because of increasing resistance, potential myelotoxicity, lack of availability, and, most importantly, the availability of alternatives with a better safety profile.
Clinical Context: The anticonvulsant action of carbamazepine may involve depressing activity in the nucleus ventralis anterior of thalamus, resulting in reduction of polysynaptic responses and blocking of posttetanic potentiation. It reduces sustained high-frequency repetitive neural firing.
Clinical Context: Lamotrigine is a triazine derivative that is effective as an adjunctive and primary drug in the management of partial seizures, generalized seizures, and neuralgia. It inhibits the release of glutamate and inhibits voltage-sensitive sodium channels, leading to stabilization of the neuronal membrane.
Clinical Context: Topiramate is a sulfamate-substituted monosaccharide with a broad spectrum of antiepileptic activity that may have a state-dependent sodium channel blocking action, potentiating the inhibitory activity of the neurotransmitter gamma-amino butyric acid (GABA). It may block glutamate activity.
Clinical Context: Gabapentin is a membrane stabilizer, a structural analogue of the inhibitory neurotransmitter GABA, which paradoxically is thought to not exert effects on GABA receptors. It appears to exert action via the alpha2-delta1 and alpha2-delta2 auxiliary subunits of voltage-gated calcium channels. It is as adjunctive therapy in the treatment of partial seizures.
Seizures that occur on presentation and during the earliest acute phase of Hib meningitis do so because of transient focal derangements in the cortex or because of metabolic disturbances such as hyponatremia or hypoglycemia. Treatment may require the administration of anticonvulsants, the choice of which involves consideration of the type of seizures, the age of the patient, and the route of drug administration.
Clinical Context: Mannitol can be used to treat increased ICP.
These agents are used in an attempt to lower pressure in the subarachnoid space. As water diffuses from the subarachnoid space into the intravascular compartment, pressure in the subarachnoid compartment may decrease.
Clinical Context: Dexamethasone has many pharmacologic benefits but significant adverse effects. It stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, and inhibits prostaglandin and proinflammatory cytokines (eg, TNF-alpha, IL-6, IL-2, and IFN-gamma). The inhibition of chemotactic factors and factors that increase capillary permeability inhibits the recruitment of inflammatory cells into affected areas. If dexamethasone treatment is elected, the recommended dose is 0.15 mg/kg every 6 hours for the first 2 days after the initial diagnosis and treatment. In addition, care must be exerted to avoid complications such as gastrointestinal hemorrhage.
Anti-inflammatory therapy remains controversial, but dexamethasone may help prevent hearing loss. Administering the dexamethasone either before or concomitant with the first dose of antimicrobial therapy is likely of considerable importance if a positive effect is expected.
Clinical Context: This vaccine is used for routine immunization of children against invasive diseases caused by Hib by decreasing nasopharyngeal colonization.
Clinical Context: This conjugate Hib vaccine uses covalent binding of a capsular polysaccharide of Hib to the OMPC carrier to produce antigen postulated to convert T-independent antigen into T-dependent antigen, which enhances the antibody response and immunologic memory.
Clinical Context: This combination vaccine is used for active immunization against diphtheria, tetanus, pertussis, poliomyelitis, and invasive disease caused by Hib in children aged 6 weeks to 4 years.
Clinical Context: MenHibrix is a combination vaccine approved for use in children as young as 6 weeks old and is indicated to prevent invasive disease caused by Neisseria meningitides serogroups C and Y, and Haemophilus influenzae type b. MenHibrix was newly approved in 2012 and is a 4-dose sequence.
Vaccines may be used in the prevention of Hib infection. Several studies in the United States and internationally have demonstrated a significant reduction in the incidence of invasive Hib infection soon after the introduction of the vaccine.