AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Throughout the modern era of bacteriology, Haemophilus influenzae type b (Hib) has been identified as one of the three most common causes of bacterial meningitis. The others are Neisseria meningitidis and Streptococcus pneumoniae. These three bacteria have accounted, prior to the development of effective immunizations, for more than 80% of all cases of meningitis in industrialized nations.

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

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

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

The bacterium was first identified in culture by Pfeiffer in 1892; the designation influenza bacillus was applied because he mistakenly thought that it was the cause of the influenza pandemic of 1890. In the same year, Pfull was the first to recover this agent from postmortem human brain cultures obtained from children who had died from meningitis. The first successful culture of the bacterium from purulent spinal fluid obtained from lumbar puncture was made by Slawyk in 1898. The genus designation Haemophilus, indicating the hemophilic or blood-loving characteristic of H influenzae, was applied because growth of the organism in culture requires the presence whole blood factors V and X.

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

The first attempts at treatment, which resulted in only modest reductions in the high mortality rate of Hib meningitis, involved the administration of antisera generated by intrathecal inoculation of horses. Untoward immune-mediated consequences of this form of immunotherapy were not infrequently encountered, including serum sickness, conjunctival edema, and anaphylaxis. Alexander developed much more effective antisera in rabbits in 1939. Although sulfonamides proved disappointing at first, combination of this antibiotic with Alexander's antisera in 1942 resulted in the first great therapeutic breakthrough, reducing the mortality rate to 26%, although the combination induced untoward immune-mediated reactions in more than 40% of patients.

After 1944, the use of streptomycin administered systemically and intrathecally, 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 the excellent penetration of blood-brain barrier (BBB) obviated the need for intrathecal treatment. In combination with sulfadiazine, this remained the treatment of choice until this role was assumed by ampicillin.

Pathophysiology

Haemophilus species are small oxidase-positive pleomorphic gram-negative aerobic or facultative anaerobic coccobacilli. They can be divided into 2 strains, encapsulated and 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 (LPS) also contribute to the degree of virulence. The capsular antigens are employed to subdivide encapsulated strains into 6 serotypes designated A through F. Unencapsulated strains lack the polysaccharide capsule and are designated untypeable strains.

Of the encapsulated strains, Hib is the most virulent, and prior to vaccination, accounting for more than 95% of all cases of H influenzae meningitis in the prevaccination era. 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 polyribosyl-ribitol-phosphate (PRP) that has been shown to be a particularly important virulence factor.

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

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

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

Infection of distant sites appears to require the achievement of a particular degree of bacteremia sufficient to overcome the bacterial defense systems of the particular host. Containment of colonized bacteria is possibly easier for hosts to achieve than clearance of bacteria within the circulating blood. The capacity to eliminate Hib from circulation clearly entails intact 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. Also, preceding viral infections are possibly permissive of Hib invasiveness (from colonized site to blood stream or from blood stream to target tissues) either by disruption of barriers or by interference with critical aspects of the host immune response. Upper respiratory infections or otitis media, presumably due to viruses, often precede Hib meningitis.

Once this 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 nervous system may involve patterns of venous drainage from sites of nasopharyngeal colonization to vulnerable nearby central nervous system sites (eg, cribriform plate, thin sinus walls) or more likely high blood flow to sites of reduced 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 play a role in 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.

Most invasive infections are caused by encapsulated strains of H influenzae, in particular the type B serotype. The polysaccharide capsule of these organisms not only confers virulence and invasiveness, but it also provides resistance to opsonization and complement-mediated bactericidal activities and inhibits neutrophil phagocytosis. Unencapsulated Haemophilus species may be associated with noninvasive infections. Usually, the infection is in a site contiguous with the upper respiratory tract. Unencapsulated species are among the most common causes of sinusitis and otitis media in children. Unencapsulated strains also cause noninvasive lower respiratory infections in children, community acquired pneumonia, and exacerbation of chronic bronchitis in adults. These noninvasive infections are also preceded by a probable viral respiratory illness. Bacteremia due to unencapsulated Haemophilus is rare.

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 the passive transfer of maternal antibodies. These antibodies are considerably diminished by 2 months of life and are often completely gone by 4 months of life. This period of limited vulnerability appears to be prolonged in breastfed infants, likely because of continued passive transfer of antibodies. This effect is thought by some authorities to account for the fact that young children who develop Hib meningitis in Northern Europe do so at an older average age than children who develop Hib meningitis in North America. These authorities suggest that more Northern European mothers engage in breastfeeding of infants and that they tend to do so for longer periods than North American mothers.

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

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

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

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

Frequency

United States

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

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

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

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

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

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

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

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

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

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

International

As has been noted, 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 have suggested that the incidence of Hib meningitis was lower in the preimmunization era is some parts of Europe. 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.

As has been noted above, Northern European prevalence figures tended to be somewhat lower than those ascertained in the United States. Some of this variation may have been due to differences in methods of assessment. Thus, some data have been acquired by voluntary reporting, and other figures are derived from 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 (eg, breastfeeding practices, as noted above), or other unknown influences.

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 (Vistuc, 1993), 6 cases per 100,000 in Spain (Simarro, 2000), 8 cases per 100,000 in Romania (Luca, 2004), and 8 cases per 100,000 in Greece (Septogiannopoulos, 1995). 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 [Luca, 2004]). 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 (Hanna, 1991). This high incidence may reflect increased vulnerability of 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 remains the enormous threat to public health that it once was in the United States and Northern Europe. Incidence in this post-polysaccharide-protein conjugate vaccine era remains high in developing countries that have lacked the resources to devote to a vaccination program. 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.

A critical problem in international health is the virtual absence or delayed initiation of anti-Hib vaccination programs in many or perhaps most tropical and many Asian nations and those currently experiencing the disruption produced by warfare. 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 (Helena, 2004).

Nonetheless, some Middle Eastern or 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 (Rerks-Ngarm, 2004), 6 cases per 100,000 in South Korea (Kim, 2004), and variously 1-10 cases per 100,000 in regions of China (Yung, 1998; Dong, 2004). Curiously, staphylococcal meningitis incidence was much higher in the Dong study than Hib meningitis.

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 same epidemiological methods found rates of more than 50 cases per 100,000 per year in Ghana and Uganda (Feikin, 2004). 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 (Al-Mazrou, 2004).

To some extent, low incidence rates and the high variability from country to country may reflect data gathering methodology, although the data of Rerks-Ngarm (2004), though some methodological flaws have been raised (Helena, 2005), appear to have been diligently and carefully obtained. On the other hand, pertinent to the hypothesis that Asian incidence of Hib meningitis is low, are data from other South East Asian locations demonstrating much annual higher incidence such as two studies in the Philippines showing annual incidence of 18-95 cases per 100,000 per year in children younger than 5 years (Lupisan, 2000; Limcango, 2000).

Thus, data concerning incidence of meningitis and other serious Hib illnesses in children younger than 5 years in South East Asia and in various other tropical regions of the world remain controversial, particularly where it is suggested that low incidence of these diseases is found even without immunization. A particularly significant problem has been interpretation of results of blood and CSF cultures in the large number of children who have previously received antibiotics, 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 (Adegbola, 2006) that 5 years after the introduction of Hib vaccination in the Gambia, the annual incidence of Hib meningitis fell from 60 cases per 100,000 children younger than 5 years to 0 cases per 100,000. Given the incomplete coverage achieved by Gambian children (estimated to be less than 70% coverage), 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 prior to immunization the annual incidence of Hib meningitis in children younger than 5 years was 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—possible surrogate markers for assessment of efficacy of Hib immunization in developing countries (Martin, 2004).

The expense of vaccination, amounting to more than $2 US dollars, is quite considerable for many nations. Institution of vaccination programs has also been delayed by considerations such as establishing current rates of infection and discerning which regions of the country contain children at greatest risk.

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, rendering consideration of the relatively small expense of immunization 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 one of international self-interest. This logical formulation has not resulted to date in adequate support from wealthier nations for such a program.

Fortunately, the Global Alliance for Vaccines and Immunization has established a Vaccine Fund and 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.

Mortality/Morbidity

The mortality rate of Hib meningitis in the preantibiotic era was greater than 90%. The availability of effective antibiotics reduced the mortality rate to less than 10% in children who received prompt treatment.

Conjugated Hib vaccine has dramatically reduced the annual incidence of Hib meningitis–related morbidity and mortality in a properly vaccinated population because of the profound decline in Hib meningitis. However, children in a vaccinated population that do develop Hib meningitis continue to experience a mortality rate as high as 3-4% despite early standard treatment.

Morbidity in children in vaccinated populations who develop Hib meningitis and who receive early standard treatment has always existed and unfortunately remains high, although prompt treatment has likely reduced morbidity. In addition to antibiotics, appropriate treatment of elevations of intracranial pressure and other complications of Hib meningitis has contributed to lowering morbidity. Whether anti-inflammatory therapy reduces the risk of morbidity such as deafness remains controversial.

Delay in treatment likely increases 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 such as roads, transportation, and facilities for evaluation and care of sick children.

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 increased morbidity and mortality where such agents are the cause of meningitis, perhaps by as much as 3-fold (Saha, 2005). This too is a problem faced more commonly in developing nations that have inadequate immunization programs.

Race

Conflicting data and conclusions have been reported regarding the influence of race on susceptibility to Hib meningitis. To some extent the inconsistencies of these observations derive from the artificiality of the demographic construct termed race and the lack of available scientific measures of the genetic contribution that gives rise to the superficially expressed characteristics upon which a racial assignment is based. These studies are further compromised by the comorbidities that may be associated with racial classification, such as poverty, crowding, poor healthcare, and poor nutrition. However, certain correlations are suggested by the available data.

Several studies have found a significantly higher rate of disease among blacks than 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.

Some data suggest higher risk for Native Americans/Eskimos than for black populations. Thus, one prevalence study from Washington State showed prevaccination era annual prevalences of 2.2 cases per 100,000 white children, 3.4 cases per 100,000 black children, and 13.5 cases per 100,000 Native American children.

Some studies reporting race-related predilection have found that enhanced risk is defined not only by race but also by age. Thus, some data suggest that enhanced risk in blacks is found only in children older than 1 year of age but not in children younger than 1 year. Other studies have found no racial predilection for Hib meningitis. Some authorities think that other risk factors confound racial incidence studies and may account for perceived race-related determination of risk.

Urban crowding may enhance the risk for Hib infection and therefore the population risk for Hib meningitis, or it 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.

Sex

Some 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 effective vaccination, showed the annual prevalence of Hib meningitis among boys younger than 5 years to be 89 cases per 100,000 population as compared to 37 cases per 100,000 population for girls younger than 5 years.
• One large study of serious Hib diseases found that in addition to the preponderance of cases of Hib meningitis in boys, boys account for approximately two thirds of cases of epiglottitis, the second most prevalent serious Hib disease. On the other hand, cases affecting boys were found to account for only 44% of the other serious Hib diseases (eg, sepsis, cellulitis, pneumonia, pyelonephritis).
• Other studies have not confirmed a sex-related predilection for Hib meningitis.

Age

A very striking and robust age-related predilection for Hib meningitis has been found in virtually all studies conducted in the prevaccine era on children from North America or Northern Europe. One study showed that nearly 1 out of 200 of unvaccinated children experienced some form of invasive Hib disease prior to their fifth birthday. More than 95% of all Hib meningitis cases occurred in children younger then 5 years, and 79% occurred in children younger than 3 years.

The peak Hib meningitis risk for unvaccinated North American children was found to occur 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 to 65 cases per 100,000 population per year for infants aged 18-23 years. After 23 months, a rapid decline in prevalence was observed.

Other studies have shown the risk for Hib meningitis to be 67 cases per 100,000 population per year in children aged 2-12 years and 18 cases per 100,000 population per year for children aged 1-5 years. Northern European studies have shown that the peak risk for Hib meningitis occurs in older children in their unvaccinated populations than in those of 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.

Infants younger than 6 months accounted, in prevaccination studies, 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.

In contrast to the age-related risk for Hib meningitis, the peak risk for Hib epiglottitis was generally found to occur in children between the third and fourth birthdays.

Hib meningitis is quite uncommon in children younger than 2 months, probably because of passive acquisition of maternal antibodies. Fothergill and Wright demonstrated this in 1933, and they demonstrated that this maternally conferred protection was largely dissipated by age 4 months. Rarely, infants are diagnosed with Hib meningitis in the first 2 months of life. Fothergill and Wright showed in 1933 that children younger than 2 months accounted for less than 0.004% of all cases. More recent studies have suggested that Hib may account for 0.3% of such 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.

Risk for Hib meningitis declines rapidly after the second birthday and becomes quite low after the fourth. Decline in risk appears to be due to the gradual acquisition of antibodies directed at capsular determinants of Hib and possibly to other aspects of maturation of the immune system. Exposure and colonization with Hib is the only possible cause of rise in specific antibody titers. Quite possibly, pertinent antibodies develop as the result of exposure to other genera of capsulated 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.

Although adults are subject to Hib sepsis or pneumonia, adults account for less than 5% of all Hib meningitis cases. 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, cerebrospinal fluid fistula, asplenia, agammaglobulinemia, neoplasms (eg, chronic lymphocytic leukemia, multiple myeloma, Hodgkin disease), and AIDS as well as by chemotherapy or radiotherapy. Cases of Hib meningitis have occurred in adults who have no clearly identified risk factors.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Some elements of the history are helpful in establishing the risk that a child presenting with possible meningitis has Hib meningitis. These risk factors are pertinent to children older than 2 months and younger than 5 years.
• • Presentation at some time between June and November is suggestive (in the temperate or sub-Arctic latitudes of the Northern hemisphere).
  • Presentation with meningitis in an unvaccinated population carries a risk for Hib meningitis diagnosis as high as 95%.
  • A child presenting with meningitis who has not been vaccinated 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.
  • Whether or not they have been vaccinated, the risk of Hib diagnosis is greater in children who present with possible meningitis and have a personal history of agammaglobulinemia, IgG2 subclass deficiency, cystic fibrosis or other form of chronic lung disease, CSF fistula, sickle cell disease or other causes of asplenism, malignancy, or a history of chemotherapy, radiation therapy, or other causes of suppression of the immune system.
  • 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. Sixty to 80% of children who develop Hib meningitis have had otitis media or an upper respiratory illness (presumed to be due to a virus) immediately prior to the development of Hib meningitis. Some children in this vulnerable age group develop Hib meningitis in the wake of a presumably viral gastrointestinal illness. A meningitic presentation in the wake of epiglottitis may be particularly suggestive of Hib etiology, although this presentation is uncommon.
• Hib meningitis if often preceded by an upper respiratory illness or otitis media. Initial manifestations of meningitis that follow in more than half of all cases include lethargy, fever, headache, photophobia, meningismus, irritability, anorexia, nausea, or vomiting.
• The report of any one or more of these features and the finding on physical examination of meningismus should provoke earnest consideration of a lumbar puncture.
• Lethargy is an early sign in at least half of all cases of bacterial meningitis as compared to approximately one third of all viral meningitis cases.
• 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.
• Increasing lethargy or the occurrence of convulsive seizures is the usual reason for parents to bring such children to medical attention. These cases should be carefully investigated for any evidence of meningismus.
• 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. In some instances the seizures due to Hib meningitis are initially mistakenly designated febrile seizures. Evidence for meningismus should carefully be sought. Lumbar punctures should be strongly considered in all infants aged 2-12 months with a history suggesting the possibility of Hib meningitis, especially if they appear ill or manifest focality with their seizures.
• Review of the histories of children younger than 16 months (ie, those at greatest risk for Hib meningitis) may pose particular diagnostic 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.
• Special care should be shown to infants that have not received Hib immunization or who are known to have a pertinent immunodeficiency. However, remember that Hib-immunized children may develop Haemophilus meningitis because of unrecognized immunodeficiency, vaccine failure, or because they are infected with an untypeable or other non-B Haemophilus strain.
• Most children younger than 18 months who present with a history of fever and seizures but who have normal findings on examination (including reliable exclusion of meningismus) do not have meningitis. One study showed that the risk for meningitis in such infants is approximately 1.2%. Of the 4 children in that study who did have meningitis, 3 had viral and 1 had Hib meningitis. Children older than 18 months who present with a history of fever and a seizure but who have normal examination findings are even less likely to have meningitis. Occasionally, children present with the report of fulminant deterioration in mental status, with or without seizures, sometimes after cardiopulmonary arrest.
• Fulminant presentations of Hib meningitis have tended to occur in older infants and in toddlers in the setting of Hib meningitis epidemics due to particularly virulent strains. 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.
• Meningitic presentations in individuals older than 5 years are less likely to be due to Hib than to other agents, although certain qualifying data must be considered.
• 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 these older children. The risk for Hib in these older children or adolescents is greatest in individuals who have abnormalities of immunoglobulin production or function, sickle cell disease or other causes of actual or functional splenectomy, nephrosis and other forms of chronic renal disease, cystic fibrosis and other forms of chronic pulmonary disease, history of malignancy requiring chemotherapy or radiotherapy (as well as other diseases requiring the use of immunosuppressive agents), and cranial defects associated with abnormal communications of the external environment with the subarachnoid space. It is unclear whether diabetes mellitus or alcoholism, which are factors that may predispose to Hib meningitis in adults, also predispose adolescents to Hib meningitis.
• Hib meningitis does occur in adults, albeit rarely. Historical features that favor diagnosis of Hib in an adult presenting with meningitis include a history of abnormal immunoglobulin production or function, actual or functional asplenism, nephrosis, diabetes mellitus, chronic alcoholism, or cerebrospinal fluid fistula.

Physical

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 greater than 38.5°C is found in at least 94% of individuals with meningitis. The temperature tends to be higher in bacterial than viral meningitis. Studies wherein most cases of childhood meningitis were due to Hib have shown that approximately 80% of children with meningitis have temperatures greater than 38.8°C on presentation as compared to 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. They tend to be rather severe at presentation, and the hypothermia portends a worse prognosis. In part, the poorer outcome may be due to enhanced bacterial replication at lower temperatures.
• 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.
• Anorexia or vomiting is noted in many children with meningitis and, in association with fever, may cause the 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 when no diarrhea is associated.
• Skin color may be abnormal and 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.
• Skin rashes are much more commonly associated with such differential considerations as N meningitidis meningitis, Rocky Mountain spotted fever, subacute bacterial endocarditis, or viral (eg, echovirus 9) meningoencephalitis. In these diseases, the rash is typically erythematous and macular or maculopapular at onset and may quickly progress to petechia and purpura. Note that rashes of this sort are occasionally observed in Hib encephalitis.
• Changes in mental status are found in most children with meningitis, and other neurologic deficits are found in at least 40% of patients at or shortly after presentation. Altered level of consciousness ranging from drowsiness to stupor or coma is common. Associated irritability is also quite common. The effect that this has on cry is noted above. 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 reaction to 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.
• Changes in mental status have been shown to be important indicators of enhanced risk for the diagnosis of serious infectious illnesses (ie, meningitis, sepsis, pneumonia, urinary tract infection) in children younger than 2 years of age. Special care must be taken to exclude meningitis in such cases because it is has the greatest potential to produce devastating consequences when it is not recognized and treated swiftly.
• 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 abnormal cry, 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 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. Meningismus may be absent in the earliest and mildest stages of illness. 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, especially in children younger than 8 months. Absence of meningismus at the onset of meningitis is reported in rare instances in children that 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.
• 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, Koenig and Brudzinski signs are found in approximately half.
• 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. 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 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 contralateral sign is found if a patient who has manifested an identical sign immediately follows it by a small kick due to sudden partial extension at the knee.
• 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, Kernig sign is present. Kernig and Brudzinski signs may be difficult to judge in irritable infants.
• Evidence for elevation of intracranial pressure 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 intracranial pressure 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, dilated and poorly reactive pupils may be found, 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. Cushing reflex may be detected, consisting of hypertension with bradycardia. Papilledema may be found.
• Unilateral pupillary dilatation, 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 elevation of intracranial pressure. 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.

Causes

Risk factors for Hib meningitis have been considered above.

• Definite factors include the following:
• • Age younger than 5 years
  • Compromised immune status
  • • Immunologic illnesses (eg, agammaglobulinemia, IgG2 subclass deficiency)
    • Illnesses or treatments that result in immunocompromise (eg, neoplasms, AIDS, malnutrition, chemotherapy, radiotherapy, other forms of immunosuppression)
  • Lack of Hib immunization with conjugate vaccines
  • Hib colonization at a vulnerable age
• Probable factors include the following:
• Male sex (during the first few years of life)
• Anatomic abnormalities predisposing to bacterial invasion of the CNS
• Certain chronic pulmonary or renal illnesses
• Viral illnesses occurring prior to onset of Hib meningitis in children who are colonized with Hib
• Possible factors include genetic factors, with greater risk in blacks than in whites and greater risk in American Indians than in blacks.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Brain abscess
Posterior fossa subdural or subdural empyema
Sepsis
Rocky Mountain spotted fever
Typhus
Cerebral malaria
Fungal meningitis
Carcinomatous meningitis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• White blood cell count is elevated in the majority of cases at presentation, with a left shift. As with Hib epiglottitis, counts in excess of 20,000/µL may be found.
• Hib may be grown from blood cultures in at least 50-80% of cases if no prior treatment with antibiotics has been undertaken. Accurately diagnosing the agent responsible for meningitis may be more complicated in developing countries by the widespread use of antibiotics before blood or CSF cultures can be obtained. This approach is more 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.
• Chemistry, and in particular sodium, 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. Proper diagnosis requires demonstration of serum sodium less than 135 mEq/L, serum osmolality less than 270 mOsm/L, urine osmolality greater than twice serum osmolality, urine sodium greater than 30 mEq/L, and no evidence of confounding hypovolemia or dehydration. In some instances, low sodium is due to cerebral salt wasting, rather than SIADH. Unlike SIADH, serum salt wasting is associated with decline in patient mass, rather than increase in mass. In other instances, hyponatremia is produced by the excessive intravenous administration of hyposmolar fluids.

Imaging Studies

• Brain imaging studies may be of importance in patients with Hib meningitis. They 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 such risks as may be associated with lumbar puncture. Hence, evidence for 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 upon. If lumbar puncture is deferred until after scanning, adequate intravenous 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 necessary and seizures have occurred or may continue to occur, full intravenous loading with an anticonvulsant should be considered. The authors regard phenobarbital as the treatment of choice in young children because its sedative properties may make other forms of sedation unnecessary. The wide therapeutic window of this agent permits multiple additional doses to be administered if seizures are resistant to treatment, and phenobarbital 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 intracranial pressure by reducing irritability and also 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 where the image findings or clinical circumstances and other testing do not disclose an alternative diagnosis.
• Either CT scanning 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 scanning is obtained because it is usually more readily available and requires less time. Patients must be monitored by qualified personnel during imaging because, during the scan interval, these patients may have or develop untreated seizures or critical elevation in intracranial pressure.
• 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) on CT scanning. Findings on CT scanning may be quite 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 manifesting ventricular debris, periventricular hyperintense signal, and periventricular ependymal enhancement (Nakayasu, 2005).
• Other important abnormalities that scans may detect tend to develop later in the course of illness and constitute complications of Hib meningitis. In many cases, these abnormalities are better defined by MRI than CT scanning. Special circumstances of the clinical or laboratory course may serve as indications for obtaining scans. Indications for obtaining such scans, whether CT or MRI, and the abnormalities that may be found in explanation of such findings in Hib meningitis include the following:
• • Persistence of fever after several days of appropriate intravenous antibiotic therapy have been provided (found in approximately 10% of all cases of Hib meningitis): Causes include nosocomial infection (eg, of the intravenous lines), subdural effusions (20-30% of cases), and comorbidity of pneumonia or arteritis (uncommon).
  • Return of fever after achievement of an afebrile state with appropriate intravenous antibiotic therapy (see discussion of prolonged fever above)
  • Evidence suggesting increased intracranial pressure (eg, bulging fontanelle, Cushing reflex, obtundation, meningismus, cranial nerve signs suggestive of herniation), hydrocephalus, large subdural effusion, or empyema
  • Focal neurologic deficits
  • Prolonged obtundation or coma
• On CT scanning performed because of these various indications, one or another of these various abnormalities is found in slightly more than 50% of all such scans. However, in most instances, these abnormalities do not require specific interventions and may not prove helpful in estimating prognosis. Discussions of the most common complications found on scans are discussed.
• Transependymal movement of CSF may be detected, especially in instances where noncommunicating hydrocephalus develops. Brain swelling may be found, and diffuse increased T2-weighted signal may be found, representing interstitial cerebral edema. This change may be diffuse. These various changes may indicate the need for management of increased intracranial pressure.
• Subdural effusions may develop in Hib meningitis. They are due to increased permeability of capillaries and veins of the inner dural surface. Only a small percentage of these are of clinical significance. They are usually sterile and seldom exert mass effect, although in a small number of cases they are infected and they may in rare cases produce mass effects. However, in general, they follow a self-limited course and become completely resorbed. Prolonged fever despite adequate antibiotic coverage may result from an effusion that has become secondarily infected. This is suggested by the presence of contrast enhancement. 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.
• Hydrocephalus, either communicating or obstructive, may occur in Hib meningitis. Such a process should be suspected with 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.
• Cerebral infarction as a consequence of meningitic vasculitis may be found. MRI is usually superior for the demonstration of these changes, 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.
• Abscess formation may be detected in scans obtained because of the development of focal deficits or seizure, although this complication is uncommon in Hib meningitis.

Other Tests

• Electroencephalography: Electroencephalography is sometimes indicated to evaluate for seizure activity. This includes patients with 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.
• Brainstem auditory evoked response
• • Hearing impairment is a common complication in Hib meningitis. If present, it is usually permanent. Hearing may be difficult to assess clinically, and all children should have brainstem auditory evoked response (BAER) testing at some point during hospitalization or in the early period of posthospitalization recovery. However, the timing of BAER testing is important, and this form of testing does not influence acute management.
  • 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.

Procedures

• Lumbar puncture is critical in the evaluation of patients with suspected meningitis and 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. Performing such a puncture avoids the diagnostic problems associated with partially treated meningitis in the event that the infant returns within the next few days with clinical worsening.
• 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.
• Care must be taken not to perform lumbar punctures in patients who are at risk for herniation or are manifesting signs of impending herniation. Although the scientific underpinnings of the allegations of 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 onset for herniation or impending herniation include focal brainstem signs, especially if present unilaterally (eg, dilation of 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 several hours of increase in intracranial pressure have passed, 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 afterwards is crucial so that scanning the brain does not delay initiation of treatment. The authors re-emphasize the fact 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 antibiotics have been administered immediately prior to CT scanning, 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 for raised intracranial pressure is not considered to represent a categorical contraindication to lumbar puncture, as long as no signs suggesting focal space-occupying lesions are found. If evidence exists for increased intracranial pressure, 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.
• 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% are viral, 20-26% are found to be bacterial, and the cause remains unclear or unknown in 5-10%.
• Opening pressure should be recorded. In bacterial meningitis, it is frequently elevated and may have an impact on treatment. In small calm infants, pressures should be less than 160 mm H₂0. Older infants and children should have pressures less than 180 mm H₂0. Normal pressures of some obese individuals are as high as 250 mm H₂0. Pressure should only be recorded in individuals who are in the lateral recumbent position, while they are as relaxed and calm as possible. In fulminant cases of Hib meningitis, pressures as high as 300 mm H₂0 to more than 500 mm H₂0 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. However, in bacterial meningitis, the presence of more than 200/mL white cells or more than 400/mL red cells or more than 100 mg/dL protein or more 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 greater than 150 mg/dL cause the fluid to appear xanthochromic.
• CSF Gram stain 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 intravenous pretreatment with antibiotics may disable the identification of organisms by Gram stain. Indeed, the presence of organisms on Gram stain 24 hours after intravenous treatment has been initiated may be an important indicator of treatment failure.
• CSF should be examined promptly for white cells because they tend to begin to disintegrate within about 90 minutes of the lumbar puncture. Greater than 10 WBC is usually considered abnormal, while the presence of even one polymorphonuclear (PMN) leukocyte is considered abnormal. WBC differential counts from cytocentrifuged CSF may falsely elevate the PMN leukocytes. The occurrence of a preceding convulsive seizure may elevate the white 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 with 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 most cases of the fully developed CSF pleocytosis of viral meningitis manifest lymphocytic predominance, 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 are found to have early lymphocytic predominance, especially in cases where the CSF WBC count is less 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 one week after initiation, and in some cases, an elevated count 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 at the time of the lumbar puncture. The CSF-to-serum glucose ratios ought to be approximately 2:3 (ie, 0.6).
• CSF glucose within the reference range in the presence of elevated serum glucose may not actually be normal because the CSF value must be interpreted with respect to serum glucose concentration. Serum glucose values are often low or high in cases of acute bacterial meningitis. A CSF-to-serum glucose ratio of less then 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 intravenous antibiotic treatment for bacterial meningitis, CSF glucose concentration returns to the reference range by the third day of that treatment. However, even with appropriate treatment some patients continue to exhibit low CSF glucose for 7-10 days after the initiation of appropriate intravenous antibiotic treatment.
• As happens with any process that disturbs the BBB function, 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. In the event that ventricular CSF is available for analysis, note that abnormal values are those greater than 15 mg/dL. In the event of a traumatic tap, protein values may be grossly estimated by the subtraction of 1 mg/dL of protein for every 1000 RBC/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. 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, elevation of CSF lactate may be due to other potential alternative diagnoses such as 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 interval after effective antimicrobial therapy has resulted in amelioration of brain edema and restoration of intracranial pressure to the reference range.
• Repeated lactate estimation (lumbar CSF analysis or 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 intracranial pressure and pressure-passive nature of dysregulation of cerebral circulation in meningitis.
• Culture of the CSF yields the most specific information. However, CSF cultures are positive within 48 hours in approximately 75-80% of cases with sensitivity of 95% and specificity of 99%.
• 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 it prevents most physicians from any subsequent course other than completing the usual course of therapy for meningitis.
• The best method of confirming that Hib in culture is the cause of meningitis is to have found the organism on Gram stain of the initial CSF. This result is the other most sensitive method of confirming the diagnosis of meningitis in any given case where the diagnosis is considered. Although other tests, such as cell counts and CSF chemistries, are critical for the initial management, the results may (unless very abnormal) be less sensitive or specific than positive cultures and Gram stains. Evidence suggests that CSF glucose less than 34 mg/dL, a ratio of CSF to blood glucose of less than 0.23, CSF leukocyte counts greater than 2000/µL, or CSF neutrophil counts of greater than 1180/µL predict bacterial meningitis in cases with a clinically consistent picture with 99% certainty.
• Moreover, in cases where individuals have been treated with antibiotics within the week prior to the lumbar puncture, the less-irrefutable approaches to meningitis diagnosis by CSF cell counts and chemistries must nonetheless be relied upon for decisions concerning initiation of and persistence in therapy. Two careful prospective studies of the effect of pretreatment have been published and indicate that as many as one third of children with Hib meningitis receive such treatment, usually for suspected otitis media.
• Pretreatment with oral antibiotics may significantly reduce not only the yield of CSF culture and Gram stain, but also CSF protein concentration and neutrophil percentage. On the other hand, pretreatment was not shown to significantly decrease the yield of blood culture, total CSF white cell count, CSF glucose concentration, CSF-to-serum glucose ratio, or positivity of CSF counterimmunoelectrophoresis or latex agglutination studies for bacterial antigens. Attenuation of the significance of some of these indicators of bacterial meningitis was thought to be due to the fact that oral antibiotics had attenuated the severity of illness, although they had not prevented the development of meningitis. This concept is supported by the fact that pretreated children tended to present for lumbar puncture several days later than untreated children after an initial premonitory meningitic phase with otitis media or upper respiratory illness such as commonly precedes Hib meningitis.
• Studies of the effects of intravenous antibiotic administration on CSF characteristics of children who do have meningitis have shown that as many as several days of intravenous treatment with appropriate antibiotics does not significantly alter CSF protein, glucose, or white blood cell concentrations, although the yield of Gram stain and culture is lost.
• No results of CSF cell counts or chemistries can be employed to irrefutably rule out a meningitis diagnosis where the clinical indications of possible meningitis are present. This is particularly true because of the possibility of viral meningitis in such cases.
• A positive CSF culture provides the additional benefit of permitting the establishment of antimicrobial sensitivity in subcultures of recovered organisms, permitting the adjustment of treatment to these findings. However, several additional days after recovery of the organism may be necessary for such results to be available.
• 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 forms of meningitis. The latex particle agglutination antigen tests for Hib have sensitivity of 97% and specificity of 95%.
• Polymerase chain reaction (PCR) is an emerging technique that may ultimately be useful in identifying the organism in patients 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.
• Some children have been pretreated with oral antibiotics prior to presentation. Treatment may impact the results of CSF analysis. CSF Gram stain and cultures are the most sensitive to pretreatment with antibiotics and may be rendered negative within 24 hours of treatment. However, bacterial antigens and PCR are not affected and therefore remain effective in identifying the organism, although not its antimicrobial sensitivities. CSF protein, glucose, and WBC counts are not significantly influenced by pretreatment.
• 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.

Histologic Findings

No specific findings are noted on histologic studies of any tissues other than brain.

Staging

No system of staging exists.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

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. Initial and subsequent antimicrobial management of Hib meningitis is considered in Medication.

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. Ampicillin and gentamicin remain the agents of 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.

Given the considerable decline of prevalence of Hib meningitis in vaccinated children younger than 6 years, the percentage of cases of S pneumoniae in that age group has increased. Furthermore, because S pneumoniae resistance 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.

Until recently, ampicillin and chloramphenicol were recommended for the treatment of Hib meningitis. However, resistance has emerged to both antibiotics. 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 prevalenc