Clinical manifestations

Presentation and course

Meningitis is the most serious form of Haemophilus influenzae type b (Hib) disease. A history of an upper respiratory tract infection preceding the onset of meningitis frequently can be obtained. Meningitis symptoms typically include fever, headache, nausea, vomiting, irritability, and lethargy, proceeding to further clouding of consciousness and, ultimately, death. Neonates with meningitis often show nonspecific signs and symptoms, such as poor feeding, irritability, hypertonia or hypotonia, and respiratory distress. (98; 99). Clinical signs include evidence of meningeal irritation, though this can be lacking in neonates, the elderly, and the deeply comatose. Focal signs may also appear, probably reflecting a complicating vasculitis. The course is frequently fulminant, with rapid neurologic deterioration leading to respiratory arrest and death (44). Therefore, initiation of appropriate antibiotic treatment must not be delayed. From an initial respiratory infection, the bacteria typically spread to the meninges hematogenously; therefore, it is no surprise that vasogenic shock frequently occurs (63). For similar reasons, Hib meningitis is frequently associated with other blood disorders, including coagulopathy, purpura, and anemia (83).

Non-type b H influenzae can also cause meningitis and manifests similarly to Hib meningitis. Widespread vaccination programs in the early 1990s shifted the paradigm with decreased incidence of Hib and increases in non-type H. influenzae. One study in Brazil found 98% of H. influenzae meningitis cases were type b from 1990 to 1999 versus 59% from 2000 to 2008, whereas non-b serotypes increased from 1% to 19% and non-typeable H. influenzae increased from 2% to 22% (34; 64; 17; 112). The mortality of these strains can be quite significant; for example, type f showed a mortality of 20% in children and 30% in adults in the United States (96), and type a showed mortality of 17% in children in Brazil (77).

Unencapsulated, nontypeable strains of H. influenzae can also cause meningitis. However, these strains usually spread by direct extension from a focus of infection rather than hematogenously (79). Thus, most patients who develop nontypeable H. influenzae (NTHi) meningitis have a preceding NTHi sinusitis or otitis media. Patients can also develop NTHi meningitis after head trauma, after a neurosurgical procedure, or if they have another cause of a cerebrospinal fluid leak. In fact, because of the association with the presence of a CSF leak, NTHi is a relatively common cause of recurrent bacterial meningitis (102; 82). Though the CSF leak can be difficult to diagnose and repair, the possibility should be carefully evaluated in any case of NTHi meningitis because repair can prevent recurrence (08; 82).

Due to its life-threatening nature, meningitis is usually the predominant clinical concern when it develops in patients with H. influenzae infection. However, the presence of meningitis does not exclude the presence of the other complications of this infection as well. As a respiratory pathogen, the most typical coexisting complications will be seen to affect the upper or lower airways. Epiglottitis is seen most often in children, involves edema of the upper airway, and can be life-threatening because acute airway obstruction can occur. It usually occurs before the development of meningitis and may be the manifestation that brings the patient to the hospital. Symptoms are often sudden in onset and include high fever, pharyngitis, stridor, cough, and dyspnea. As the throat closes, the child cannot swallow, secretions pool, and drooling occurs. Some warning symptoms may be lacking, and throat closure can be rapid. Rapid recognition of epiglottitis is important because death can occur within hours unless an airway is established (79).

Concomitant pneumonia is frequent in patients with Hib meningitis. Hib pneumonia typically has an insidious onset compared to many other bacterial pneumonias and may become clinically important before or after the onset of meningitis. On chest x-ray, the infiltrate usually appears lobar, and an associated pleural effusion often occurs. The presence of a lung focus was an independent poor prognostic factor in a Danish study (72). Unfortunately, the infection can spread directly to the pericardium, causing a purulent pericarditis (35). This complication may initially manifest as severely worsening dyspnea and tachycardia and can eventually lead to cardiac failure. However, with proper monitoring and treatment, the outcome in patients with Hib pneumonia can be good (79).

Other complications of H. influenzae infection include pyogenic arthritis and osteomyelitis, especially in children under 2 years old and usually in a single large joint (33). Sometimes arthritis can develop after a week or more of treatment for H. influenzae meningitis. These latter cases are frequently culture negative, generally considered a reactive inflammation, and attributed to immune complex deposition in the joint (76).

There is no typical rash associated with H. influenzae infection that can help in making the diagnosis, as there is for other bacterial meningitides. However, in young children who become bacteremic with H. influenzae, warm, tender cellulitis can develop, usually affecting the face. The facial location and violaceous color of this cellulitis can suggest the diagnosis (79). Because this cellulitis develops in the setting of bacteremia, patients with cellulitis are at increased risk for the bacteria to seed in yet another location, such as the meninges. Meningitis develops in up to 10% of children with H. influenzae cellulitis (36; 07; 22).

Other manifestations of H. influenzae infection include otitis media, conjunctivitis, sinusitis, urinary tract infection, and peritonitis. There have been cases of venous sinus thrombosis as a complication of meningitis (38) as well as sphenoid sinusitis related to H. influenzae (70). A strain of NTHi has been linked to a case of Fisher syndrome via molecular mimicry (42).

Prognosis and complications

Complications during acute illness are similar to those seen with meningitides of any etiology and include subdural effusion, empyema, ischemic or hemorrhagic stroke, cerebritis, ventriculitis, abscess, and hydrocephalus (79).

Biological basis

Etiology and pathogenesis

Haemophilus influenzae is a small (0.3 to 1.0 µm), gram-negative coccobacillus, sometimes appearing in short chains. It can grow under both aerobic and anaerobic conditions, is nonmotile, and often is difficult to visualize in clinical specimens.

Six distinct serotypes of H. influenzae have been identified based on the structure and antigenicity of their polysaccharide capsules. These are designated types a through f. A two-step, real-time, PCR-based assay that can differentiate all six capsulation loci in clinical specimens with high sensitivity and specificity has been developed (55). Moreover, a newer triplex direct real-time PCR detecting all six serotypes of H. influenzae in two reactions with high sensitivity and specificity has been described (57). Additionally, nonencapsulated serotypes are identified based on failure to react with antisera against capsules; these are termed “nontypeable” H. influenzae. Nontypeable strains are classified into biotypes (109). A PCR-based assay for identifying nontypeable H. influenzae has also been developed (10).

Typical, community-acquired H. influenzae meningitis is usually caused by type b, with an incidence of 4% in adults, whereas meningitis developing as a result of risk factors such as sinusitis or head trauma or remote neurosurgery is usually caused by NTHi (14; 23). Before vaccination availability, about 20,000 young children developed meningitis from Hib; now, fewer than 50 cases of Hib disease occur, most commonly in those who did not get any or all recommended doses of Hib vaccine (18; 19).

Encapsulated H. influenzae is transmitted by the respiratory route. Many individuals, particularly school-aged children, are asymptomatically colonized (86; 66). The development of symptomatic infection has largely been attributed to host factors. These include smoking or alcohol abuse, coinfection with a viral respiratory pathogen, and probable genetic susceptibilities related to local respiratory immune function and anatomy (78; 98; 99).

Various bacterial factors have also been identified that assist in pathogenicity. The bacterium has factors that promote adherence to respiratory mucous and epithelial cells (107; 80; 74; 51). Interestingly, a study suggested that viral coinfection can increase the expression of receptors for bacteria on respiratory epithelial cells, including non-typeable H. influenzae, thus promoting bacterial adhesion, colonization, and possibly subsequent disease (06). Encapsulated H. influenzae uses proteins such as protein H and Haemophilus surface fibrils (Hsf) (48). H. influenzae also has several mechanisms to evade the respiratory tract’s immune response, including the production of IgA protease, antigenic variation, and microcolony formation (49; 31; 30; 41; 62). Several components of the bacteria’s capsule interfere with mucociliary clearance from the lung. These include the lipo-oligosaccharide lipid A, peptidoglycan, and a glycerophosphodiesterase called protein D (46; 47; 45).

Transient bacteremia is common in nearly all invasive Hib and NTHi infections and is related to the bacteria’s ability to adhere to and enter the epithelial cells and penetrate the epithelial tight junctions of the nasopharynx and respiratory tract (81; 108; 87; 103; 104; 105; 16). Hib (and probably other encapsulated types) is more likely than NTHi to persist in the blood and seed distant sites such as the meninges. Survival in the bloodstream is facilitated by an anti-phagocytic polysaccharide capsule that acts as an inert shield, inhibiting surface deposition of opsonins such as complement factors and promoting evasion of immune recognition (79; 98; 99). In in vitro and animal models, strains of Haemophilus associated with invasiveness and meningitis interact with toll-like receptors, particularly -2 and -4, to trigger an inflammatory response (60) and a shift from Th1 to Th2 cytokines (24). Interestingly, two pediatric cases of severe central nervous system infection with H. influenzae type a occurred in the same week by capsule switching by horizontal gene transfer, suggesting another mechanism of vaccine evasion (92).

Epidemiology

Hib conjugate vaccines have reduced the incidence of invasive Hib disease in children younger than 5 years by 99% in the United States. Although invasive Hib disease occurs primarily in unimmunized children and among infants too young to have completed the primary immunization series in the United States, Hib remains an important pathogen in many resource-limited regions where Hib vaccine coverage is less optimal (50).

Before development of the Hib vaccine, Hib was found colonizing the nasopharynx of 3% to 5% of children and a smaller percentage of adults (52). Hib was the leading cause of bacterial meningitis in children under 5 years of age and accounted for 20,000 cases per year in the United States (18; 19). Both colonization and meningitis due to this organism have now been nearly eradicated in infants and children who are routinely vaccinated (11; 75). Nontypeable strains, on the other hand, continue to colonize 10% to 60% of both children and adults (20; 40), frequently causing otitis media and rarely causing severe disease.

Before the vaccine, Hib was the most common cause of bacterial meningitis in young children, and approximately 1 in 200 children in the United States developed bacteremia with this organism, along with its associated complications, including meningitis, by the age of 5 years. Peak incidence was 6 to 18 months of age (79; 50). Again, these complications have largely been eradicated in vaccinated populations (43). With the vaccination of children, the epidemiology of H. influenzae has shifted toward an adult age distribution and also toward women, perhaps as unvaccinated primary caregivers for children (32). The higher incidence of invasive Hib infection in adults in the United States and Canada is particularly evident in those 65 years and older. Vaccination guidelines may require reconsideration to include age groups of 65 years and older (02; 28).

Ethnic groups at increased risk include non-Hispanic Black, American Indian or Alaska Native (AI/AN), and Hispanic adults (12). Even with good vaccine coverage, Native Alaskans have higher rates of H. influenzae disease than non-Native Alaskans and other U.S. children, probably due to other environmental and household factors contributing to transmission (85). Additionally, serotype replacement with non-type b strains has resulted in a re-emergence of invasive disease in these children (15). Other risk factors include childcare center attendance and overcrowded living conditions (68; 39). Of course, the greatest risk factor is inadequate vaccination.

Although vaccine coverage in the United States in 2019 was estimated to be 92% per the World Health Organization, global coverage is estimated to be 72%; six nations failed to achieve greater than 60% coverage: Venezuela, Ukraine, Nigeria, Papua New Guinea, South Sudan, and Samoa. It is also still important to consider the possibility of Hib-associated meningitis in patients from low- and middle-income countries. In fact, worldwide cases of severe Hib disease in children younger than 5 years of age have been estimated to have declined from more than 8 million to 340,000, with estimated Hib-related deaths in the same age group also noted to decline from 371,000 to less than 30,000 (106).

Another important population at risk includes those with medical conditions that produce immunocompromise, especially compromise of the ability to clear encapsulated organisms. Such conditions would include asplenia (anatomic or functional), sickle cell disease, HIV infection or IgG2 subclass deficiency, chemotherapy, and bone marrow transplantation (79). Unfortunately, the Hib vaccination may not be as effective in some of these conditions, such as in persons living with HIV (56). Vaccination of bone marrow donors prior to transplant may improve antibody concentrations in recipients after transplant (69).

There is a rise in the prevalence of multidrug-resistant H. influenzae in Asian countries (24.6%) compared to Western regions (15.7%), especially cases of meningitis (01).

Prevention

The increasing resistance of Hib to antibiotic agents has been reported from many parts of the world, and vaccination is the only public health tool that can rapidly reduce the incidence of Hib disease globally (World Health Organization 2023).

There are at least five (three single antigen or monovalent, and two combination) highly effective vaccines to prevent infection with Haemophilus influenzae type b. These vaccines conjugate the capsular antigen of type b, polyribosylribitol phosphate, to an immunogenic adjuvant. The available vaccines essentially differ in the choice of adjuvant and type of linkage between adjuvant and capsular antigen. As a result, they have slightly differing immunogenicities, and it is important to read the prescribing information for each vaccine to ensure it is administered appropriately. For example, some vaccines require a series of four injections, and some require three. All of the vaccines are well tolerated, highly effective, and can be administered simultaneously as other vaccines (50).

The Hib vaccine is one of the greatest success stories in the field of neurology and, indeed, all of medicine. Since it was first introduced in 1987, 192 countries worldwide now routinely use Hib conjugate vaccines in childhood vaccination programs. Some developing countries with high meningitis rates (for example, Chile, Uruguay, and the Gambia) have shown promising results with trials introducing Hib vaccination. This has had a significant beneficial effect on the global disease burden of bacterial meningitis (99).

There are no available vaccines that offer protection against NTHi. Although an investigational NTHi vaccine was tested in a phase 2, observer-blind, controlled trial in adults with chronic obstructive pulmonary disease with acceptable safety, reactogenicity profile, and good immunogenicity (110), a multicentre, randomized, placebo-controlled phase 2b trial did not show efficacy in reducing the yearly rate of moderate to severe exacerbation of chronic obstructive pulmonary disease (04).

A bacterial polysaccharide immunoglobulin (BPIg) preparation was tested for passive immunization. It was prepared from the plasma of adult donors immunized with Hib, meningococcal, and pneumococcal polysaccharide vaccines. Due to the need for frequent, large-volume injections and the subsequent availability of effective conjugate vaccines for infants, BPIg was not licensed for use in the United States (21).

When a case of Hib is discovered in a household with one or more children under 12 months of age, with children under 4 years who have not been adequately vaccinated, or with immunocompromised children, everyone in the household should receive prophylaxis with rifampin (20 mg/kg orally, maximum dose 600 mg) once daily for four days in individuals older than 1 month). This effectively prevents the spread of disease and decreases the incidence of severe disease, including meningitis. Similar guidelines are suggested for all children and personnel at a childcare center that has experienced two cases within a 60-day period. Prophylaxis after a single case at a childcare center is controversial (50).

Differential diagnosis

The history and examination data obtained from any given case of acute bacterial meningitis can be variable. This is especially true for young children, the most common patient population to get H. influenzae meningitis. Invariably, some of the typical findings are present, whereas others are absent. Additionally, the signs and symptoms frequently seen with acute bacterial meningitis, including fever, behavioral or personality changes, and mental status changes, can be nonspecific and suggest other diagnoses, including systemic infection or sepsis, viral encephalitis or meningitis, fungal or tuberculous meningitis, trauma or closed head injury or child abuse, multiple metabolic abnormalities (hypoglycemia, ketoacidosis, electrolyte imbalance, uremia, toxic exposure), seizure, and brain tumor. Even meningismus, which is often not present in children, does not exclude alternative diagnoses such as subarachnoid hemorrhage, intracranial hemorrhage, and epidural abscess. To prevent morbidity and mortality from missed diagnoses, it is important to keep a high index of suspicion for acute bacterial meningitis and err on the side of starting treatment early.

Before widespread use of the Hib vaccine, H. influenzae type b was the leading cause of acute bacterial meningitis in children under the age of 5 years (25). It is still prevalent in developing countries but is largely eradicated in the United States (11; 75). Streptococcus pneumoniae and Neisseria meningitidis are now the most common etiological agents in children after the neonatal period. In children under 1 year of age, group B streptococci and gram-negative enteric bacilli, particularly Escherichia coli, are the leading etiologic agents, presumably because of exposure to these agents during birth. Due to the passive transfer of maternal antibodies, these neonates did not typically develop H. influenzae, streptococcal meningitis, or meningococcal meningitis, even prior to the use of the vaccine (88).

In the setting of a preceding sinusitis, otitis media, head trauma, neurosurgical procedure, or cerebrospinal fluid leak, S. pneumoniae and NTHi are both common etiologic agents of recurrent meningitis (102; 82), as both are a common part of “normal” skin and nasopharyngeal colonization. There is good evidence that surgical repair of CSF leaks of various origins effectively prevents recurrent bacterial meningitis (08; 82).

In patients over 65 years of age, the most common causes of bacterial meningitis include Streptococcus pneumoniae, Neisseria Meningitidis, and Listeria monocytogenes (100; 101; 98; 99). S. aureus is common in neurosurgical patients (94).

Diagnostic workup

Bacterial meningitis, including that caused by H. influenzae, should be considered and promptly treated in any patient with a compatible presentation–keeping in mind that the presentation may be atypical in some patients, especially young children. CSF examination showing a predominantly neutrophilic pleocytosis is strongly suggestive of bacterial meningitis and should prompt broad coverage treatment; though, in the proper clinical setting, treatment should not be delayed even to obtain CSF. Brain imaging (CT scan) should also be considered before CSF examination because many of these organisms, including H. influenzae, can cause enough brain edema to make a lumbar puncture hazardous. Other contraindications to immediate lumbar puncture include coagulation disorders, septic shock, and respiratory failure. No tests are available to confirm H. influenzae as the causative organism are rapid enough to base initial treatment on. Therefore, the primary value of these tests is to confirm the correct initial clinical diagnosis (99).

With H. influenzae meningitis, both blood and CSF cultures will usually be positive. However, treatment should be initiated without delay, even prior to obtaining culture samples. Gram stain of the CSF will be positive for gram-negative coccobacilli in approximately 70% of cases (79). Antigen testing, such as latex agglutination, has become less favorable due to false-positive results, low sensitivity, and lower likelihood of helping with decision-making for treatment (93).

The US Food and Drug Administration approved the multiplex nucleic acid amplification test (NAAT) (meningitis/encephalitis [ME] panel from BioFire Diagnostics), which detects most common causes of community-acquired bacterial meningitis, such as N. meningitidis, H. influenzae, and S. pneumoniae, with a sensitivity of 65% to 75% for H. influenzae meningitis (95; 54). It has the advantage of being useful in patients who have already received antibiotic treatment. However, its limitations include false-negative and false-positive results. Therefore, cultures, as well as H. influenzae-specific quantitative PCR(qPCR), are highly recommended whenever multiplex NAATs are used (111). A two-step, real-time PCR-based assay that can differentiate all six capsulation loci in clinical specimens with high sensitivity and specificity has been developed (55), as has a PCR-based assay for identifying nontypeable Haemophilus influenzae (10); however, these assays are not commercially available, so culture is required to determine serotype and antimicrobial susceptibility.

Metagenomic next-generation sequencing (mNGS) is a rapidly evolving molecular technology that can provide accurate analysis of H. influenzae genomes and their genotype/serotypes rapidly without reliance on targeted molecular tests or traditional culture (61; 29). mNGS results should be confirmed by another method. No molecular method is able to provide antibiotic sensitivity profiles, which can only be provided by bacterial culture.

Management

When bacterial meningitis is suspected, emergent antibiotic treatment must be initiated, without waiting for speciation to be made. Due to the widespread use of the H. influenzae vaccine, H. influenzae is no longer considered a common etiology for community-acquired meningitis, even in children (25; 11; 75). Treatment is, therefore, directed primarily against S. pneumoniae and N. Meningitidis. Recommendations for treatment of community-acquired meningitis for ages 1 months to 18 years is vancomycin 60 mg/kg/day intravenously (maximum dose 4 g/day) in four divided doses plus ceftriaxone 100 mg/kg/day intravenously (maximum dose 4 g/day) in two divided doses, or cefotaxime 300 mg/kg/day intravenously (maximum dose 12 g/day) in three to four divided doses (50). Recommendations for adults include ceftriaxone 2 g intravenously every 12 hours or cefotaxime 2 g intravenously every 4 to 6 hours plus vancomycin 15 to 20 mg/kg intravenously every 8 to 12 hours (not to exceed 2 g per dose; achieve vancomycin serum trough concentration 15 to 20 mcg/mL) (99). The recommended treatment for patients with a penicillin or cephalosporin allergy includes carbapenems and fluroquinolones (50). In adults older than 50 years, add ampicillin 2 g intravenously every 4 hours in addition to the above regimen (99).

After speciation of H. influenzae, the cephalosporin, either cefotaxime or ceftriaxone, is continued. Both have potent activity against H. influenzae, and both penetrate the CSF well (37; 05; 67). The total duration of treatment is 7 to 10 days (88). Alternative antibiotics for beta-lactamase-positive pathogens include cefepime or meropenem (88). Ampicillin is used only if the infecting pathogen is beta-lactamase negative (67).

Dexamethasone 0.15 mg/kg every 6 hours given at the same with antibiotics or up to 4 hours after starting treatment with antibiotics for the first 4 days of therapy may also be beneficial for the initial treatment of community-acquired bacterial meningitis. Studies show a decrease in the risk of mortality, severe hearing loss, and neurologic sequelae in adults and children with community-acquired bacterial meningitis treated with dexamethasone (53; 65; 89; 97).

It is imperative that appropriate supportive care be instituted in addition to medication therapies. Advancements in intensive care techniques offer significant benefits for patients with bacterial meningitis, including H. influenzae meningitis.

Outcomes

The prognosis of H. influenzae meningitis, as with most bacterial meningitis, relates directly to early diagnosis and initiation of appropriate antibiotic therapy. With appropriate therapy instituted early, mortality is 5% or less. Unfavorable outcomes (Glasgow Outcome Scale score lower than 5 at discharge) are reduced over the years to less than 20% (23). Acute neurologic complications are also associated with later behavioral and developmental difficulties (91; 90), hearing loss, and seizures (58; 27). H. influenzae meningitis was once the leading cause of acquired intellectual disability in the United States, with about a third of patients going on to have intellectual disability (13). Intellectual disability due to Hib has now been almost completely eliminated due to the vaccination. Hearing loss remains the most common sequelae in adults (10% to 25%) and children (16%) (14; 72).

Special considerations

Pregnancy

Haemophilus influenzae is no longer considered a common maternal pathogen after introduction of the Hib vaccination program in many regions of the world. However, pregnancy is associated with 6- to 25-fold increased risk of invasive H. influenzae diseases (71; 09). A retrospective observational study in Israel found NTHi was the predominant cause in pregnant women suffering from H. influenzae infection (113). Maternal infections were associated with maternal and neonatal adverse outcomes, such as invasive neonatal H. influenzae disease within 24 hours of birth, longer length of hospitalization, lower birth weight, and a higher rate of early neonatal sepsis (26; 113; 48). Little is known about the neurologic complications of H. influenzae infection in pregnancy, but they are presumably similar to the complications seen in nonpregnant individuals. Treatment is also similar; the cephalosporins are felt to be safe in pregnancy.

Vaccination of pregnant women against the polyribophosphate capsular antigen of Haemophilus influenzae type b at 34 to 36 weeks gestation leads to a large boost in their antibody levels against this antigen. This boost is transferred to their newborn infants, such that newborn serum antipolyribophosphate capsular antigen level at birth is 100-fold greater than that of control newborn infants. Furthermore, this antibody persists at a protective level for 12 months, whereas control newborn infants lose significant antibodies by 3 months (03).

Postpartum infections, such as endometritis, tubo-ovarian abscess, chronic salpingitis, and sepsis, have been linked to NTHi (48).

Anesthesia

H. influenzae accounted for 19% of cases of postoperative pneumonia in a case series of 837 patients (59). Pneumonia in trauma patients in intensive care was significantly more likely due to H. influenzae (54%) (84).