Haemophilus influenzae meningitis …

Pooja Raibagkar MD

Infectious Disorders

Updated 05.29.2025
Released 02.28.2005
Expires For CME 05.29.2028

Haemophilus influenzae meningitis

Author: Pooja Raibagkar MD

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Editor: Christina M Marra MD

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Haemophilus influenzae meningitis

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Introduction

Overview

Haemophilus influenzae is a significant public health concern in many parts of the world, with up to 3 million cases of severe disease every year worldwide. H influenzae type b (Hib) is a leading cause of meningitis and epiglottitis in children and pneumonia in adults in vaccine-deprived areas of the globe. In this article, the author reviews key features of the epidemiology, pathophysiology, and clinical manifestations, with a focus on making timely diagnoses and preventing mortality and morbidity. Newer methods for identification and typing of the organism are discussed. With the increase in antibiotic-resistant Hib, vaccination is the most powerful public health measure to reduce incidence globally. The most current vaccination guidelines and treatment recommendations are discussed in detail.

Historical note and terminology

Haemophilus influenzae was first isolated by Pfeiffer during the 1889 influenza pandemic (59), and it was believed to be the causative agent of influenza. It was called the “influenza bacillus.” Eventually, the error of this diagnostic association was recognized. The organism was given the genus name Haemophilus, meaning “blood-loving,” and the species name influenzae in recognition of the historical association.

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 is common. Meningitis symptoms typically include fever, meningismus, headache, nausea, vomiting, irritability, and lethargy, proceeding to further clouding of consciousness and, in the absence of treatment, death. Neonates with meningitis often have nonspecific signs and symptoms, such as poor feeding, irritability, hypertonia or hypotonia, and respiratory distress. (82; 83). Meningismus may be absent in neonates, the elderly, and the deeply comatose. Focal signs may also appear, probably reflecting a complicating vasculitis. The course is frequently fulminant (35). 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 (52). For similar reasons, Hib meningitis is frequently associated with other blood disorders, including coagulopathy, purpura, and anemia (69).

As with Hib, non-type b H influenzae can also cause meningitis. Widespread vaccination programs in the early 1990s led to a decrease in incidence of Hib infection and increase in incidence of non-type b H influenzae infection. The mortality of these strains is high. For example, type a showed a mortality of 8% in the United States, highest among adults 65 years of age and older (72). In Brazil, type a showed a mortality of 17% in children (64). Type f showed mortality of 15% globally (61).

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 (65). 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. Because of its association with a CSF leak, NTHi is a relatively common cause of recurrent bacterial meningitis (86; 68).

The presence of meningitis does not exclude the presence of the other complications of H influenzae infection. As a respiratory pathogen, the most typical coexisting complications 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. 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 (65).

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, often with associated pleural effusion. The presence of a lung focus was an independent poor prognostic factor in a Danish study (58). Unfortunately, the infection can spread directly to the pericardium, causing a purulent pericarditis (27). This complication may initially manifest as severely worsening dyspnea and tachycardia and can eventually lead to cardiac failure.

Other complications of H influenzae infection include pyogenic arthritis, usually in a single large joint, and osteomyelitis, especially in children under 2 years old (26). Arthritis that develops after a week or more of treatment for H influenzae meningitis is frequently culture negative and is attributed to immune complex deposition in the joint (63).

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 (65). Because this cellulitis develops in the setting of bacteremia, these patients are at risk for meningitis, which may develop in up to 10% (28; 06; 17).

Other manifestations of H influenzae infection include otitis media, conjunctivitis, sinusitis, urinary tract infection, and peritonitis.

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, hydrocephalus (65), and venous sinus thrombosis (30).

Biological basis

Etiology and pathogenesis

H 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. PCR-based tests can detect all six serotypes of H influenzae (46). Nonencapsulated serotypes can be identified serologically; these are termed “nontypeable” H influenzae. Nontypeable strains are classified into biotypes (93). A PCR-based assay for inontypeable H influenzae has also been developed (09).

Encapsulated H influenzae is transmitted by the respiratory route. Many individuals, particularly school-aged children, are asymptomatically colonized (73; 54). The development of symptomatic infection is 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 (82; 83).

Viral coinfection can increase the expression of receptors for bacteria on respiratory epithelial cells in all H influenzae, including NTHi, thus, promoting bacterial adhesion, colonization, and possibly subsequent disease (05; 43). Encapsulated H influenzae uses proteins, such as protein H and Haemophilus surface fibrils (Hsf), to attach to respiratory epithelium (39). 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 (40; 24; 23; 33; 51). Several components of the bacterial capsule interfere with mucociliary clearance from the lung. These include the lipo-oligosaccharide lipid A, peptidoglycan, and a glycerophosphodiesterase called protein D (37; 38; 36).

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 to penetrate the epithelial tight junctions of the nasopharynx and respiratory tract (67; 92; 74; 87; 88; 89; 13). Hib (and probably other encapsulated types) is more likely than NTHi to persist in the blood and seed distant sites. Survival in the bloodstream is facilitated by an anti-phagocytic polysaccharide capsule that inhibits surface deposition of opsonins, such as complement factors, and promotes evasion of immune recognition (65; 82; 83). 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 (49) and a shift from Th1 to Th2 immune response (19).

Epidemiology

	• Vaccination with Hib conjugate vaccine leads to decreases in oropharyngeal colonization among both vaccinated and unvaccinated children.
	• Most of the Hib disease in the United States occurs among unimmunized and under-immunized infants and children.

Hib conjugate vaccines have reduced the incidence of invasive Hib disease in children younger than 5 years by 99% in the United States, where fewer than 50 cases of Hib disease occur each year (14). Although invasive Hib disease occurs primarily in unimmunized or under-immunized children and in 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 (41).

Hib colonization is nearly eradicated in infants and children who are vaccinated (10; 62). Nontypeable strains, on the other hand, continue to colonize 10% to 60% of both children and adults (16; 32), frequently causing otitis media and rarely causing severe disease. Surveillance of invasive H influenzae disease in the UK between 2012 and 2023 identified NTHi (83%) and Hif (10%) as most common isolates. Bacteremic pneumonia was the most common diagnosis (56%) (31).

With the vaccination of children, the epidemiology of H influenzae has shifted toward adults and women, perhaps as unvaccinated primary caregivers for children (25). The higher incidence of invasive Hib infection in adults in the United States and Canada is particularly evident in those 65 years and older.

Populations at risk for H influenzae disease include non-Hispanic Black, American Indian or Alaska Native, and Hispanic adults (11). Individuals with conditions that impair the ability to clear encapsulated organisms are also at increased risk, including those with anatomic or functional asplenia; sickle cell disease; PWH; antibody and complement deficiency syndromes; and those receiving cancer chemotherapy, radiation treatment, and bone marrow transplantation (65).

Differential diagnosis

Confusing conditions

The history and examination 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 absent 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.

Streptococcus pneumoniae and Neisseria meningitidis are the most common causes of acute bacterial meningitis 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 causes, presumably because of exposure to these agents during birth.

In the setting of a preceding sinusitis, otitis media, head trauma, neurosurgical procedure, or cerebrospinal fluid leak, S. pneumoniae and NTHi are common causes of recurrent meningitis (86; 68), as both are part of “normal” skin and nasopharyngeal colonization. Surgical repair of CSF leaks effectively prevents recurrent bacterial meningitis (07; 68).

In patients over 65 years of age, the most common causes of bacterial meningitis include Streptococcus pneumoniae, Neisseria Meningitidis, and Listeria monocytogenes (84; 85; 82; 83). S aureus is common in neurosurgical patients (78).

Diagnostic workup

	• PCR identification of bacterial DNA in CSF and blood is a quick and highly specific method for early pathogen identification.
	• CSF culture is the gold standard for diagnosing bacterial meningitis due to any organism, including H influenzae, and enables identification of drug susceptibility.

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. Predominantly neutrophilic pleocytosis is strongly suggestive of bacterial meningitis and should prompt empiric treatment, which, in the proper clinical setting, should not be delayed even to obtain CSF. Brain imaging (CT scan) should 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 lumbar puncture include coagulation disorders, septic shock, and respiratory failure.

Blood and CSF cultures will usually be positive in individuals with H influenzae meningitis. However, treatment should be initiated without delay, even prior to obtaining culture samples. Gram stain of the CSF will show gram-negative coccobacilli in approximately 70% of cases (65). CSF antigen testing is not recommended (77).

The U.S. Food and Drug Administration has approved two multiplex PCR assays: (1) meningitis/encephalitis [ME] panel from BioFire Diagnostics, and (2) meningitis/encephalitis panel from ARUP Laboratories. These detect the most common causes of community-acquired bacterial meningitis, such as N meningitidis, H influenzae, and S pneumoniae, with a sensitivity of 90% to 94% for H influenzae meningitis (15). 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 and an inability to provide antibiotic sensitivity. Therefore, cultures, as well as H influenzae–specific PCR, are recommended whenever multiplex PCRs are used (96).

Metagenomic next-generation sequencing (mNGS) is a molecular technology that can provide rapid detection of H influenzae genomes and their genotype/serotypes (50; 22). 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

	• Bacterial meningitis is a medical emergency, start the treatment without waiting for speciation.
	• Dexamethasone should be strongly considered in any patient with suspected community-acquired bacterial meningitis.

When bacterial meningitis is suspected, emergent empiric antibiotic treatment must be initiated, without waiting for speciation. Because H influenzae is no longer a common etiology for community-acquired meningitis (Cochi and Broome 1986; 10; 62), empiric antibiotics for community-acquired meningitis in children and young adults are directed 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 (41). 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) (83). The recommended treatment for patients with a penicillin or cephalosporin allergy includes carbapenems and fluroquinolones (41). In adults older than 50 years, add ampicillin 2 g intravenously every 4 hours in addition to the above regimen (83).

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 (29; 04; 55). Alternative antibiotics for beta-lactamase-positive pathogens include cefepime or meropenem (75). Ampicillin is used only if the infecting pathogen is beta-lactamase negative (55). The total duration of treatment is 7 to 10 days (75).

Chloramphenicol should be considered in the case of severe beta lactam allergy. However, it is highly recommended to obtain information about the nature and severity of the allergy, and if the allergic reaction is not severe, cephalosporin should still be considered based on risk-benefit analysis of cephalosporin relative to chloramphenicol as an alternative, especially in pregnant women (53).

Dexamethasone 0.15 mg/kg intravenously every 6 hours given up to 12 hours after starting antibiotics for the first 4 days of therapy decreases mortality, severe hearing loss, and neurologic sequelae in adults and children with community-acquired bacterial meningitis (47; 81).

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

Outcomes

Mortality with NTHi remains significant, even with early treatment (71). The prognosis of Hib meningitis, as with most bacterial meningitis, is directly related to early diagnosis and treatment. With appropriate early therapy, mortality is 5% or less. Unfavorable outcomes (Glasgow Outcome Scale score lower than 5 at discharge) are less than 20% (18). Hearing loss remains the most common sequelae in adults (10% to 25%) and children (16%) (12; 58).

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Pooja Raibagkar MD

Dr. Raibagkar of Lahey Hospital & Medical Center has no relevant financial relationship to disclose.
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Christina M Marra MD

Dr. Marra of the University of Washington School of Medicine has no relevant financial relationships to disclose.
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Jeffrey A Rumbaugh MD
Karen L Roos MD FAAN

Patient Profile

Age range of presentation: 1 month to 65+ years
Sex preponderance: male>female, >1:1
Heredity: none
Population groups selectively affected: Eskimo

Native American Indian

African American
Occupation groups selectively affected: child care center personnel

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Haemophilus influenzae meningitis

Associated Disorders

Cellulitis
Epiglottitis
Pneumonia

Differential Diagnosis

encephalitis
systemic infection
sepsis
viral encephalitis
viral meningitis
- fungal meningitis
- tuberculous meningitis
- trauma
- closed head injury
- child abuse
- hypoglycemia
- ketoacidosis
- electrolyte imbalance
- uremia
- toxic exposure
- seizure
- brain tumor
- subarachnoid hemorrhage
- intracranial hemorrhage
- epidural abscess
- Streptococcus pneumoniae
- Neisseria meningitidis
- Group B streptococci
- gram-negative enteric bacilli
- Escherichia coli
- Enterobacter
- Pseudomonas
- Listeria monocytogenes
- S. aureus

Also Relevant

Bacterial meningitis
Diagnosis of CNS infections
Gram-negative bacillary meningitis
Neurologic complications of vaccination
Recurrent meningitis

Haemophilus influenzae meningitis …

Haemophilus influenzae meningitis

Cite this article

Introduction

Overview

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Haemophilus influenzae meningitis

Cite this article

Introduction

Overview

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Genital herpes: neurologic complications

Cryptococcal meningitis

Tuberculosis of the CNS

Headache associated with HIV and AIDS

Whipple disease

Post-polio syndrome

Coccidioidomycosis: neurologic manifestations

Tetanus

This is an article preview.
Start a Free Account
to access the full version.