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

Haemophilus influenzae is a small (1 µm X 0.3 µm), pleomorphic, gram-negative coccobacillus. It is a nonmotile, non–spore-forming, fastidious, facultative anaerobe. Some strains of H influenzae possess a polysaccharide capsule. These strains are serotyped into 6 different types (a-f) based on their biochemically different capsules. Some strains have no capsule and are termed nonencapsulated H influenzae or nontypeable H influenzae (NTHi). The different strains can be identified with slide agglutination for serotyping or polymerase chain reaction (PCR) for capsular typing.

The most virulent strain is H influenzae type b (Hib), with its polyribosyl ribitol phosphate (PRP) capsule. It accounts for more than 95% of H influenzae invasive diseases in children and half of invasive diseases in adults, including bacteremia, meningitis, cellulitis, epiglottitis, septic arthritis, pneumonia, and empyema. Less-common invasive Hib infections include endophthalmitis, urinary tract infection, abscesses, cervical adenitis, glossitis, osteomyelitis, and endocarditis.

The other encapsulated strains H influenzae occasionally cause invasive disease similar to that of Hib. H influenzae type A (Hia) has been known to cause invasive disease (eg, meningitis) clinically indistinguishable from that caused by Hib. The nonencapsulated, or NTHi, strains cause mucosal infections, including otitis media, conjunctivitis, sinusitis, bronchitis, and pneumonia. Less commonly, these strains cause invasive disease in children but account for half of the invasive infections in adults.

Hib conjugate vaccine has led to dramatic declines in incidence and prevalence of these diseases. The Hib carriage rate is 2-4% in children aged 2-5 years, the age when children usually become colonized. Hib carriage rates are lowest in adults and infants and highest in preschoolers. Since the advent of conjugate Hib vaccine, the nasopharyngeal carrier rate has decreased (<1% in vaccinated individuals). Only a small percentage of H influenzae carriers develop invasive disease. The frequency of Hib infections in patients with asplenia, splenectomy, sickle cell disease, malignancies, and congenital or acquired immunodeficiencies is higher than in individuals without these conditions. Unvaccinated infants younger than 12 months with a history of invasive disease have a higher risk of recurrence than vaccinated infants.

Currently, the incidence of Hib invasive diseases has greatly decreased in the United States because of the widespread of the Hib conjugate vaccine, while NTHi strains have become the most common cause of invasive disease in all age groups. However, in many developing countries where Hib vaccination is not routine, invasive Hib disease is still a significant cause of morbidity and mortality.

Pathophysiology

The nomenclature (Haemophilus is Greek for "blood loving") acknowledges the fact that H influenzae requires 2 erythrocyte factors for growth: X (hemin) and V (nicotinamide-adenine-dinucleotide). These factors are released following lysis of red blood cells, thereby allowing growth of this fastidious organism on chocolate agar. H influenzae consists of 8 biotypes; biotype 3 (Haemophilus aegyptius) is associated with Brazilian purpuric fever, and biotype 4 is a neonatal, maternal, and genital pathogen. Humans are the only natural hosts. NTHi strains are a common resident of the nasopharyngeal mucosa and, in some instances, of the conjunctivae and genital tract.

Transmission is by direct contact or by inhalation of respiratory tract droplets. Nasopharyngeal colonization of encapsulated H influenzae is uncommon, occurring in 2-5% of children in the prevaccine era and even less after widespread vaccination. The incubation period is not known. A larger bacterial load or the presence of a concomitant viral infection can potentiate the infection. The colonizing bacteria invade the mucosa and enter the bloodstream. The presence of antibodies, complements, and phagocytes determines the clearance of the bacteremia. The antiphagocytic nature of the Hib capsule and the absence of the anticapsular antibody lead to increasing bacterial proliferation. When the bacterial concentration exceeds a critical level, it can disseminate to various sites, including meninges, subcutaneous tissue, joints, pleura, pericardia, and lungs.

Host defenses include the activation of the alternative and classical complement pathways and antibodies to the PRP capsule. The antibody to the Hib capsule plays the primary role in conferring immunity. Newborns have a low risk of infection, likely because of acquired maternal antibodies. When these transplacental antibodies to the PRP antigen wane, infants are at high risk of developing invasive H influenzae disease, and their immune responses are low even after the disease. Therefore, they are at high risk of repeat infections since prior episodes of H influenzae do not confer immunity. By age 5 years, most children have naturally acquired antibodies. The Hib conjugate vaccine induces protection by inducing antibodies against the PRP capsule. The Hib conjugate vaccine does not provide protection against NTHi strains. Since the widespread use of the Hib conjugate vaccine, NTHi has become more of a pathogen.

The NTHi strains colonize the nasopharynx in up to 80% of individuals. The spread of bacteria by direct extension to the eustachian tubes causes otitis media. Spread to the sinuses leads to sinusitis. Spread down the respiratory tract results in bronchitis and pneumonia. Eustachian tube dysfunction, antecedent viral upper respiratory tract infection (URTI), foreign bodies, and mucosal irritants, including smoking, can promote infection. In patients with underlying chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF), NTHi frequently colonizes the lower respiratory tract and can exacerbate the disease.

NTHi strains form biofilm in vitro and ex vivo and have been implicated in chronic infection such as otitis media, sinusitis, and bronchitis. NTHi biofilm formation was found in patients with CF on the apical surface of airway epithelia with decreased antibiotic susceptibility. Studies into the nature of this biofilm structure and proteins will help develop strategies to fight chronic infections. Persons at risk for invasive H influenzae disease include those with asplenia, sickle cell disease, complement deficiencies, Hodgkin disease, congenital or acquired hypogammaglobulinemia, and T-cell immunodeficiency states (eg, HIV infection).

Frequency

United States

Before a vaccine became available in 1988, the annual attack rate of invasive Hib disease was estimated at 64-129 cases per 100,000 children younger than 5 years. By 2000, the number of cases in children younger than 5 years decreased by more than 99%. With the success of the Hib conjugate vaccine, at least half of invasive H influenzae infections are now caused by the nonencapsulated strains, and Hib meningitis has almost disappeared in the United States and Canada.

In 2006, the Active Bacterial Core Surveillance Report for H influenzae infection reported the following prevalences in 10 studied states (with a total study population of 35,599,550 persons):

• Hib infection - 0.04 cases per 100,000 general population
• Non-Hib infection - 0.36 cases per 100,000 general population
• NTHi infection - 0.99 cases per 100,000 general population (NTHi infections accounted for 353 of the 551 H influenzae infection cases reported in this series.¹)

The prevalence of Hia infections has increased in some countries since the advent of the Hib conjugate vaccine. However, in the United States, the number of Hia infections reported has remained constant.²

International

Before vaccines became available, invasive Hib disease was a leading infectious illness among children worldwide. Hib vaccine is routine in the Americas, most of Europe, and a few countries in Africa and the Middle East.

In the 1990s, frequency decreased remarkably, and even developing countries reported a frequency of only 2-3 cases per 100,000 of the population younger than 5 years.

In Canada, 10 centers reported 485 cases of invasive H influenzae disease in 1985. In 2000, 8 years after Canada implemented their Hib immunization program, their Immunization Monitoring Program Active reported only 4 cases. A report of invasive Hib disease in Canadian children identified 29 cases from 2001-2003. The number of cases progressively decreased over the 3 years, with 16 cases reported in 2001, 10 in 2002, and only 3 cases in 2003. A total of 15 cases of meningitis were reported. Six cases of pneumonia with bacteremia and 4 cases of epiglottitis were reported. Two Hib-related deaths occurred. Twenty of these children were unvaccinated or incompletely vaccinated, and 11 were younger than 6 months. Eight of the 9 children who had completed the vaccination series were immunocompromised or had other predisposing conditions. The report noted that the number of cases in older children was unchanged from previous years and that protection did not decline with age.

In England and Wales, the Hib vaccine was introduced in 1992, and the number of invasive Hib cases in children and adults dramatically decreased. Some felt that this was because of herd immunity due to interruption of transmission from immunized children to those who were unvaccinated. Since 1998, the number of Hib cases has been rising, and, in 2002, 134 cases occurred in children aged 4 years or younger. The increase in invasive Hib in England and Wales was also seen in persons aged 15 years and older and reached prevaccine levels. This was associated with reduced antibody concentration in the older age group. This reduction in herd immunity may be due to reduced transmission of Hib organisms from persons who were vaccinated to adults who were unimmunized, providing fewer opportunities for boosting of natural immunity.

In Africa and Asia, routine Hib vaccination is not the standard of care, so Hib remains an important disease pathogen. Although measures have been taken to immunize infants and children against Hib in developing countries, the progress has been relatively slow, partly because of financing for the vaccine, sustainable immunization programs, and the need for data on the burden of invasive Hib disease. In Lambok, Indonesia, from 1998-2002, high incidences of vaccine-preventable Hib meningitis and Hib pneumonia were reported in children younger than 2 years. In a district in Malawi, Africa, the incidence of H influenzae meningitis decreased from 20-40 per 100,000 to zero in 2005 after the vaccine was introduced in 2002.

In many developing countries where Hib vaccine is not administered, Hib infection is a major cause of lower respiratory tract infections and is the leading cause of deaths due to bacterial pneumonia in children.³

Mortality/Morbidity

• Overall mortality from Hib meningitis is approximately 5%. Morbidity rates from meningitis, however, are high. If subtle neurologic changes are included, as many as 50% of individuals with Hib meningitis have some neurologic sequelae, including partial-to-total sensorineural hearing loss, developmental delay, language delay, behavioral abnormalities, language disorders, impaired vision, mental retardation, motor problems, ataxia, seizures, and hydrocephalus. Approximately 6% of individuals with Hib meningitis experience permanent sensorineural hearing loss. Epiglottitis carries a mortality rate of 5-10% (because of acute respiratory tract obstruction), and neonatal H influenzae disease carries a mortality rate of 55%.
• From the 1980s (prevaccine era) to 2005 (vaccine era), the incidence of vaccine-preventable invasive Hib disease decreased by ≥99.8%, and the associated mortality rate decreased by ≥99.5%.⁴
• Licensing of the Hib conjugate vaccine led to a substantial decline of Hib disease in the United States. In parts of the world where the vaccine is not in regular use, morbidity and mortality rates of Hib disease remain high.
• In 2006, the Active Bacterial Core Surveillance Report estimated that, in the United States, 4800 cases (1.6 per 100,000 population) of invasive H influenzae infection occurred, resulting in 700 deaths (0.23 per 100,000 population).¹
• Bacteremia and invasive disease associated with NTHi are becoming more prevalent and carry a significant mortality rate.¹

Race

The frequency of Hib disease is especially high in certain ethnic groups, including African Americans, American Indians (eg, Alaskan Eskimos, Navajo, Apache, Yakima, Athabaskan), and Australian Aborigines. Prior to availability of the Hib vaccine, the incidence of invasive disease was 10% higher in American Indians and Alaskan native children than the rest of the US population. The rate of Hib disease among rural Alaskan native children is high (5.4 per 100,000) despite Hib vaccination.⁵

Sex

Hib disease has no sexual predilection; however, women are at risk for postpartum sepsis, tuboovarian abscess, and chronic salpingitis caused by NTHi that colonize the genital tract.

Age

• In general, Hib infections are rare in patients older than 6 years because of the acquisition of secondary immunity; however, immunocompromised individuals remain susceptible.
• Hib meningitis primarily affects children younger than 2 years, with a peak frequency in infants aged 6-9 months. Epiglottitis is most common in children aged 2-7 years but can also occur in adults. Hib pneumonia typically occurs in children aged 4 months to 4 years. Hib causes septic arthritis and cellulitis in children younger than 2 years; before the conjugate vaccine became available, Hib was the leading cause of arthritis in this age group. Hib septic arthritis also occurs in adults. Prior to introduction of the Hib vaccine, Hib was the leading cause of occult bacteremia after Streptococcus pneumoniae in children aged 6-36 months. In the vaccine era, Hib occult bacteremia is rare. H influenzae otitis media can occur at any age but is most common in children aged 6 months to 6 years.
• NTHi causes neonatal sepsis through vertical transmission via the female genital tract, maternal sepsis, and, infrequently, other invasive diseases. It also causes otitis media, sinusitis, bronchitis, and pneumonia in all age groups.
• In 2006, the Active Bacterial Core Surveillance Report found that NTHi infection was most common among persons younger than one year and those aged 65 years or older, accounting for 6.5 and 4.3 cases per 100,000 general population, respectively.¹

CLINICAL

Section 3 of 10  

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

History

• Meningitis
• • Meningitis is the most serious manifestation of H influenzae type b (Hib) infection. Symptoms of antecedent URTI are common. Altered mental status and fever are the most common presenting features. Headache and photophobia are usually present in older children.
  • Symptoms related to other infectious foci (eg, cellulitis, arthritis, pneumonia) are encountered in 10-20% of children. Infants have nonspecific symptoms, including irritability, fever, lethargy, poor feeding, and vomiting.
  • H influenzae accounts for 5-10% cases of adult meningitis, and patients can present with at least one of the classic triad of fever, neck stiffness, and altered mental status.
• Cellulitis: The buccal and periorbital regions are most commonly involved with associated fever. Orbital cellulitis is uncommon and tends to be a complication of ethmoid or sphenoid sinusitis.
• Epiglottitis: Patients have histories of fever, sore throat, dysphagia, drooling, and difficulty breathing.
• Pneumonia: Hib pneumonia is clinically indistinguishable from other bacterial pneumonias except for its insidious onset and a patient history of fever, cough, and purulent sputum production.
• Pericarditis: Patients with Hib pericarditis present with a history of fever, respiratory distress, and tachycardia.
• Septic arthritis: Patients note joint pain, swelling, and decreased mobility.
• Occult bacteremia: Fever, anorexia, and lethargy occur in persons with occult bacteremia.
• Underlying medical conditions: Pulmonary disease, HIV infection (and other immunodeficiency states), alcoholism, pregnancy, and malignancy may predominate in adults with invasive Hib disease.
• Neonatal infections
• • Neonates with H influenzae disease present within 24 hours of birth; these infections are caused by NTHi strains, which colonize the maternal genital tract.
  • Premature birth, premature rupture of membranes, low birth weight, and maternal chorioamnionitis are associated with H influenzae disease.
  • Manifestations may be nonspecific and may include those of bacteremia, sepsis, meningitis, pneumonia, respiratory distress, scalp abscess, conjunctivitis, and vesicular eruption.
  • NTHi is a major cause of pneumonia in infants in developing countries.
• Nonencapsulated H influenzae infections
• • Nonencapsulated H influenzae commonly causes various mucosal infections, including otitis media and conjunctivitis.
  • S pneumoniae and nonencapsulated H influenzae are the most common causes of otitis media, which manifests in infants as fever and irritability and in older patients as ear pain. Frequently, a history of URTI exists.
  • NTHi is a major cause of conjunctivitis in older children and can cause outbreaks, especially in daycare centers. After S pneumoniae, NTHi is the most common cause of community-acquired bacterial pneumonia in adults. It is common in patients with COPD and HIV disease and exacerbates COPD, symptoms of which include low-grade fever, increased cough and sputum production, and dyspnea. NTHi invasive disease is frequently associated with underlying medical conditions, including prematurity, advanced age, alcoholism, malignancy, CF, asthma, cerebrospinal fluid (CSF) leak, CNS shunts, congenital heart disease, and immunoglobulin deficiency.

Physical

• Meningitis
• • Clinical manifestations of Hib meningitis are indistinguishable from other causes of bacterial meningitis.
  • The usual presentation consists of a few days of mild illness followed by ominous deterioration.
  • Altered mental status and fever are the most common findings.
  • Seizures and coma develop as the disease progresses.
  • Children may have few specific signs. Nuchal rigidity is often absent in children younger than 18 months. In infants, the disease course may be fulminant, with death occurring within a few hours.
  • Consider the possibility of subdural effusion, a common complication of Hib meningitis, in a patient who has been treated for 3 days with appropriate antibiotics and has experienced a tense anterior fontanelle, seizures (especially if focal), hemiparesis, or altered CNS function.
• Cellulitis
• • The clinical features are fever and a raised, indurated, tender area with indistinct margins mostly on the head and neck, particularly the buccal and preseptal areas. This is often caused by contiguous sinus disease. The indurated area may progress to a violaceous hue, although this is not specific to Hib.
  • Orbital cellulitis may also occur and is distinguished from preorbital cellulitis based on the presence of proptosis, chemosis, impaired vision, limitation of extraocular movements, and pain with eye movement. A secondary focus of infection, including meningitis, is evident in 10-15% of patients with orbital cellulitis.
• Epiglottitis: Clinical manifestations in children include a toxic anxious appearance, progressive respiratory difficulty, and the inability to swallow secretions while sitting in the tripod position (ie, sitting with arms back, trunk leaning forward, neck hyperextended and chin forward in an attempt to open the airway fully).
• Pneumonia: Hib pneumonia is clinically indistinguishable from other bacterial pneumonias.
• Pericarditis: The individual is acutely ill with fever and respiratory distress.
• Septic arthritis
• • Hib septic arthritis affects single large joints (eg, knee, ankle, hip, elbow).
  • Symptoms, usually preceded by a URTI, include decreased range of motion, erythema, and warmth and swelling in affected joints, in addition to fever.
  • In adults, joint involvement can be monoarticular or polyarticular.
  • Extra-articular sites of infection, including those associated with meningitis, pneumonia, cellulitis, and sinusitis, may also be evident.
• Occult bacteremia: Occult bacteremia is characterized by fever (temperature >39°C) with no obvious focus of infection. About 30-50% of patients have focal infections.
• Nonencapsulated H influenzae infections can manifest in various mucosal infections (eg, otitis media, conjunctivitis, sinusitis, bronchitis). An otitis media diagnosis is confirmed with pneumatic otoscopy. Conjunctivitis is usually bilateral and characterized by conjunctival hyperemia and purulent eye discharge.
• NTHi strains can cause postpartum sepsis with endometritis, tuboovarian abscess, and chronic salpingitis.
• Signs of invasive disease in neonates include sepsis, pneumonia, conjunctivitis, respiratory distress syndrome, scalp abscess, cellulitis, meningitis, congenital vesicular eruption, mastoiditis, and septic arthritis.

Causes

• Bacteremia precedes Hib meningitis and other invasive Hib diseases.
• • Direct extension of infection from the sinuses or ears is rare.
  • The magnitude and duration of bacteremia are the primary determinants of CNS invasion, which occurs via the choroid plexus.
  • The magnitude of the CSF bacterial density correlates with the severity of the disease.
  • Morbidity and mortality associated with meningitis result from inflammation, edema, and increased CSF pressure.
  • Brain parenchymal invasion is rare.
• In epiglottitis, Hib invades the epiglottis and supraglottic tissues, causing cellulitis and swelling that causes the epiglottis to curl posteriorly and inferiorly over the airway, thus obstructing airflow during inspiration but allowing normal expiration. An acute airway obstruction follows.
• Invasive H influenzae disease in neonates is rare and is caused most often by NTHi strains.
• • This condition is associated with premature birth, premature rupture of membranes, low birth weight, and maternal chorioamnionitis.
  • Transmission occurs through the maternal genital tract.
  • NTHi biotype 4 can colonize the genital tract and is a major cause of invasive disease.

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Otitis media
Epiglottitis

WORKUP

Section 5 of 10  

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

Lab Studies

• Gram stain: Test results on body fluids from various sites of infection that reveal small, gram-negative, pleomorphic coccobacilli with polymorphonuclear cells are strong evidence of infection.
• Bacterial culture  
• • Detection of the organism in a blood culture or any other body fluid is the most confirmatory method of establishing the diagnosis.
  • Slide agglutination with type-specific antisera is used for serotyping H influenzae. In one study, molecular typing with PCR was found to be more accurate than slide agglutination serotyping.⁶
  • Seventy to 90% of patients with epiglottitis have positive blood culture results. However, to avoid laryngospasm, perform venipuncture and cultures of the inflamed epiglottitis only after the airway has been secured.
• Immunologic studies  
• • Detection of the PRP polysaccharide capsule via countercurrent immunoelectrophoresis, latex particle agglutination, co-agglutination, and enzyme-linked immunosorbent assay is an important adjunct to culturing in establishing a rapid diagnosis.
  • Even if antibiotics were previously administered, the diagnosis can be confirmed based on the detection of the polysaccharide capsule in body fluids, including serum, CSF, urine, and pleural, pericardial, and articular fluid. False-positive results in CSF are rare but occur with serum or urine because of nonspecific agglutination and antigenic cross-reactivity with other bacteria.
• CSF features  
• • In meningitis, the CSF examination demonstrates pleocytosis (mean, 4000-5000 WBCs/µL) with a predominance of neutrophils.
  • Decreased CSF glucose levels are encountered in 75% of patients, increased CSF protein levels and detectable capsular antigen in 90%, and a positive CSF Gram stain result in 80%.
  • Prior antibiotic treatment significantly decreases the H influenzae type b (Hib) concentration in the CSF and decreases the sensitivity of the Gram stain; however, antibiotics do not substantially affect the total CSF blood cell count, differential, chemistries, and presence of the PRP capsule in pretreated patients.
• Blood cell counts: Perform blood cell counts for anemia, leukocytosis, and thrombocytosis or thrombocytopenia.
• Acute phase reactants: Elevated erythrocyte sedimentation rates (ESRs) and C-reactive protein levels are characteristically observed in patients with septic arthritis.

Imaging Studies

• CT scanning  
• • In meningitis, a CT scan of the head is not required routinely unless focal neurologic findings are present or clinical response is lacking after 3 days' administration of appropriate antibiotics. In these situations, a head CT scan helps identify subdural effusion.
  • In patients with orbital cellulitis, a CT scan of the head is useful in delineating the extent of the lesion.
• Chest radiography  
• • Patients with Hib pneumonias tend to have more pleural and pericardial involvement (50% of patients) than those with other bacterial pneumonias.
  • Community-acquired pneumonias due to NTHi are characterized by alveolar infiltrates in patchy or lobar distributions.
• Lateral neck radiography  
• • In epiglottitis, a lateral neck radiograph reveals dilatation of the hypopharynx and a swollen epiglottis (termed the thumbprint sign). In addition, the cervical spine is usually straightened.
  • If epiglottitis is clinically suspected, obtain radiography only if a functional airway is guaranteed.
• Echocardiography: Obtain this when pericarditis is suspected.

Other Tests

• In patients with cellulitis, direct aspiration of the soft tissue or aspiration after injecting the subcutaneous tissue with sterile nonbacteriostatic solution can be used to detect the organisms via Gram stain and culture.

Procedures

• Perform a lumbar puncture when meningitis is suspected.
• The following invasive procedures can be used to obtain appropriate fluid and to establish an etiologic diagnosis:  
• • Bronchoscopy
  • Joint, lung, sinus, and soft-tissue aspiration
  • Transtracheal aspiration
  • Tympanocentesis
  • Pericardiocentesis
• In women, obtain tubal cultures via laparoscopy and peritoneal fluid cultures by culdocentesis for NTHi.
• In patients with epiglottitis, use endotracheal intubation or tracheostomy to secure an airway.

TREATMENT

Section 6 of 10  

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

Medical Care

• Antibiotics and supportive care
• • These are the mainstays of treatment.
  • Initially, invasive and serious H influenzae type b (Hib) infections are best treated with an intravenous third-generation cephalosporin until antibiotic sensitivities become available. In Malawi, Africa, intramuscular ceftriaxone was compared with intravenous ceftriaxone and was not found to increase the mortality rate. This may be important in developing countries where the intravenous route may not be possible.⁷
  • The site of infection and the clinical response determine the length of antibiotic treatment.
• Meningitis
• • Administer parenteral antibiotics (eg, ceftriaxone, ceftazidime, cefotaxime, ampicillin-sulbactam, fluoroquinolones, azithromycin) to patients with uncomplicated meningitis for 7-14 days. Cefotaxime and ceftriaxone are the initial drugs of choice for suspected Hib meningitis.
  • Once the susceptibilities are known, adjust antibiotics accordingly.
  • Do not use ampicillin empirically, since as many as 50% of the isolates are resistant, usually because of plasmid-mediated beta-lactamase production.
  • Cefuroxime is also not recommended because delayed sterilization is more common.
  • Chloramphenicol produces adequate bactericidal blood and CSF levels but is now used infrequently because it requires monitoring of drug levels and can result in dose-dependent (though reversible) bone marrow toxicity (particularly in neonates and patients with liver disease) or an idiosyncratic aplastic anemia.
  • Dexamethasone is an important adjunctive treatment in patients with meningitis who are older than 2 months because it has been shown to decrease the inflammatory response and the rate of hearing loss⁸ and other neurological complications.⁹
  • • The 2004 Infectious Disease Society of America (IDSA) guidelines recommend that dexamethasone 0.15 mg/kg/d q6h for 2-4 days be administered to children (but not adults) with H influenzae meningitis. When steroids are used, they must be administered either prior to or along with antibiotics, as dexamethasone administered after antimicrobials is unlikely to be beneficial.¹⁰
    • In January 2007, a systematic review of randomized controlled trials involving adjuvant corticosteroids therapy in acute bacterial meningitis found a significant benefit in children from developed countries but no beneficial or harmful effects in children in developing countries. This meta-analysis also found that dexamethasone administered to adults with community-acquired meningitis (including that caused by H influenzae) decreased the risk of mortality and neurologic sequelae. Based on data from 18 randomized controlled trials, the authors concluded that all adults and children with acute bacterial meningitis in developed countries who have good access to medical care should receive adjuvant corticosteroids. The authors also found no significant increase in adverse effects due to corticosteroids. The recommended dose for dexamethasone in adults and children is 0.6 mg/kg/d for 4 days.⁸
    • A randomized prospective study in 1994 found that, in treatment for bacterial meningitis, a 2-day course of dexamethasone provided effectiveness similar to that of a 4-day course.¹¹ However, most studies recommend a 4-day dexamethasone course.
    • In November 2007, a prospective randomized double-blind placebo-controlled trial studied adjuvant glycerol and dexamethasone in children with bacterial meningitis. All patients were given ceftriaxone and randomized to receive intravenous dexamethasone, oral glycerol, both agents, or neither agent. In addition, a subgroup of patients with Hib meningitis was studied. Findings showed that glycerol, an inexpensive osmotic diuretic that can be administered orally, reduced the incidence of neurologic sequelae and death. Dexamethasone prevented profound hearing loss when the timing of dexamethasone and ceftriaxone administration was not taken into account. Few adverse effects were found with either adjuvant medication. Additional studies need to be performed to evaluate the impact of glycerol in bacterial meningitis.¹²
    • In 2007, a Vietnamese study evaluated the benefit of dexamethasone in adults and adolescents with confirmed or suspected bacterial meningitis. Overall, initial findings showed that dexamethasone did not decrease the mortality rate at 1 month or the incidence of mortality or disability at 6 months. However, when the results were compared with culture-proven disease, dexamethasone was found to confer a significant benefit in terms of both mortality and disability in patients with confirmed bacterial meningitis. Among the patients studied, only 7 had H influenzae meningitis, and 6 of these were in the placebo group.¹³
    • In a 2007 study in Malawi, Africa, dexamethasone was given to adults with bacterial meningitis but was not found to reduce mortality or morbidity. However, 90% of the study patients had HIV infection. Of the 465 patients studied in this group, only 3 had H influenzae meningitis.⁷
  • Treatment of H influenzae meningitis also includes ongoing supportive care and management of complications such as shock, inappropriate secretion of antidiuretic hormone syndrome, seizures, subdural empyema, and secondary foci of infection.
  • Small, clinically insignificant subdural effusions are common.
  • In uncomplicated cases, a repeat lumbar puncture is unnecessary to ensure sterility of the CSF.
• Cellulitis
• • In patients with Hib cellulitis, administer parenteral antibiotics until the patient shows defervescence and the cellulitis subsides. Then, administer appropriate oral antibiotics until the course of therapy, usually 7-10 days, is finished. Empiric therapy for preseptal cellulitis should cover not only Hib but also S pneumoniae, Staphylococcus aureus, and group A beta-hemolytic streptococci. Patients with orbital cellulitis require at least 14 days of parenteral therapy.
  • Surgical drainage may be needed for the underlying sinusitis or for orbital abscesses.
• Epiglottitis
• • Maintenance of a patent airway via intubation or tracheostomy is the mainstay of treatment for epiglottitis.
  • Administer antimicrobial therapy parenterally once the airway is secured, and continue until the patient can receive oral fluids. The total duration of therapy is 7-10 days.
• Arthritis
• • So far, no studies have accurately defined the appropriate length of therapy for septic arthritis. However, uncomplicated septic arthritis usually requires systemic antibiotics for at least 7 days.
  • If an appropriate clinical response is obtained, oral therapy for 2-3 weeks may follow. Therapy may continue beyond 3 weeks until the ESR begins to normalize. The ESR may lag behind successful clinical response for weeks; accordingly, the C-reactive protein test may be a more useful laboratory tool because its values tend to normalize more rapidly.
• Bacteremia and other Hib infections
• • Bacteremia precedes essentially all invasive Hib infection.
  • Approximately 30-50% of children with occult Hib bacteremia (bacteremia without an identifiable cause) develop a focus of infection such as meningitis, cellulitis, or pneumonia. Therefore, reevaluate these children (including with lumbar punctures and chest radiography) for an infectious focus and obtain repeat blood cultures.
  • Administer parenteral antibiotics for at least 2-5 days and guide subsequent therapy based on the focus of infection. If no focus is identified, substitute oral antibiotics to complete 10 days of therapy. Patients with pericarditis, empyema, endocarditis, endophthalmitis, or osteomyelitis require an extended antibiotic treatment duration of 3-6 weeks.
• Nonencapsulated H influenzae
• • These organisms can cause mucosal infections treatable with oral antibiotics. The first-line antibiotic for otitis media is amoxicillin (80-90 mg/kg/d for 7-10 d) because of its safety and low cost. If the organism produces beta-lactamase or if other treatment fails, treatment with amoxicillin-clavulanate is recommended. Penicillin-allergic individuals may be treated with erythromycin-sulfisoxazole or cefaclor. Cefaclor has weak activity against beta-lactamase–producing bacteria and causes a serum sickness–like illness in 2% of patients. Approximately 25-50% of NTHi strains produce beta-lactamase and, therefore, are resistant to amoxicillin and ampicillin.
  • Oral antibiotics with activity against beta-lactamase–producing H influenzae include trimethoprim-sulfamethoxazole, cefuroxime axetil, cefixime, clarithromycin, azithromycin, and fluoroquinolones. The duration of therapy is 10 days for otitis media and at least 14 days for sinusitis. Patients with conjunctivitis should receive topical antibiotics such as sulfacetamide and erythromycin.
  • Administer parenteral antibiotics to patients with invasive NTHi infection, which can be treated similarly to invasive Hib disease.

Surgical Care

• Patients with subdural and pleural empyema may require surgical drainage if orbital cellulitis is extensive.
• Patients with pericarditis require systemic antibiotics and drainage via early pericardectomy or pericardiostomy rather than multiple pericardiocentesis.
• Patients with septic arthritis of the hip require surgical drainage to avoid avascular necrosis of the femoral head. Repeated aspirations or surgical drain placement may be needed in other infected joints to reduce pressure.

Consultations

• Consult an ear, nose, and throat specialist and an anesthesiologist for help in securing difficult airways in all cases of suspected epiglottitis.
• Consult a neurosurgeon for suppurative complications of nervous system involvement.
• Consult an ophthalmologist for management of orbital cellulitis.
• Consult an infectious disease specialist for assistance with complicated infections.
• Consult an orthopedic surgeon for surgical drainage of a joint.

MEDICATION

Section 7 of 10  

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

Initially, patients with invasive and serious H influenzae infections are best treated with an intravenous third-generation cephalosporin.

Drug Category: Antibiotics

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting. Penicillins are useful in management of mucosal infections caused by nonencapsulated H influenzae. As many as 25-50% of isolates produce beta-lactamase; therefore, they are resistant to this class of drugs. Third-generation cephalosporins are highly effective in H influenzae infections. Meropenem or ampicillin and chloramphenicol are alternative regimens.

Drug Category: Glucocorticoids

These agents are used as adjunctive therapy in H influenza meningitis for the anti-inflammatory effects and prevention of sensorineural deafness. Administer before or with antibiotics, not after. Utility of steroids has been demonstrated primarily in nonimmunized children, and its usefulness in adults or vaccinated children is not known.

FOLLOW-UP

Section 8 of 10  

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

Further Inpatient Care

• Index patients younger than 2 years who will be in contact with unvaccinated or incompletely immunized children younger than 4 years and who were treated with a regimen other than cefotaxime of ceftriaxone should be treated with rifampin before or at discharge from the hospital because other antibiotics used for the treatment of H influenzae type b (Hib) meningitis do not reliably eradicate Hib from the nasopharynx. Treatment with cefotaxime and ceftriaxone eradicates Hib colonization and therefore eliminates the need for chemoprophylaxis of the index patient.
• Search for secondary foci of infection, such as septic arthritis, if patients have prolonged fever during treatment of meningitis.
• Droplet precautions should be followed for the first 24 hours following the initiation of appropriate therapy in patients with invasive Hib disease.¹⁴

Further Outpatient Care

• Unvaccinated or undervaccinated children younger than 4 years who have household contact with an index patient have a 600-fold increased risk of Hib disease.
• Begin chemoprophylaxis as soon as possible because the risk of secondary disease is greatest within a few days after disease onset in the index case. Rifampin is the drug of choice for chemoprophylaxis because it achieves high bactericidal concentrations intracellularly and in mucosal secretions, thereby eradicating 95% of Hib from the nasopharynx. Administer rifampin to all household contacts, including adults, children, and the index patient, if a close household contact is immunocompromised, regardless of immunization status; younger than 48 months and is not completely immunized or unimmunized; or younger than 12 months and has not received the 2- to 3-dose primary series.  Chemoprophylaxis is not needed in contacts of patients with non-Hib invasive disease.¹⁴
• Full immunization is defined as having received at least one of the following:¹⁴
• • One dose of a Hib conjugate vaccine when at age 15 months or older
  • Two doses at age 12-14 months
  • Two or more doses at age 12 months or older
  • Three doses before age 12 months, with a booster dose at age 12 months or older
• If the close contact group includes a fully vaccinated child who is immunocompromised, then make an exception because the vaccination may have been ineffective. A close contact group is defined as persons who reside with the patient or a nonresident who has spent 4 hours or more with the index patient for at least 5 of the 7 days preceding the day of hospitalization of the patient.¹⁴
• • Administer rifampin within 7 days after hospitalization of the index patient to ensure effectiveness.
  • The need for chemoprophylaxis has decreased dramatically because the Hib conjugate vaccine now protects many children.
• The need for all daycare center contacts to be treated is debatable when a single case has occurred because of uncertainty about the actual risk of secondary Hib disease in this setting.¹⁴
• • If 2 or more cases of Hib disease have occurred in a childcare center within 60 days, the consensus is to institute prophylaxis to all attendees and staff members.
  • Pharyngeal cultures do not need to be obtained to determine prophylaxis, as this delays administration of rifampin.
  • Administer H influenzae conjugate vaccine to patients younger than 24 months with invasive Hib disease during convalescence regardless of prior immunization. Patients aged 24 months or older with invasive Hib disease do not need immunization.
  • Patients with recurrent invasive Hib disease despite receiving Hib immunization should undergo immunologic evaluation.

In/Out Patient Meds

• If the patient has significantly improved clinically, oral antibiotics may follow parenteral antibiotics started in the hospital to finish the course of treatment.
• Adjust antibiotics based on susceptibilities of the involved organism.

Deterrence/Prevention

• The highly effective Hib conjugate vaccine, now routinely administered to infants and children, has dramatically reduced the prevalence of invasive Hib disease. The vaccine elicits a protective antibody and prevents disease by reducing pharyngeal colonization with Hib. Presently, no vaccines prevent disease caused by NTHi.
• The first Hib vaccine was an unconjugated polysaccharide vaccine composed of the purified PRP capsular polysaccharide. This vaccine induced an ambiguous immune response, did not provide complete protection in children, and provided no antibody protection in infants. This led to the development of the conjugate vaccines in which PRP is covalently linked to a protein.
• Currently, 3 licensed vaccines are available. They differ in the protein carrier used, the molecular size of the saccharide, and the method of conjugating the protein to the saccharide. These include HibTITER (HbOC [mutant diphtheria toxin as the carrier protein]), PedvaxHIB (PRP-OMP [major outer membrane protein of N meningitidis serogroup B as the carrier protein]), and ActHIB/OmniHIB (PRP-T [tetanus toxoid as the carrier protein]).¹⁴
• • PRP-OMP induces a good immune response after a single dose in infants, but antibody levels after 3 doses are lower than those induced by HbOC and PRP-T.
  • The PRP-OMP vaccine is therefore recommended in American Indians and Alaska native children because of a rapid seroconversion of protective antibodies with the PRP-OMP vaccine.
  • The vaccines are well tolerated, with occasional redness and swelling at the site of vaccination (10-15% of infants), more commonly after the initial dose than after subsequent injections.
  • The estimated effectiveness of the vaccine in children younger than 5 years is 98%.
• The combination of Hib conjugate vaccine (PRP-OMP) with hepatitis B vaccine (Recombivax HB) is licensed for use at age 2 months, 4 months, and 12-15 months. The DTaP-Hib is another combination vaccine that is licensed for use but only as a fourth dose in the DTaP and Hib series.¹⁴
• Administer routine immunization of the Hib conjugate vaccine in all infants and children.
• • In the primary series, administer a 3-dose regimen of HbOC or PRP-T or a 2-dose regimen of PRP-OMP at 2-months intervals, beginning at age 2 months. Any conjugate Hib vaccine can serve as the booster immunization given in children aged 12-15 months. Lack of the booster dose in the United Kingdom might be a reason for the recent increase in Hib disease since the Hib vaccine was introduced there in 1992.
  • Children with decreased or absent splenic function who have received their full immunization series need not be immunized further.
  • Children who have received the primary series and a booster dose and are undergoing scheduled splenectomy (eg, for Hodgkin disease, spherocytosis) may benefit from an additional dose of any licensed conjugate vaccine given 7-10 days before the procedure.
  • Unimmunized children older than 59 months with an underlying disease may be immunized with 2 doses of vaccine 2 months apart.

Complications

• Complications of meningitis include seizures, cerebral edema, subdural effusion or empyema, inappropriate secretion of antidiuretic hormone syndrome, cortical infarction, cerebritis, intracerebral abscess, hydrocephalus, and cerebral herniation. Protracted fever is not uncommon, with approximately 10% of children remaining febrile for at least 10 days.
• Complications of orbital cellulitis include subperiosteal or orbital abscesses.
• Complications of pneumonia include empyema and pericarditis.
• Complications of otitis and sinusitis include mastoiditis and parameningeal abscess.

Prognosis

• The prognosis of meningitis depends on age at presentation, duration of illness prior to antimicrobial therapy, CSF capsular polysaccharide concentration, and the rapidity with which it is cleared from the CSF, blood, and urine. Dexamethasone administered concurrently or shortly before the initial administration of antibiotics decreases the likelihood of hearing loss associated with Hib meningitis.
• The prognosis of uncomplicated Hib pneumonia and nonencapsulated H influenzae infections is usually good.

Patient Education

• Alert parents and caregivers of the index patient that if any exposure to the index patient has occurred within a childcare setting to seek prompt medical care for any signs or symptoms that may be related to Hib infection.
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Cold and Flu Center. Also, see eMedicine's patient education articles Sepsis (Blood Infection); Immunization Schedule, Children; and Flu in Children.

MISCELLANEOUS

Section 9 of 10  

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

Medical/Legal Pitfalls

• H influenzae type b (Hib) resistance to several antibiotics, including ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, rifampin, and some second-generation cephalosporins, has increased worldwide. When choosing an antibiotic, consider the local antibiotic susceptibility patterns of invasive isolates.
• The treatment of Hib bacteremia and its invasive disease should include penetration of the blood-brain barrier (since occult CNS disease must be considered in any Hib infection), achievement of bactericidal titers, and an adequate duration of therapy to sterilize primary and potential secondary foci.
• The nasopharyngeal carriage rate of NTHi is high; therefore, a positive culture result is not helpful and should not be used to confirm a diagnosis of H influenzae disease.
• If epiglottitis is suspected, securing an airway prior to doing anything that might make the patient more anxious is crucial.

Special Concerns

• R