INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: Haemophilus influenzae is a small (1 X 0.3 mm), pleomorphic, gram-negative coccobacillus. It is a nonmotile, non–spore-forming, fastidious, facultative anaerobe. Some strains of H influenzae possess a polysaccharide capsule. All strains are serotyped into 6 different types (a-f) based on their biochemically different capsules.

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 occasionally cause invasive disease similar to that of Hib. The nonencapsulated, or nontypeable, H influenzae 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. The more common invasive Hib infections and the nontypeable H influenzae diseases are discussed in this article.

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, at which time 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.

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. H influenzae is 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 nontypeable strains. Since the widespread use of the Hib conjugate vaccine, nontypeable H influenzae has become more of a pathogen.

The nontypeable H influenzae 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), nontypeable H influenzae frequently colonizes the lower respiratory tract and can exacerbate the disease.

Nontypeable H influenzae form biofilm in vitro and ex vivo and has been implicated in chronic infection such as otitis media, sinusitis, and bronchitis. Nontypeable H influenzae 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, persons infected with human immunodeficiency virus [HIV]).

Frequency:

• In the US: 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.

• Internationally: 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.

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. The mortality rate for epiglottitis is 5-10% (because of acute respiratory tract obstruction), and, for neonatal H influenzae disease, 55%.

• 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.

• Bacteremia and invasive disease associated with nontypeable H influenzae are rare but have a significant mortality rate.

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 compared with the rest of the United States.

Sex: Hib disease has no sex predilection; however, women are at risk for postpartum sepsis, tubo-ovarian abscess, and chronic salpingitis caused by nontypeable H influenzae 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 rate occurring in infants aged 6-9 months. Epiglottitis most commonly occurs 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 manifests in adults as well. 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 a rare occurrence. H influenzae otitis media can occur at any age but is most common in children aged 6 months to 6 years.

• Nontypeable H influenzae 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.

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History:

• Meningitis

• This 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 infrequent 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: Symptoms of chronic 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 the nontypeable H influenzae, which colonizes on 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.

• Nontypeable H influenzae is a major cause of pneumonia in infants in developing countries.

• Nonencapsulated H influenzae infections

• Nonencapsulated H influenzae commonly causes a variety of 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.

• Nontypeable H influenzae is a major pathogen for conjunctivitis in older children and can cause outbreaks, especially in daycare centers. After S pneumoniae, nontypeable H influenzae is the most common cause of community-acquired bacterial pneumonia in adults. It is common in patients with COPD and HIV disease and leads to an exacerbation of COPD, symptoms of which include low-grade fever, increased cough and sputum production, and dyspnea. Nontypeable H influenzae 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 by 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

• These can manifest in various mucosal infections (eg, otitis media, conjunctivitis, sinusitis, bronchitis). An otitis media diagnosis is confirmed based on pneumatic otoscopy. Conjunctivitis is usually bilateral and characterized by conjunctival hyperemia and purulent eye discharge.

• Nontypeable H influenzae 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 nontypeable 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.

• Nontypeable H influenzae biotype 4 can colonize the genital tract and is a major cause of invasive disease.