Haemophilus Influenzae Infections

Updated: Nov 29, 2017
  • Author: Joseph Adrian L Buensalido, MD; Chief Editor: Pranatharthi Haran Chandrasekar, MBBS, MD  more...
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Overview

Practice Essentials

Haemophilus influenzae is a small (1 µm × 0.3 µm), pleomorphic, gram-negative coccobacillus. Some strains of H influenzae possess a polysaccharide capsule, and these 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). Some H influenzae strains have no capsule and are termed nonencapsulated H influenzae or nontypeable H influenzae (NTHi). The incidence of invasive Hib diseases has greatly decreased because of widespread use of the Hib conjugate vaccine, while NTHi strains have become the most common cause of invasive disease in all age groups in countries with routine Hib vaccination.

Signs and symptoms

Signs and symptoms are as follows:

  • Hib meningitis: Most serious manifestation of Hib infection; antecedent upper respiratory tract infections are common; Hib meningitis manifestations indistinguishable from other bacterial meningitis causes
  • Cellulitis: Most commonly involves the buccal and periorbital regions; usually associated with fever
  • Epiglottitis: Fever, sore throat, dysphagia, drooling, and difficulty breathing
  • Hib pneumonia: Clinically indistinguishable from other bacterial pneumonias—but usually with insidious onset and a history of fever, cough, and purulent sputum production
  • Hib pericarditis: Fever, respiratory distress, and tachycardia
  • Septic arthritis: Joint pain, swelling, and decreased mobility
  • Occult bacteremia: Fever, anorexia, and lethargy
  • Underlying medical conditions (especially with invasive Hib disease): Pulmonary disease, immunodeficiency states (eg, HIV infection), alcoholism, pregnancy, and malignancy
  • Neonatal infections: May have nonspecific manifestations; may include signs/symptoms of bacteremia, sepsis, meningitis, pneumonia, respiratory distress, scalp abscess, conjunctivitis, and vesicular eruption
  • NTHi infections: Commonly causes various mucosal infections, including otitis media and conjunctivitis

Persons at risk for invasive H influenzae disease include the following:

  • Children younger than 4 years
  • Contacts (eg, household and daycare) of someone with Hib disease
  • Persons with sickle cell disease,
  • Persons with asplenia
  • Individuals with HIV infection
  • Individuals with immunoglobulin deficiencies and complement component deficiencies
  • Hematopoietic stem cell transplant recipients
  • Patients undergoing chemotherapy or radiation therapy for malignant neoplasms
  • American Indians and Alaska Natives

See Clinical Presentation for more detail.

Diagnosis

Laboratory testing

  • Gram staining of body fluids from various sites of infection
  • Bacterial culture (blood, other body fluids): The most confirmatory method of establishing the diagnosis; slide agglutination with type-specific antisera is used for serotyping H influenzae
  • Immunologic studies: Detection of the polyribosyl ribitol phosphate (PRP) polysaccharide capsule via countercurrent immunoelectrophoresis, latex particle agglutination, co-agglutination, and enzyme-linked immunosorbent assay; important adjuncts to culturing for rapid diagnosis
  • Cerebrospinal fluid (CSF) studies (eg, Gram stain, culture, glucose/protein levels)
  • Blood cell counts: Assessment for anemia, leukocytosis, thrombocytosis, and/or thrombocytopenia
  • Acute phase reactants: Characteristic elevated erythrocyte sedimentation rates (ESRs) and C-reactive protein (CRP) levels in patients with septic arthritis

Imaging studies

Computed tomography (CT) scanning of the head

In infants and children with suspected bacterial meningitis, CT scanning is recommended before lumbar puncture in patients with the following: [1]

  • Immunocompromise
  • History of selected CNS disease, particularly those with CSF shunts, hydrocephalus, space-occupying lesions, history of trauma, post-neurosurgery
  • Papilledema
  • Selected focal neurologic deficits, but not cranial nerve palsy of VI or VII
  • Delayed diagnostic lumbar puncture

In adults with suspected bacterial meningitis, CT scanning is recommended before lumbar puncture in patients with the following: [1]

  • Immunocompromise
  • History of CNS disease
  • Newly onset seizure
  • Papilledema
  • Altered consciousness
  • Focal neurologic deficit
  • Delayed diagnostic lumbar puncture
  • Chest radiography: For suspected pulmonary disease (eg, pneumonia)
  • Lateral neck radiography (only if functional airway is guaranteed): To confirm epiglottitis and/or assess cervical spine
  • Echocardiography: For suspected pericarditis

Procedures

  • Endotracheal intubation or tracheostomy: To secure airway in patients with epiglottitis
  • Lumbar puncture: When meningitis is suspected
  • Bronchoscopy
  • Aspiration of soft or subcutaneous tissue in the presence of cellulitis
  • Joint, lung, and sinus aspiration
  • Transtracheal aspiration
  • Tympanocentesis
  • Pericardiocentesis
  • Laparoscopy and tubal cultures in women: For suspected NTHi
  • Culdocentesis and peritoneal fluid cultures in women: For suspected NTHi

See Workup for more detail.

Management

Antibiotics and supportive care are the mainstays of treatment for H influenzae infections. Immunization/vaccination is an essential component for prevention of Hib infections.

Pharmacotherapy

  • Antibiotics (eg, azithromycin, cefotaxime, ceftriaxone, cefuroxime, ampicillin, amoxicillin, amoxicillin and clavulanic acid, chloramphenicol, erythromycin and sulfisoxazole, meropenem, rifampin)
  • Glucocorticoids (eg, dexamethasone)

Surgery

  • Subdural and pleural empyema: May require surgical drainage if orbital cellulitis is extensive
  • Pericarditis: Systemic antibiotics and drainage via early pericardectomy or pericardiostomy rather than multiple pericardiocenteses
  • Septic arthritis of the hip: 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

See Treatment and Medication for more detail.

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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. In a retrospective study in Canada conducted from 2000-2010, of the 130 H influenzae infections reported, 56% were Hia. Meningitis, bacteremia, and pneumonia were the most common clinical presentations. [2]

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. The population structure of NTHi demonstrates substantial genetic diversity, as opposed to the clonal nature of Hib. [3] Furthermore, the outer membrane proteins of NTHi show high strain-to-strain variability, making vaccine development a challenge. [4, 2]

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. [5]

In contrast, NTHi carriage rates can be as high as 70% or more. [6]

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.

In countries outside the United States with established Hib immunization programs, such as England and Wales, NTHi is now the cause of nearly all invasive H influenzae diseases across all age groups. [2]

In Kamikawa subprefecture of Hokkaido, Japan, the incidence rate of H influenzae infection ranged from 15.1-36.3 per 100,000 population from 2006-2011. The Hib vaccine was introduced in November 2008, but vaccination rates rose to more than 90% only in December 2010, when Hib immunization became national policy. Thus, the rates dropped to 10.4 per 100,000 in 2012 and then to zero after 2013. No Hib meningitis cases have been reported since 2012, demonstrating the value of the vaccine in terms of case reduction. [7]

However, in many developing countries where Hib vaccination is not routine, invasive Hib disease is still a significant cause of morbidity and mortality.

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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 a more common 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).

NTHi infection appears to disturb epithelial integrity and barrier function owing to the destruction of cell-cell contacts, which is believed to be a prominent feature in NTHi infection and has been related to a decrease in both E-cadherin mRNA and protein-levels in lung epithelial cells from patients with chronic bronchitis. [8]

Children younger than 4 years and contacts (eg, household and daycare) of individuals with Hib disease are at higher risk of infection. More research is needed to determine the risk factors for non–type B H influenzae and NTHi. However, persons with sickle cell disease, individuals with asplenia, individuals with HIV infection, persons with immunoglobulin deficiencies and complement component deficiencies, hematopoietic stem cell transplant recipients, patients undergoing chemotherapy or radiation therapy for malignant neoplasms, and American Indians and Alaska Natives are at higher risk for invasive H influenzae disease. [9]

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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. [10] )

The latest Active Bacterial Core Surveillance Report for H influenzae infection in 2015 reported the following prevalence rates in 10 studied states (with a total study population of 43,912,887 persons):

  • Hib infection: 0.02 cases per 100,000 general population
  • Non-Hib infection: 0.42 cases per 100,000 general population
  • NTHi infection: 1.24 case per 100,000 population (NTHi infections accounted for 544 of the 822 H influenzae infection cases reported in this series. [11] )

Meanwhile, 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. [12, 13]

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, the frequency of Hib diseases decreased remarkably, and even developing countries reported 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 (IMPACT) 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. However, from 1998, the number of Hib cases was noted to be 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, Hib vaccination coverage is still suboptimal, [14] 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.

However, a study of invasive disease due to H influenzae in South Africa from 2003-2009 found an increase in the incidence the disease in vaccinated children and concluded that a revision of the Hib conjugate vaccine recommendations should be considered. [15]

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. [16]

A prospective multicenter (10 primary healthcare centers) study of pediatric nasopharyngeal carriers of H influenzae was conducted in the Mediterranean coastal region of Spain, and results showed that all were NTHi. Among all the isolates, 20% were resistant to ampicillin (10% of which were beta-lactamase–producing). During winter, carriage rates more than doubled. [17]

In 12 European countries from 2007-2014, NTHi infections comprised 78% of all H influenzae cases, increasing in those younger than 1 month and those older than 20 years. H influenzae serotype f cases increased in patients older than 60 years. Hib cases decreased in patients aged 1-5 months, 1-4 years, and older than 40 years, highlighting the success of Hib vaccination. [18]

In 2017, 2 cases of Hia infection were reported in Italy, and both were of the ST23 clone (previously only known to have been present outside Europe), which was concerning. [19] In the North America Arctic area, which includes Nunavik and Nunavut, Canada, and Alaska, invasive Hia isolates also belonged to the ST23 clonal complex. [20]

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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%.

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Epidemiology

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%. [21]

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.

Epidemiologic studies suggest that Hia infection occurs more in indigenous North American populations, with clinical presentation closely resembling that of Hib infection. [22]

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). [10] In contrast, the latest Active Bacterial Core Surveillance Report for H influenzae infection in 2015 reported 6,100 (1.9 per 100,000) cases of invasive disease and 1,015 (0.32 per 100,000) deaths. [11]

Bacteremia and invasive disease associated with NTHi are becoming more prevalent and carry a significant mortality rate. [10] Increased NTHi cases can also be seen in patients with cancer, consistent with the changing H influenzae epidemiology in the rest of the population after the Hib vaccine was introduced. [23]

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. [24]

In Queensland, Australia, the yearly incidence rate in all children younger than 5 years was 7.4 per 100,000, but the indigenous children (aboriginal and Torres Strait Islander) of the same ages appeared to be more vulnerable, with an annual incidence rate of 10.2 per 100,000. [25]

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. [10] By 2015, NTHi rates were 4.88 and 2.72 per 100,000 in the same age groups, respectively, although rates were highest in individuals aged 85 years and older, at 11.37 per 100,000. [11]

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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.

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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 eMedicineHealth's Cold and Flu Center. Also, see eMedicineHealth's patient education articles Sepsis (Blood Infection)Immunization Schedule, Children; and Flu in Children.

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