Chapter 8: Haemophilus influenzae

Overview

Haemophilus influenzae is a bacterium that causes often-severe infections, particularly among infants. It was first described by Richard Pfeiffer in 1892. During an outbreak of influenza, he found H. influenzae in patients' sputum and proposed a causal association between this bacterium and the clinical syndrome known as influenza. The organism was given the name Haemophilus by Charles-Edward Winslow, et al. in 1920. It was not until 1933 that it was established that influenza was caused by a virus and that H. influenzae was a cause of secondary infection.

In the 1930s, Margaret Pittman demonstrated that H. influenzae could be isolated in encapsulated (typeable) and unencapsulated (nontypeable) forms. She observed that virtually all isolates from cerebrospinal fluid (CSF) and blood were of the capsular type b.

Before the introduction of effective vaccines, H. influenzae type b (Hib) was the leading cause of bacterial meningitis and other invasive bacterial disease, primarily among children younger than age 5 years; approximately one in 200 children in this age group developed invasive Hib disease. Approximately two-thirds of all cases occurred among children younger than age 18 months.

A pure polysaccharide vaccine was licensed for use in the United States in 1985 and was used until 1988. The first Hib conjugate vaccine was licensed in 1987.

Haemophilus influenzae

H. influenzae, a fastidious, pleomorphic, gram-negative coccobacillus, requires hemin (X factor) and nicotinamide-adenine-dinucleotide (NAD, also known as V factor) for in vitro growth. It is generally aerobic, but can grow as an anaerobe under certain conditions.

The outermost structure of encapsulated H. influenzae is composed of a polysaccharide, a key virulence factor. Six antigenically and biochemically distinct capsular polysaccharide types have been described; these are designated serotypes a through f. Hib capsule is composed of polyribosyl-ribitol-phosphate (PRP), a polysaccharide used in Hib vaccines. There are currently no vaccines to prevent disease caused by non-b encapsulated or nontypeable strains. In the pre-Hib-vaccine era, type b organisms accounted for 95% of all H. influenzae strains that caused invasive disease.

Hib does not survive in the environment on inanimate surfaces.

Pathogenesis

H. influenzae enters the body through the nasopharynx. Organisms colonize the nasopharynx and may remain only transiently or for several months in the absence of symptoms (asymptomatic carrier). In the prevaccine era, Hib could be isolated from the nasopharynx of 0.5% to 3% of healthy infants and children, but was uncommon in adults. Nontypeable strains also frequently inhabit the human respiratory tract.

In some persons, H. influenzae causes an invasive infection. The exact mode of invasion of the bloodstream is unknown. A preceding viral or mycoplasma infection of the upper respiratory tract may be a contributing factor. The bacteria spread in the bloodstream to distant sites in the body. Meninges are especially likely to be affected.

Incidence is strikingly age-dependent. In the prevaccine era, up to 60% of invasive disease occurred before age 12 months, although some infants received passive protection from maternal IgG antibodies passed through the placenta and breastfeeding during the first 6 months of life. Peak occurrence was among children age 6 to 11 months.

Antibodies to Hib capsular polysaccharide are protective. The precise level of antibody required for protection against invasive disease is not clearly established. However, a titer of 1 µg/mL 3 weeks postvaccination correlated with protection in studies following vaccination with unconjugated, purified, PRP vaccine and suggested long-term protection from invasive disease.

In the prevaccine era, most children acquired immunity by age 5 or 6 years through asymptomatic nasopharyngeal carriage of Hib bacteria. Since only a relatively small proportion of children carry Hib at any time, it has been assumed exposure to organisms that share common antigenic structures with the capsule of Hib (so-called "cross-reacting organisms") may also stimulate the development of anticapsular antibodies against Hib. Natural exposure to Hib also induces antibodies to outer membrane proteins, lipopolysaccharides, and other antigens on the surface of the bacterium. The higher the age-specific incidence of Hib disease, the less likely there will be acquisition of both anticapsular and serum bactericidal antibody.

The genetic constitution of the host may also be important in susceptibility to Hib infection. Risk for Hib disease has been associated with a number of genetic markers, but the mechanism of these associations is unknown. No single genetic relationship regulating susceptibility or immune responses to polysaccharide antigens has yet been convincingly demonstrated.

Clinical Features

Hib can affect many organ systems. The most common types of disease are meningitis, bacteremia, epiglottitis, pneumonia, arthritis, and cellulitis.

Meningitis, an infection of the membranes covering the brain and spinal cord, is the most common clinical manifestation of invasive Hib disease, accounting for 50% to 65% of cases in the prevaccine era. Hallmarks of meningitis are fever, decreased mental status, and stiff neck. Hearing impairment or other neurologic sequelae occur in 15% to 30% of survivors. The case fatality ratio is 3% to 6%, despite appropriate antimicrobial therapy.

Epiglottitis is an infection and swelling of the epiglottis, the tissue in the throat that covers and protects the larynx during swallowing. Epiglottitis may cause life-threatening airway obstruction.

Septic arthritis, cellulitis, and pneumonia (which can be mild focal or severe empyema) are common manifestations of invasive Hib disease. Osteomyelitis and pericarditis are less common forms of invasive disease.

Otitis media and acute bronchitis due to H. influenzae are generally caused by nontypeable strains. Hib strains account for only 5% to 10% of H. influenzae causing otitis media.

Non-type b encapsulated strains can cause invasive disease similar to type b infections. Nontypeable strains are generally less virulent than encapsulated strains among previously healthy individuals, but may cause invasive disease, particularly among neonates and those older than age 65 years.

Epidemiology

Secular Trends in the United States

Before the availability of national reporting data, several areas conducted active surveillance for H. influenzae disease, which allowed national estimates of disease. In the early 1980s, it was estimated that about 20,000 cases occurred annually in the United States, primarily among children younger than age 5 years (40 to 50 cases per 100,000 population). The incidence of invasive Hib disease began to decline dramatically in the late 1980s, coinciding with licensure of Hib conjugate vaccines, and has declined by more than 99% since the prevaccine era.

Active Bacterial Core surveillance (ABCs) data includes serotype information on all invasive H. influenzae isolates. The number of cases and deaths of invasive H. influenzae infections in the United States increased from 3,400 in 1997 to 6,840 in 2018. Approximately 11.8% of cases died. While the rate of invasive H. influenzae infections increased from 1.23 per 100,000 population in 1997 to 2.08 per 100,000 population in 2018 in the surveillance areas, the rate of Hib infections decreased from 0.1 per 100,000 population in 1997 to 0.02 per 100,000 population in 2018. Among children younger than age 5 years in 2018, the rate of invasive H. influenzae disease was 0.08 per 100,000 population and 38 cases of invasive disease due to Hib were reported in the United States. An additional 9 cases of Hib are estimated to have occurred among the 175 reports of invasive H. influenzae infections with an unknown serotype.

From 2009–2018, 36 Hib cases in patients younger than age 5 years were reported to ABCs. Two (5.6%) were too young to have received Hib vaccine, 12 (33.3%) were unvaccinated, and 14 (38.9%) were undervaccinated (10 of 14 had received the 3-dose primary series but were missing a booster dose at age 12 through 15 months). Eight (22.2%) were age-appropriately vaccinated and had no reported underlying conditions; three of these were 3-month-old infants who had been age-eligible for only the first dose of Hib vaccine.

Secondary cases of Hib disease occur but are rare. Secondary Hib disease is defined as illness occurring 1 to 60 days following contact with an ill person, and accounts for less than 5% of all invasive Hib disease. Secondary attack rates are higher among household contacts younger than age 48 months (2.1%), especially those younger than age 12 months (6%) and younger than age 24 months (3%). In these household contacts, 64% of secondary cases occurred within the first week (excluding the first 24 hours) of disease onset in the index patient, 20% during the second week, and 16% during the third and fourth weeks.

Among children born during 2016–2017, 92.2% had received the Hib vaccine primary series (at least 2 or 3 doses, depending on product) and 79.9% had received the full series (primary series and booster; at least 3 or 4 doses, depending on product type) by age 24 months.

Haemophilus influenzae type b Vaccines

A pure polysaccharide vaccine was licensed for use in the United States in 1985 and was used until 1988. The vaccine had low efficacy and is no longer available in the United States.

The characteristics of the Hib polysaccharide vaccine were similar to other polysaccharide vaccines. The response to the vaccine was typical of a T-independent antigen, most notably an age-dependent immune response and poor immunogenicity in children age 2 years or younger. In addition, no boost in antibody titer was observed with repeated doses, the antibody that was produced was relatively low-affinity IgM, and switching to IgG production was minimal.

The first Hib conjugate vaccine was licensed in 1987. Conjugation is the process of chemically bonding a polysaccharide to a more effective protein carrier. This process changes the polysaccharide from a T-independent to a T-dependent antigen and greatly improves immunogenicity, particularly in young children. In addition, repeat doses of conjugate vaccines elicit booster responses and allow maturation of class-specific immunity with predominance of IgG antibody. The conjugates also cause carrier priming and elicit antibody to "useful" carrier protein.

Three monovalent Hib polysaccharide-protein conjugate vaccines (ActHIB, PedvaxHIB, and Hiberix) are currently licensed for use in the United States.

Two combination vaccines containing Hib are currently licensed for use, DTaP-IPV/Hib (Pentacel) and DTaP-IPV-Hib-HepB (Vaxelis).

Vaccination Schedule and Use

All infants should receive a primary series of Hib conjugate vaccine (monovalent or combination vaccine) beginning at age 2 months. The number of doses in the primary series depends on the type of vaccine used. A primary series of Hib (PRP-T) requires 3 doses, whereas Hib (PRP-OMP) requires 2 doses. A booster dose is recommended at age 12 through 15 months, regardless of which vaccine is used for the primary series. The recommended age for dose 4 of DTaP-IPV/Hib is age 15 through 18 months, but it can be administered as early as age 12 months, provided at least 6 months have elapsed since dose 3.

Haemophilus influenzae type b (Hib) Routine Vaccination Schedule

_{*The recommended age for dose 4 of DTaP-IPV/Hib (Pentacel) is age 15 through 18 months, but it can be administered as early as 12 months, provided at least 6 months have elapsed since dose 3.
†The recommended age for dose 4 of Hib (PRP-T) (Hiberix) is age 15 months, but to facilitate timely booster vaccination, it may be administered as early as age 12 months.
§The recommended minimum age for dose 3 of DTaP-IPV-Hib-HepB (Vaxelis) is 24 weeks, the minimum age for completion of the hepatitis B vaccine series.}

The recommended interval between doses in the primary series is 8 weeks, with a minimum interval of 4 weeks. At least 8 weeks should separate the booster dose from the previous (2nd or 3rd) dose. If DTaP-IPV/Hib is administered for the booster dose, at least 6 months need to have elapsed since dose 3.

Hib vaccines should be given at the same visit as other recommended vaccines.

Limited data suggest Hib conjugate vaccines administered before age 6 weeks can induce immunologic tolerance, reducing the response to subsequent doses of Hib vaccine. Therefore, Hib vaccines, including combination vaccines containing Hib conjugate vaccine, should never be administered to a child younger than age 6 weeks.

The monovalent Hib conjugate vaccines are interchangeable. A series that includes vaccine of more than one brand will induce a protective antibody level. If a child receives different brands of Hib vaccine at age 2 and 4 months, a 3rd dose of any brand should be administered at age 6 months to complete the primary series. Any of these vaccines may be used for the booster dose, regardless of which vaccines were administered for the primary series. Data on the interchangeability of Hib combination vaccine with monovalent vaccines are limited. Whenever feasible, the same combination vaccine should be used for the subsequent doses.

Unvaccinated children age 7 months or older may not require a full series of 3 or 4 doses. The number of doses a child needs to complete the series depends on the child's current age.

Haemophilus influenzae type b Vaccine Schedule for Previously Unvaccinated Children

Contraindications and Precautions to Vaccination

As with other vaccines, a history of a severe allergic reaction (anaphylaxis) to a vaccine component or following a prior dose is a contraindication to further doses. Moderate or severe acute illness with or without fever in a patient is considered a precaution to vaccination, although persons with minor illness may be vaccinated.

Hib conjugate vaccines are contraindicated for children younger than age 6 weeks because of the potential for development of immunologic tolerance.

Contraindications to combination vaccines that contain Hib include the contraindications to the individual component vaccines, but specific ingredients might differ.

Vaccine Safety

Adverse reactions following Hib conjugate vaccines are not common. Swelling, redness, or pain have been reported in 5% to 30% of recipients and usually resolve within 12 to 24 hours. Systemic reactions such as fever and irritability are infrequent.

Among reports to the Vaccine Adverse Event Reporting System (VAERS) following Hib vaccination, the most frequently reported adverse events were fever (31%), crying (11%), injection site erythema (11%), irritability (10%), and rash (9%). The median time from vaccination to onset of an adverse event was 1 day. The adverse event reporting frequencies for Hib vaccines are similar to those of other childhood vaccines; no unusual or unexpected safety concerns were observed in VAERS data for Hib vaccines.

In an observational study conducted by the Vaccine Safety Datalink of DTaP-IPV/Hib, children age 1 to 2 years who received DTaP-IPV/Hib had an elevated risk of fever compared to children who received DTaP-containing control vaccine (i.e., without Hib vaccine). DTaP-IPV/Hib was not associated with any other medically-attended adverse health event.

Vaccine Storage and Handling

Hib vaccines should be maintained at refrigerator temperature between 2°C and 8°C (36°F and 46°F). Manufacturer package inserts contain additional information. For complete information on best practices and recommendations for vaccine storage and handling, please refer to CDC’s Vaccine Storage and Handling Toolkit. 

Surveillance and Reporting of Hib Disease

Reporting of H. influenzae varies by state. Invasive H. influenzae infections became nationally notifiable in 1991. Reporting of serotype information continues to be incomplete. For information on the case definition and guidance on case and contact investigations, please consult the Manual for the Surveillance of Vaccine-Preventable Diseases.

Acknowledgements

The editors would like to acknowledge Elizabeth Briere, Susan Hariri, and Heidi Soeters for their contributions to this chapter.

Selected References

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