Haemophilus influenzae Type b Vaccines

Clinical Overview

Hib can cause a variety of clinical syndromes such as meningitis, pneumonia, epiglottitis, orbital cellulitis empyema, osteomyelitis, septic arthritis, cellulitis, and bacteremia without focus. Fig. 25.1 shows the distribution of bacterial culture–positive invasive Hib diseases (i.e., those where Hib is isolated from blood, CSF [cerebrospinal fluid], or other normally sterile fluids) seen globally in the prevaccine era. The global burden of morbidity and mortality was largely due to pneumonia and meningitis ( Table 25.1 ). Hib can rarely cause diseases of the upper respiratory tract disease, including otitis media and sinusitis, and bronchitis. Other diseases that have been associated with Hib include epididymitis, endocarditis, peritonitis, and tracheitis. Although many diseases associated with Hib have virtually disappeared in areas that have adopted the conjugate vaccine, it is important to educate healthcare providers about the devastating consequences of Hib disease as an impetus to promote vaccination.

Microbiology

H. influenzae is a non–spore-forming Gram-negative coccobacillus. It requires two accessory (X and V) factors for growth in vitro, both naturally present in erythrocytes. The X factor is a porphyrin, such as hemin, and the V factor is nicotinamide adenine dinucleotide. The requirement of both factors for multiplication differentiates H. influenzae from other Haemophilus species.

A polysaccharide capsule is a major virulence factor for several bacteria, including H. influenzae . Capsules are thought to facilitate evasion of the mucosal immune response by resisting the bactericidal and opsonic activities of complement and protecting the bacterium from phagocytosis. ^, The greater pathogenic potential of type b encapsulated H. influenzae strains as compared with the other encapsulated H. influenzae serotypes has been the subject of intense investigation. Hib possesses a capsule composed of polyribosylribitol phosphate (PRP), the structure of which was initially described in 1975. The Hib polysaccharide capsule is thought to be particularly effective for evading complement-mediated killing and to avoid splenic clearance. ^,

Additionally, polysaccharide antigens induce a T-cell–independent antibody response. They are recognized by B-cell receptors, but they cannot be presented to T cells in conjunction with major histocompatibility complex class II molecules. With T-cell–independent immune responses, the development of memory B cells does not occur, and poor immunologic memory is induced. In addition, polysaccharide antigens induce relatively low titers of serum antibodies in children younger than 2 years of age. The reason for the poor antibody response in young children remains unclear, but on the basis of animal models has been attributed to immunologic immaturity, increased suppressor T-cell activity, immature antigen processing by macrophages, and absence of a late-appearing class of T-cell–independent B cells that play a role in the production of antipolysaccharide antibodies. ^,

There are also noncapsular factors that contribute to the virulence of Hib and other H. influenzae strains. An important component of the H. influenzae cell envelope is the lipooligosaccharide (LOS), which contains endotoxin. It has been suggested that genes encoding LOS of type b strains result in the expression of surface-exposed epitopes that are toxic to the epithelial cells of the upper respiratory tract of animals. ^, The LOS of Hib strains may also aid in protecting the organism from host immune defenses by affecting the ability of the organism to survive and replicate in macrophages. ^, Several strains of H. influenzae are capable of expressing pili, which are considered to have a role in mediating adherence to host cells. Piliated variants of Hib have shown increased binding to human oropharyngeal cells in vitro compared with nonpiliated organisms. In addition, the ability to alternate between piliated and nonpiliated forms may increase the virulence of the organism. In a nasopharyngeal tissue culture model, Hib was shown to bind to the mucus above the epithelial surface, with piliated organisms having a growth advantage at this stage. At 12 hours into infection, Hib organisms were seen intracellularly, with nonpiliated bacteria having an advantage at this invasion stage. This variable expression of pili enables the organism to adapt successfully at the different stages of colonization and infection.

Pathogenesis

Hib is an obligate human pathogen that spreads from person to person via respiratory droplets and direct contact with respiratory secretions. It enters the body via the upper respiratory tract and colonizes the pharyngeal mucosa. Hib disease is caused by spread through the respiratory tract or by invasion of the mucosal surface and subsequent hematogenous spread. Individuals may remain colonized with Hib for months. Prevalence of pharyngeal carriage varies with geographic location, age, crowding, and vaccine coverage in the population. In the prevaccine era, 3–5% of healthy preschool-age children in high-income nations were asymptomatic Hib carriers. ^{, ,} Studies in India and Thailand from the prevaccine years showed Hib carriage prevalence of 6–8%. ^, Before routine vaccine use in the United States, carriage prevalence among white infants was low (0.7%) in the first 6 months of life and increased to approximately 2% in the 6- to 11-month age group. The highest prevalence (up to 5%) was seen in the preschool-age group, and the prevalence gradually declined in adulthood. Among Navajo and Apache infants before the use of the Hib-CVs, the prevalence of carriage was 3% in children as young as 3 months of age, which may have contributed to the high incidence rates of invasive Hib disease seen in young children in these populations. ^, Household crowding and attendance at a daycare center where there was an infected child are associated with an increased risk of carriage. ^{, ,}

Only a small fraction of people colonized with Hib become ill. It has been hypothesized that disruption of the respiratory epithelium, such as with viral infection, cigarette smoke, or indoor air pollution, facilitates binding to and/or penetration of the upper respiratory tract by various bacteria. Recent viral infections are a risk factor for developing invasive Hib disease. One study showed that rats infected intranasally with influenza A virus had increased frequency and magnitude of bacteremia following subsequent inoculation with Hib. Once Hib enters the bloodstream, the organism causes disease at distant sites if not cleared by the host immune system. The occurrence of different disease syndromes is thought to depend, at least partially, on the density of organisms circulating in the host bloodstream. For Hib meningitis, a density of 10 ³ colony-forming units (CFU) per milliliter was needed in the bloodstream for at least 6 hours in infant primate models. Studies in children with Hib meningitis demonstrate that the majority had more than 10 ³ CFU/mL of Hib circulating in the blood at admission implying that serious consequences of infections with Hib such as meningitis are more likely to occur when there is a higher concentration of Hib in the blood. ^,

Diagnosis

Definitive diagnosis of Hib disease is based on detecting bacterial growth or molecular markers of the Hib bacteria in a sample in the appropriate clinical setting. Culturing Hib from blood or other infected body fluids requires specific transport and growth conditions. Ideally, processing should occur within a few hours of specimen collection. Bacterial growth requires chocolate agar or another medium that contains the accessory factors hemin and nicotinamide adenine dinucleotide, a 3–5% carbon dioxide environment, and a constant temperature between 35°C and 37°C. Automated culture systems have alleviated many issues with growing Hib in high resource settings. Of note, antibiotic use before specimen collection reduces the sensitivity of culture significantly.

Nonculture diagnostic methods are more sensitive and rapid. They are critical in settings where conditions for Hib isolation from traditional culture methods are not ideal because of the use of antibiotics prior to obtaining laboratory specimen or poor laboratory facilities. Studies demonstrate that analysis of CSF by polymerase chain reaction (PCR) has 100% sensitivity and 75–96% specificity compared with culture. ^, Detection of the Hib polysaccharide antigen in the CSF is diagnostic of Hib meningitis. Proven CSF antigen-detection methods include counterimmunoelectrophoresis (CIE), coagglutination, latex agglutination (LA), and latex particle agglutination (LPA). The CIE method uses an applied electrical field across a diffusion medium to evaluate the binding of an antibody to an antigen. Coagglutination involves mixing an agglutinin into a sample to observe the aggregation of the antigens. The LPA method involves mixing a sample with latex beads coated with an antibody to observe whether clumping occurs by an antigen binding with the antibodies. One study compared all three detection methods with CSF culture and found that LPA had a sensitivity of 78% and specificity of 100%; CIE, a sensitivity and specificity of 67%; and coagglutination, a sensitivity of 78% and specificity of 97%. PCR and antigen detection methods are able to identify Hib in CSF even in the presence of prior antibiotic use. ^{, ,} These diagnostic techniques were essential to demonstrate the burden of disease, particularly in Asia where positive culture rates for invasive Hib were low because of antibiotic use prior to diagnosis or limited diagnostic capabilities.

Urine and serum antigen detection was examined to aid in the diagnosis of Hib disease. In studies of patients with bacteremic pneumonia and meningitis, detection of antigenemia using LPA had a sensitivity of 90–100%. However, the specificity of the Hib antigenemia and antigenuria approach is limited due to several factors. Hib carriage can cause Hib antigen to be present even in the absence of clinical disease, there is cross-reactivity with certain bacteria such as Escherichia coli K1 and K100 and Streptococcus pneumoniae type 6, and vaccination with Hib-CV has been shown to induce transient Hib antigen presence. ^, Studies in Navajo infants in the United States and in The Gambia have shown a prevalence of antigenuria in more than 80% children of in the week following Hib-CV, and that antigenuria persisted for several weeks in some children. ^, Given the widespread use of vaccine, poor specificity, and decrease in disease burden, there is limited interest to explore such diagnostic methods.

Treatment

Treatment of Hib disease requires early assessment and identification of the illness, administration of appropriate antibiotic therapy, and supportive management of sequelae. Most diseases that Hib can cause, such as pneumonia and meningitis, are initially treated empirically to cover all common etiologic agents based on the antibiotic resistance in the community. Regional and global guidelines are available. ^, Once a specific etiology is determined, antibiotics are then narrowed to cover the specific pathogen guided by the antibiotic susceptibility profile of the organism.

Chemoprophylaxis of household contacts is recommended in certain cases because of the occurrence of secondary infections. Rates of secondary disease were documented to be approximately 0.6% in one study, with contacts younger than 2 years of age at highest risk. ^, One national study showed that in the 30 days following initial illness, the risk for household contacts developing Hib meningitis was 585 times the risk in the age-adjusted general U.S. population. Chemoprophylaxis with rifampin is recommended for all household contacts of a case of Hib if the household has a child younger than 12 months of age who has not received the primary Hib-CV series, a child younger than age 4 years who is incompletely immunized, or an immunocompromised child. Daycare contacts should receive prophylaxis only if two or more cases of invasive Hib disease have occurred within 60 days.

The first antibiotic-resistant Hib isolates were reported in Europe and the United States between 1972 and 1974. Since then, the proportion of resistant strains has increased across the world. Studies show that 20–60% of isolates produce β-lactamase and are resistant to ampicillin. ^, In a study from Kenya looking at Hib susceptibility to amoxicillin, chloramphenicol, and TMP-SMX, of a total of 236 blood or CSF isolates from children admitted with meningitis or sepsis, 40% were resistant to at least two antibiotics and 28% were resistant to all three antibiotics. Resistance to these three antibiotics increased during the 9 years of the study (1994–2002). Worsening trends of resistance to ampicillin, chloramphenicol, and TMP-SMX have also been seen in many American, Asian, and African countries. Emerging resistance to the cephalosporins has been shown. A study in Korea carried out between 1992 and 1997 showed that of 55 Hib strains, 15% had only intermediate susceptibility to cefprozil and cefaclor. In Mali, of 207 Hib isolates from blood, 0.5% were resistant to ceftriaxone. Fortunately resistance to later generation cephalosporins is rare, and they remain as an effective option for empiric treatment.

Incidence and Prevalence

Before the routine use of Hib-CVs, more than 95% of all invasive H. influenzae disease was caused by serotype b. The annual incidence of invasive disease caused by Hib in the general U.S. population was estimated at 20–88 per 100,000 children younger than 5 years of age, with approximately 20,000 recognized cases each year, more than 50% of which were cases of meningitis. Reported rates of invasive disease in Europe varied. Studies in Spain and France showed invasive disease rates of 12 and 21 cases per 100,000, respectively. ^, Reported rates in Scandinavia were higher; the incidences reported from Finland and Sweden were 41 and 54 cases per 100,000 children younger than age 5 years, respectively. ^, It is not clear whether these differences in reported incidence rates reflect differences in surveillance methods or true differences in incidence.

Certain U.S. populations were at higher risk of Hib disease. For example, the incidence of invasive Hib disease in Navajo, Apache, and Alaskan Eskimos children was found to be 152, 250, and 491 per 100,000 children younger than 5 years of age, respectively. ^{, ,} Australia reported similar population differences in rates of Hib invasive disease. Nonindigenous children had an incidence rate for Hib invasive disease ranging from 33 to 60 cases per 100,000 children younger than 5 years of age, while indigenous children were found to have rates as high as 500 per 100,000 children.

The burden in developing countries was much greater than in high-income countries. In 2000 alone, prior to widespread introduction to low-income countries, Hib was estimated to cause 8.13 million cases of disease and 371,000 deaths. A review and meta-analysis estimated a global Hib meningitis incidence rate of 31 per 100,000 (uncertainty range: 16–39 per 100,000) in children younger than age 5 years in 2000. Studies in Africa have consistently found high rates of Hib disease. For example, in Uganda and The Gambia, the incidence rates of Hib meningitis in children younger than 5 years of age were 88 and 60 per 100,000 before vaccine introduction, respectively. Significant rates of Hib disease have also been documented in the Middle East and the Pacific island countries. A review of studies from Asia published between 1998 and 2009 showed that 60% of studies identified Hib as the most common cause of bacterial meningitis and that the incidence rate of Hib meningitis ranged from 0.98 to 28 per 100,000 children younger than 5 years of age. A surveillance study of children younger than age 5 years in Sri Lanka showed Hib was responsible for 50% of the 108 meningitis cases in which an etiology was identified. A prospective population-based surveillance study in India showed a Hib meningitis incidence of 7.1 per 100,000 (95% CI, 3.1–14.0) children younger than 5 years. An expert panel that reviewed the literature on Hib disease in Asia concluded that many studies underestimated the true incidence of Hib because of antibiotic use before diagnostic testing, delayed contact with health providers, low rates of lumbar puncture, and inadequate specimen processing.

In an effort to address these issues, vaccine probe studies were carried out in Indonesia and Bangladesh. ^, In Indonesia a vaccine-preventable, laboratory-confirmed Hib meningitis incidence rate of 16 (95% CI, 1.4–31) per 100,000 children younger than 2 years was found. However, the rate of meningitis with CSF findings consistent with a bacterial cause (not necessarily culture-confirmed) prevented by Hib-CV was 67 (95% CI, 22–112) per 100,000 children younger than 2 years of age. The results of this study suggest that bacterial cultures identify less than 25% of bacterial meningitis cases in areas of the world where antibiotics are extensively used prior to obtaining a CSF specimen.

Characterization of pneumonia due to Hib is challenging to assess given the difficulty of identifying an exact etiology. However studies have used vaccination as a way to determine the proportion of clinical pneumonias and pneumonias with radiographic consolidation in children that are caused by Hib. ^{, ,} Prior to widespread use of Hib-CVs in low-income countries the incidence of Hib pneumonia globally was 1303 per 100,000 children under 5 years old, resulting in an estimate 7,910,000 cases annually. The case fatality rate of pneumonia is low compared to disease such as meningitis, but the high number of pneumonia cases means that the majority of global deaths due Hib were as a result of pneumonia. In 2000 Hib pneumonia caused approximately 292,000 deaths, or 79% of all deaths due to Hib.

Risk Factors