Hib disease was the leading cause of bacterial meningitis and a major cause of other serious invasive diseases among children aged <5 years in the U.S. before Hib conjugate vaccines became available in 1987. Since the introduction of the Hib vaccine, cases of Hib disease have dropped from 20,000 in 1980 to a total of 341 cases from 1996-2000.  In 2006, the incidence of Hib disease in the United States in children < 5 years of age was 0.21/100,000.  However, the disease continues to circulate in both industrialized and developing countries and it is estimated that the disease still kills as many as 400,000 children globally every year. Although Hib disease has been reduced by 99% in the U.S., the disease could easily make a comeback should Hib vaccination rates drop. 

Worldwide, the Hib vaccine has been relatively unavailable.  However, great strides have been made in making the Hib vaccine available for the poorest children of the world.  In 2007, the number of countries that have access to the Hib vaccine had increased from 18 to 65 percent, largely due to the efforts of the Global Alliance for Vaccines and Immunization (GAVI).  

While there are six strains of H. influenzae that have been classified (types a through f) and other non-typeable strains, type b accounts for 95 percent of all strains causing invasive disease. A vaccine is available to prevent against the type b infection.
Invasive Hib disease usually manifests itself clinically as meningitis, accounting for 50 to 65 percent of all cases. Hallmarks of meningitis are fever, decreased mental stability and stiff neck. The pneumonia that follows Hib meningitis can be mild or severe.
Hib disease can also produce epiglottitis, arthritis, cellulitis, and other conditions. Septic arthritis manifests itself as joint infection; cellulitis is a rapidly growing skin infection, usually on the face, head or neck. Epiglottitis is an infection and swelling of the tissue in the throat that covers and protects the larynx during swallowing, sometimes causing a life threatening airway obstruction.

H. influenzae enter the body through the nasopharynx, where the bacteria colonize; the mode of transmission into the bloodstream is unknown. However, once in the bloodstream, H. influenzae can affect many organ systems and result in serious complications, including death.

As previously noted, Hib disease susceptibility is generally age-dependent. Hib disease generally affects children under 5 years of age; 60 percent of invasive disease occurs in those younger than 12 months with a peak occurrence at 6 to 11 months of age (prior to the introduction of Hib conjugate vaccines).  When a young child presents with fever, general malaise and decisions for evaluation are made, immunization for Haemophilus as well as pneumococcal disease should be verified.

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Epidemiology

• Occurrence - Hib disease occurs worldwide because the organism continues to circulate in both industrialized and developing countries. Hib disease remains a public health concern in the U.S. and other industrialized countries due to the reservoir of disease in the adult population and continuous circulation of the organism in the community.
   
• Reservoir/Communicability - Humans remain the only reservoir of Hib disease. Hib does not survive in the environment on inanimate surfaces. Close contact with an infected individual (e.g., household, day care, or institutional setting) can lead to outbreaks or direct secondary transmission of the disease, especially to an unimmunized child. Carriage (or colonization) rates are highest in pre-school age children. Carriage rates can be as high as 58-91% in households or daycare centers in which a case has occurred. High immunization rates are essential to continue to control this disease in the U.S.
   
• Transmission - The primary mode is presumably by the spread of respiratory droplets, although firm evidence for this mechanism is lacking.
  
  
• Temporal Pattern - Several studies in the prevaccine era described a bimodal seasonal pattern in the U.S., with one peak between September and December, and a second peak between March and May. The reason for this bimodal pattern is not known.

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Trends In The United States

H. Influenzae infections became nationally reportable in 1991. Serotype-specific reporting continues to be incomplete. Prior to the availability of national reporting data, several areas carried out active surveillance for H. influenzae disease, which allowed estimates of disease nationwide. In the early 1980s, it was estimated that about 20,000 cases occurred annually in the U.S., primarily among children younger than 5 years of age (40-50 cases per 100,000 population). The incidence of invasive Hib disease began to fall dramatically in the late 1980s due to the introduction of Hib conjugate vaccines, and has since declined by >99% compared to the prevaccine era

According to the CDC, the U.S. experience with Hib conjugate vaccines has shown a decreased rate of Hib carriage among vaccinated children, thereby decreasing the chance that unvaccinated children will be exposed. This trend would indicate that high immunization levels also decrease the circulation of the organism. According to the CDC, most recent cases of Hib disease in the U.S. have occurred in unvaccinated or incompletely vaccinated children.

From 1996 through 2000, an average of 1,247 invasive H. influenzae cases were reported to CDC in all age groups (range 1,162-1,398 per year). Of these, an average of 272 (approximately 22%) per year were among children <5 years of age. Serotype was know for 76% of the invasive cases among children aged <5 years. Three-hundred-forty-one (average of 68 cases per year) were due to type b.

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A gram stain of an infected body fluid may demonstrate small gram-negative coccobacilli suggestive of invasive Hib disease. Cerebrospinal fluid (CSF), blood, pleural fluid, joint fluid, and middle ear aspirates should be cultured on the appropriate media. A positive culture for H. influenzae establishes the diagnosis.

All isolates of H. influenzae should be serotyped. This is an essential laboratory procedure that needs to be performed on every isolate of H. influenzae, especially those obtained from children <15 years of age. This test determines whether an isolate is type b, and therefore vaccine preventable. Serotyping is performed at either a state health department laboratory or a reference laboratory.

Hospitalization for supportive care is generally required in infants and others with severe Hib disease. Antimicrobial therapy should begin immediately with treatment usually lasting 10 to 14 days.

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Prevention

Risk Factors and the Role of Carriage

Susceptibility to Hib disease depends on host and exposure factors. Localized populations such as Native American Indians, Hispanics, and African-Americans, experience higher incidence rates, despite sustained national Hib vaccination coverage of >90%. As in the prevaccine era, persistently higher invasive Hib disease rates among American Indian/Alaskan Native children suggest that Hib elimination will require additional characterization of colonization and disease among these high-risk populations.

The organism continues to circulate through oropharyngeal carriage (colonization in the mouth and throat) in the general population, underscoring the importance of maintaining high Hib vaccination rates among susceptible infants. Continuous presence of the organism in infected populations or even in the general U.S. population presents a serious barrier that needs to be addressed.

In some cases, Hib carriage is asymptomatic, but it can lead to symptomatic disease among infants and young children. Factors, such as household crowding, daycare attendance, socioeconomic status, low parental education levels, and having school-aged siblings also increase the risk for disease. Thus, disease risk is associated with the prevalence of Hib carriage among household members. High immunization rates for all recommended doses in older children are essential to control asymptomatic carriage and transmission to the greatest extent possible.

Hib carriage can persist for weeks to months before the bacteria is cleared from the oropharynx. Risk factors for Hib disease reflect person-to-person transmission through respiratory droplets from carriers and those infected with Hib disease. The ability to eliminate Hib disease and ultimately carriage may depend upon population characteristics, vaccination coverage, and Hib vaccine type used.

Experience with Hib conjugate vaccines has shown that Hib vaccines are both safe and effective. Across a wide range of epidemiologic situations, routine Hib conjugate immunization has consistently led to decreases in invasive Hib disease of 90% throughout the world.

All Hib conjugate vaccines have been shown to be efficacious against invasive Hib disease in clinical trials. However, they differ in the timing and extent of antibody response. Several researchers have linked higher anti-PRP titers following immunization with higher effectiveness of protection against Hib disease. Anti-PRP serum antibody concentrations or geometric mean concentrations (GMC) of 1.0 micrograms/ml have been generally regarded as the thresholds of long-term protection against Hib disease. Further, while the dynamics of carriage and disease transmission are likely to be multifactorial, it has been hypothesized that high serum anti-PRP IgG antibodies are responsible for decreasing carriage and colonization.

This points to the fact that optimal interventions to reduce Hib disease incidence and transmission may depend on multiple factors including vaccine type, vaccination schedule, the specific population epidemiology, and other environmental factors. Strategies to reduce Hib disease burden to the lowest possible levels need to balance epidemiological, immunological, and programmatic considerations.

The early prevention of Hib disease through immunization remains the first line of defense against the disease and its circulation.  HIB vaccine is available as a single vaccine or in combination vaccines and four conjugate Hib vaccines are currently available:

• Monovalent Hib vaccines – PedvaxHIB® [Merck] and ActHibÒ [sanofi pasteur]

• Combination vaccines – COMVAX® (Hib/hepatitis B vaccine) [Merck] and TriHIBit® (diphtheria and tetanus toxoids and acellular pertussis [DTaP]/Hib vaccine) [sanofi pasteur]

View the CDC’s 2008 Recommended Immunization Schedule for Persons Aged 0 – 6 Years

Surveillance and Reporting of Hib Disease

All cases of Hib disease should be reported immediately to your state or local health department. Information on this procedure can be found in the Reporting Guide section of Hibdisease.com. (For more details on U.S. and other surveillance systems, see Epidemiology above)

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References:

1. Adegbola, R.A., Mulholland, E.K., Secka, O., Jaffar, S., & Greenwood, B.M. (1998). Vaccination with a Haemophilus influenzae type b conjugate vaccine reduces oropharyngeal carriage of H. influenzae type b among Gambian children. Journal of Infectious Disease, 177, 1758-61.

2. Akumu, A.O. (2007). Economic evaluation of delivering Haemophilus influenzae type b vaccine in routine immunization services in Kenya.  Bulletin of the World Health Organization, 85(7), 511-8.

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6. Centers for Disease Control and Prevention (CDC). Interim recommendations for the use of Haemophilus influenzae Type b (Hib) Conjugate vaccines related to the recall of certain lots of Hib-containing Vaccines (Pedvax HIB and Comvax). MMWR, December 21, 2007, 56 (50), 1318-20.

7. Centers for Disease Control and Prevention (CDC). Recommended immunization schedules for persons aged 0-18 years – United States, 2008. MMWR, 57, (01); Q-1-Q-4.

8. Centers for Disease Control and Prevention (CDC). Morbidity & Mortality Weekly Report, March 22, 2002: Vo. 51; No. 11.

9. Centers for Disease Control and Prevention (CDC), Pink Book: Haemophilus Influenzae Type b, http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/hib.pdf, 2007.

10. Decker, M.D., Edwards, K.M., Bradley, R., & Palmer, P. (1992). Comparative trial in infants of four conjugate Haemophilus influenzae type b vaccines. Journal of Pediatrics, 120, 184-9.

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12. Granoff, D. (2001). Type b Combination Vaccines Assessing Efficacy of Haemophilus influenzae. Journal of Clinical Infectious Diseases, 33, S278-84.

13. Heath, P.T., Bowen-Morris, J., Griffiths, D., Griffiths, H., Crook, D.W., & Moxon, E.R. (1997). Antibody persistence and Haemophilus influenzae type b carriage after infant immunisation with PRP-T. Archives of Disease in Childhood, 77, 488-92.

14. Howie, S.R., Antonio, M., Akisanya, A., Sambou, S., Hakeem, I., Secka, O., & Adegbola, R.A. (2007).  Re-emergence of Haemophilus influenzae type b (Hib) disease in The Gambia following successful elimination with conjugate Hib vaccine. Vaccine, 25(34), 6305-9.

15. Marshall, G.S., Happe, L.E., Lunacsek, O.E., Szymanski, M.D., Woods, C.R., Zahn, M., & Russel, A. (2007).  Use of combination vaccines associated with improved coverage rates.  Pediatric Infectious Disease Journal, 26(6), 496-500.

16. Murphy, T.V., Pastor, P., Medley, F., Osterholm, M.T., & Granoff, D.M. (1993). Decreased Haemophilus influenzae colonization in children vaccinated with Haemophilus influenzae type b conjugate vaccine. Journal of Pediatrics, 122, 517-23.

17. Southern, J., McVernon, J., Gelb, D., Andrews, N., Morris, R., Crowley-Luke, A., Goldblatt, D., & Miller, E. (2007). Immunogenicity of a Fourth Dose of Haemophilus influenzae Type b (Hib) Conjugate Vaccine and Antibody Persistence in Young Children from the United Kingdom Who Were Primed with Acellular or Whole-Cell Pertussis Component-Containing Hib Combinations in Infancy. Clinical Vaccine Immunology, 14(10), 1328-33.

18. Takala, A.K., Eskola, J., Leinonen, M., Kayhty, H., Nissinen, A., Pekkanen, E., et al. (1991). Reduction of oropharyngeal carriage of Haemophilus influenzae type b (Hib) in children immunized with an Hib conjugate vaccine. Journal of Infectious Disease, 164, 982.

19. Takala, A.K., Santosham, M., Almeido-Hill, J., Wolff, M., Newcomer, W., Reid, R., Kayhty, H., Esko, E., & Makela, P.H. (1993). Vaccination with Haemophilus influenzae type b meningococcal protein conjugate vaccine reduces oropharyngeal carriage of Haemophilus influenzae type b among American Indian children. Pediatric Infectious Disease Journal, 12, 593-9.

20. Watt, Levine, Santosham, Submitted as a supplement to The Journal of Pediatrics; Global Reduction Of Hib Disease: What Are The Next Steps? - Proceedings Of The Meeting; Scottsdale, AZ, September 22-25, 2002.

21. Williams, E.R., Meza, Y.E., Salazar, S., Dominici, P., & Fasano, C.J. (2007). Immunization histories given by adult caregivers accompanying children 3-36 months to the emergency department: are their histories valid for the Haemophilus influenzae B and pneumococcal vaccines? Pediatric Emergency Care 23(5), 285-8.

22. World Health Organization. (2008). Progress introducing Haemophilus influenzae type b vaccine in low-income countries, 2004-2008.  Weekly Epidemiological Record, 7(15), 62-7.

23. Zhou, F., Bisgard, K.M., Yusuf, H.R., Deuson, R.R., Bath, S.K., & Murphy, T.V. (2002).  Impact of universal Haemophilus influenzae Type B vaccination starting at 2 months of age in the United States: An economic analysis.  Pediatrics, 110, 653-61. 

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