Chapter 2: Haemophilus influenzae invasive disease

Disease Description

Haemophilus influenzae invasive disease is caused by the bacterium Haemophilus influenzae. H. influenzae may be either encapsulated (typeable) or unencapsulated (nontypeable). Six antigenically distinct capsular types of H. influenzae (types a–f) have been identified. Nontypeable strains are genetically diverse, with strains differing in pathogenic potential.

Both typeable and nontypeable H. influenzae can cause invasive and noninvasive disease. Invasive H. influenzae disease includes clinical syndromes of meningitis, bacteremia or sepsis, epiglottitis, bacteremic pneumonia, septic arthritis, pericarditis, cellulitis, osteomyelitis, and endocarditis. In contrast, syndromes of mucosal infections such as bronchitis, sinusitis, and otitis media are considered noninvasive disease. The noninvasive syndromes are not nationally notifiable.

Before the introduction of effective vaccines, H. influenzae serotype b (Hib) caused more than 95% of cases of invasive H. influenzae disease among US children younger than 5 years of age. Hib was the leading cause of bacterial meningitis in the United States among children younger than 5 years of age and a major cause of other life-threatening invasive bacterial diseases in this age group. Meningitis occurred in approximately two-thirds of children with invasive Hib disease, resulting in hearing impairment or permanent neurologic sequelae, such as seizure disorder, cognitive and developmental delay, and paralysis in 15%–30% of survivors. Approximately 4% of all cases were fatal.1

Background

Since the introduction of Hib polysaccharide and conjugate vaccines in 1985 and 1990, the incidence of invasive Hib disease in children younger than 5 years of age has decreased by 99%, to less than 1 case per 100,000.2345 Continued monitoring of invasive H. influenzae disease through Active Bacterial Core surveillance (ABCs), which includes serotype information on all invasive H. influenzae isolates, has demonstrated sustained low rates of invasive Hib disease in children younger than 5 years of age; between 2015 and 2022, the average incidence was 0.14 cases per 100,000 (unpublished data).

In the post-Hib vaccine era, the epidemiology of invasive H. influenzae disease in the United States has changed. The majority of invasive H. influenzae disease in all age groups is now caused by nontypeable H. influenzae.678 Using data from ABCs sites from 2015 through 2022, the estimated annual incidence of invasive nontypeable and non-b H. influenzae disease in children younger than 5 years of age was 1.49/100,000 and 1.17/100,000, respectively (unpublished data).

Importance of Rapid Case Identification

Rapid identification of cases is important to allow for early administration of chemoprophylaxis and Hib vaccine, if needed, to household and child care classroom contacts of case-patients.9 Early notification of H. influenzae invasive disease cases in children younger than 5 years of age is also important to ensure isolates are saved for serotyping.

Importance of Surveillance

H. influenzae surveillance information is used to describe the epidemiology of invasive H. influenzae disease, detect outbreaks, ensure rates of invasive Hib disease remain low in the post-vaccine era, and inform prevention and control measures.

Case Definition

The following case definition for invasive H. influenzae disease has been approved by the Council of State and Territorial Epidemiologists (CSTE) and was published in 2014.10

Clinical case description

Invasive disease may manifest as meningitis, bacteremia or sepsis, epiglottitis, bacteremic pneumonia, septic arthritis, pericarditis, or cellulitis; less common infections include endocarditis and osteomyelitis.

Laboratory criteria for diagnosis

• Detection of H. influenzae type b antigen in cerebrospinal fluid (CSF)
• Detection of H. influenzae-specific nucleic acid in a specimen obtained from a normally sterile body site (e.g., blood or CSF), using a validated polymerase chain reaction (PCR) assay
  

OR

• Isolation of H. influenzae from a normally sterile body site (e.g., CSF, blood, joint fluid, pleural fluid, or pericardial fluid)

Case classification

Probable: Meningitis with detection of H. influenzae type b antigen in CSF

Confirmed:

• Isolation of H. influenzae from a normally sterile body site (e.g., CSF, blood, joint fluid, pleural fluid, pericardial fluid)
  

OR

• Detection of H. influenzae-specific nucleic acid in a specimen obtained from a normally sterile body site (e.g., CSF, blood, joint fluid, pleural fluid, pericardial fluid), using a validated PCR assay

Comment: Positive antigen detection test results from urine or serum samples are unreliable for diagnosis of invasive H. influenzae disease and should not be used as a basis for case classification.

Positive antigen test results can occur from circulation of Hib antigen in urine or serum; this circulation can be caused by asymptomatic Hib carriage, recent vaccination, or fecal contamination of urine specimens. Cases identified exclusively by these methods should be considered suspect cases only.

Laboratory Testing

Rapid and reliable laboratory results are critical for prompt diagnosis and implementation of appropriate prevention and control measures. Refer to Chapter 22, "Laboratory Support for Surveillance of Vaccine-preventable Diseases" for specific information on specimen collection, identifying H. influenzae, determining H. influenzae serotypes, and antimicrobial susceptibility testing. Isolates of H. influenzae are important for antimicrobial susceptibility testing.

Specimen collection

Specimen collection and shipping are important steps in obtaining laboratory diagnosis or disease confirmation. Guidelines have been published for specimen collection and handling of microbiologic agents. Information is also available on using CDC laboratories as support for reference and disease surveillance; this includes

• a central website for requesting lab testing;
• the form required for submitting specimens to CDC (see CDC Form 50.34);
• information on general requirements for shipment of etiologic agents (Appendix 24)—although written to guide specimen submission to CDC, this information may be applicable to submission of specimens to other laboratories; and
• the CDC Infectious Diseases Laboratories Test Directory, which not only contains a list of orderable tests, but also detailed information on appropriate specimen types, collection methods, specimen volume, and points of contact.

Reporting and Case Notification

Case reporting within a jurisdiction

Each state and territory has regulations or laws governing the reporting of diseases and conditions of public health importance.11 These regulations and laws list the diseases to be reported and describe those responsible for reporting, such as healthcare providers, hospitals, laboratories, schools, childcare facilities, or other institutions. Reporting of H. influenzae varies by state; while some states report all known cases of invasive H. influenzae regardless of age or serotype, other states limit reporting to only cases of Hib or invasive cases among patients younger than 5 years of age. Persons reporting should contact their state health department for state-specific reporting requirements. Detailed information on reportable conditions in each state is available through CSTE.

Vaccine failure information should be collected for case-patients who received all recommended doses of Hib vaccines but still contracted Hib.

Case notification to CDC

Provisional notification of probable and confirmed cases of H. influenzae disease should be sent to CDC using the event code 10590 in the National Notifiable Diseases Surveillance System (NNDSS), when available, within 14 days of the initial report to the state or local health department.

The H. influenzae surveillance worksheets are included as Appendix 4 [1 page] to serve as guides for data collection to be included in case investigations and case notification to CDC.

Case notification should not be delayed because of incomplete information or lack of confirmation; data can be updated electronically as more information becomes available. The state in which the patient resides at the time of diagnosis should submit the case notification to CDC.

Information to collect

The following data are epidemiologically important and should be collected during the case investigation. Additional information may be collected at the direction of the state health department.

• Demographic information
  • Name
  • Address
  • Date of birth
  • Age
  • Sex
  • Ethnicity
  • Race
• Reporting Source
  • County
  • Earliest date reported
  • Case ID
• Clinical
  • Date of illness onset
  • Type of disease syndrome (meningitis, bacteremia, epiglottitis, pneumonia, arthritis, osteomyelitis, pericarditis, cellulitis)
• Outcome (patient survived or died)
  • Date of death
• Laboratory
  • Serotype of isolate
  • Specimen source from which organism was isolated (blood, CSF, pleural fluid, peritoneal fluid, pericardial fluid, joint fluid, amniotic fluid, or other normally sterile site)
  • Date first positive culture identified as H. influenzae
  • Date of specimen collection
• Antibiotic susceptibility
• Vaccination status (for type b or unknown serotype infections only)
  • Dates of Hib immunization
  • Manufacturer name
  • Vaccine lot number
  • If not vaccinated, reason
• Epidemiologic
  • Attendance in childcare

Vaccination

A Hib vaccine series is routinely recommended for all children, with the first dose at age 2 months. For specific recommendations about Hib vaccination, refer to the Child and Adolescent Immunization Schedule and Adult Immunization Schedule. Additional information about Hib vaccination can also be found in The Pink Book, which provides general recommendations, including vaccine use and scheduling, immunization strategies for providers, vaccine content, adverse events and reactions, vaccine storage and handling, and contraindications and precautions.For specific information about Hib vaccination, refer to The Pink Book, which provides general recommendations, including vaccine use and scheduling, immunization strategies for providers, vaccine content, adverse events and reactions, vaccine storage and handling, and contraindications and precautions.

Enhancing Surveillance

Elimination of childhood Hib disease requires participation by all levels of the healthcare system so that all cases are identified, assessed, and reported promptly, and data on reported cases are used in an optimal manner to prevent disease among unvaccinated or undervaccinated populations. The activities listed here can improve the detection and reporting of cases as well as the completeness and quality of reporting. See Chapter 19, "Enhancing Surveillance", for additional recommendations for enhancing surveillance of vaccine-preventable diseases.

Ensuring that all isolates from children are serotyped

Because of the need to make rapid decisions about chemoprophylaxis, serotype should be determined and reported for all H. influenzae isolates. Serotype is needed to make rapid decisions about chemoprophylaxis, to identify vaccine breakthrough cases, and to monitor trends in incidence by serotype. Reporting serotype for cases in children younger than 5 years of age is the highest priority, followed by children 5 through 14 years of age. The state public health laboratory, CDC's Bacterial Meningitis Laboratory, or one of the Association of Public Health Laboratories (APHL) Vaccine Preventable Diseases Reference Laboratories should be able to provide serotype testing of H. influenzae isolates. Hospital laboratories unable to perform serotype testing should forward all H. influenzae isolates (or clinical specimens if culture isolate is not available) to one of these laboratories for serotyping or contact the state health department for advice.

Case Investigation

Laboratory, hospital, and clinic records should be reviewed during case investigations by health department personnel to collect important information such as serotype, immunization status, dates of vaccination, vaccine lot numbers, clinical illness description, and outcome. The Expanded Haemophilus influenzae serotype b Surveillance Worksheet (see Appendix 4) may be used as a guide for collecting demographic and epidemiologic information in a case investigation.

Chemoprophylaxis

For cases of invasive Hib disease, a key component of the case investigation is identifying persons who should receive rifampin chemoprophylaxis. The recommended rifampin dose is 20 mg/kg as a single daily dose (maximal daily dose 600 mg) for 4 days. A dose of 10 mg/kg once daily for 4 days is recommended for neonates (less than 1 month of age).9

Index Patients with Invasive Hib Disease

Index patients who are treated with an antibiotic other than cefotaxime or ceftriaxone and are younger than 2 years of age should receive rifampin before hospital discharge. Because cefotaxime and ceftriaxone eradicate Hib colonization, prophylaxis is not needed for patients treated with either of these antimicrobials.

Household Contacts of Persons with Invasive Hib Disease

Rifampin chemoprophylaxis is recommended for all household contacts in households with members younger than 4 years of age who are not fully vaccinated or members younger than 18 years of age who are immunocompromised, regardless of their vaccination status.

Childcare Center Contacts of Persons with Invasive Hib Disease

Rifampin chemoprophylaxis is recommended in childcare settings when two or more cases of invasive Hib disease have occurred within 60 days and unimmunized or underimmunized children attend the facility. When prophylaxis is indicated, it should be prescribed for all attendees, regardless of age or vaccination status, and for childcare providers.9

Chemoprophylaxis for non-b H. influenzae

There are no guidelines for control measures around cases of invasive nontypeable or non-b H. influenzae disease. However, for cases of invasive H. influenzae type a disease, the American Academy of Pediatrics Red Book 2021–2024 states that clinicians may consider using a similar chemoprophylaxis approach as for invasive Hib disease.9 Prophylaxis has also been recommended in the unusual setting of a non-b H. influenzae outbreak12; jurisdictions identifying outbreaks of non-b H. influenzae should consult with CDC about response strategy.

Vaccination

For cases of invasive Hib disease, the case investigation also provides an opportunity to vaccinate children who are close contacts and who are unvaccinated or undervaccinated against Hib. Children younger than 24 months of age who develop invasive Hib disease should also repeat the Hib vaccine series because they can remain at risk of a second episode of disease; children 24 months of age or older who develop invasive Hib disease usually develop a protective immune response and do not need immunization.9 For both index patients and close contacts, vaccination is not a substitute for rifampin chemoprophylaxis.

Resources

• Webcast related to this manual
• Hib vaccination
• Data and Surveillance of Hib
  • World Health Organization's surveillance, assessment, & monitoring