Haemophilus influenzae (type b): Infectious substances pathogen safety data sheet

Section I: Infectious agent

Name

Haemophilus influenzae (type b)

Agent type

Bacteria

Taxonomy

Family

Pasteurellaceae

Genus

Haemophilus

Species

influenzae

Subspecies/strain/clonal isolate

Type b

Synonym or cross reference

Hib, meningitis, Haemophilus meningitis, childhood pneumonia, bacteremia, epiglottitis, septic arthritis, cellulitis, osteomyelitis, pericarditis, bacterial meningitis, Pfeiffer's bacillus^{Footnote 1Footnote 2Footnote 3Footnote 4}.

Characteristics

Brief description

Haemophilus influenzae is differentiated into six capsular types (a to f) according to its capsular polysaccharide structure. Other strains do not have a capsule and are classified as nonencapsulated or nontypeable H. influenzae (NTHi). The most virulent serotype is H. influenzae type b (Hib), and its capsule, composed of polyribosyl ribitol phosphate (PRP), is the predominant virulence determinant^Footnote 5. Three biochemical tests (indole, urease, and ornithine decarboxylase) subdivide H. influenzea into 8 biotypes^Footnote 6.

Hib is a gram negative coccobaccilus^Footnote 6. The cell wall contains fewer fatty acids than other gram-negative members of the family Pasteurellaceae^Footnote 7. H. influenza type b is facultatively anaerobic, pleomorphic, and capnophilic^Footnote 8. Hib, in similarity with other members of genus Haemophilus, is nonmotile, non-spore-forming, and non-acid-fast^Footnote 7. This respiratory tract membrane obligate parasite requires hemin (X-factor) and NAD (V- factor) for in vitro growth. Colonies grown on chocolate agar arise within 24 hours and are 1-2 nm in diameter, appear smooth, convex, mucoid, and gray in colour^Footnote 7. Individual bacteria are small, between 0.3-1 micrometer8. The genome of H. influenza was the first complete genome of a free living organism ever sequenced^Footnote 9. It was determined that the genome size of H. influenzae is approximately 1.8 Mb with a GC content of 37%, though this can vary by strain^{Footnote 7Footnote 9Footnote 10}.

Properties

H. influenzae infections were most commonly caused by the type b strain prior to vaccine development^Footnote 8. The polyribosyl ribitol phosphate (PRP) capsule, which characterizes Hib, accounts for 95% of invasive disease in children and over 50% in adults^Footnote 8. The capsule confers antiphagocytic properties to the bacteria and increases proliferation^Footnote 5. Proteins such as Haemophilus surface fibrils (Hsf) and protein H are present on encapsulated strains and aid in adherence to the host cells^Footnote 8. Outer-membrane proteins contribute to virulence and some are thought to be involved in invasion of mucosal epithelium^Footnote 11. Pili mediate bacterial adherence to mucosal surfaces and facilitate respiratory tract colonization^Footnote 11. H. influenzae secretes immunoglobulin A1 (IgA1) which acts to inactivate human IgA1, thus evading host immune function and promoting colonization^Footnote 11. The lipopolysaccharide (LPS) is an important structural component, and is also involved in colonization and resistance to host immune response^Footnote 11.

Section II: Hazard identification

Pathogenicity and toxicity

Infection with Haemophilus influenzae (type b) can cause meningitis, pneumonia, epiglottitis, septic arthritis, cellulitis, osteomyelitis, endophthalmitis, urinary tract infections, abscesses, endocarditis, or generalized bacteremia^{Footnote 8Footnote 12}. A small proportion of children will have asymptomatic infections. The symptoms that present and the duration of illness are dependent on the organs infected^Footnote 8.

Meningitis may begin as minor upper respiratory infection^Footnote 3. Symptoms include behavioural or mental status change, fever, vomiting, headaches, and signs of meningeal irritation such as bulging fontanelle in infants, or stiff neck in older children or adults. Sequelae such as hearing loss, mental retardation, seizures, vision loss, and motor and speech delay may develop in severe cases^Footnote 3. The global burden of Hib meningitis has decreased significantly since the introduction of vaccination programs^Footnote 13. It was estimated that there were approximately 8.13 million cases of severe infection and over 370 000 deaths in 2000, while only 7645 cases and 857 deaths were recorded in 2020^Footnote 13.

Pneumonia will result in a high-grade fever, chills, productive purulent cough, shortness of breath, chest pain, lethargy, and generalized body aches^Footnote 8. Epiglottitis is an acute infection of the upper airway that causes oedema and inflammation of the epiglottis and adjacent tissues and may lead to complete airway obstruction in hours^Footnote 3. Symptoms include severe sore throat, fever, stridor, drooling, and cervical adenopathy^{Footnote 3Footnote 8}. Speaking, swallowing, or breathing may be impaired and respiration may be noisy^Footnote 3. Mortality due to epiglottitis also decreased significantly since the widespread application of Hib vaccination^Footnote 14. In 1979 there was an estimated 65 deaths (24 adults and 41 children), whereas in 2017 there was only 15 (14 adults and 1 child)^Footnote 14.

Cellulitis can also be associated with Hib infection, often affecting the face, head, or neck^Footnote 3. It causes localized tissue inflammation and can lead to proptosis, loss of visual acuity, limitation of extraocular movement and death. Affected children may have concomitant meningitis^Footnote 3. Occult blood stream infection can occur without any specific organ involvement^Footnote 8. Symptoms include fever, chills, fatigue, pain, vomiting, diarrhea, and confusion^Footnote 8.

Epidemiology

Prior to the availability of Hib vaccines, meningitis accounted for 52% of infection, pneumonia 12%, epiglottitis 11%, and others such as cellulitis, septic arthritis, and bacteremia without a focus 25%^Footnote 15. Hib infected 83 million children with a mortality rate of 2-5% in developed countries, and 550 million with a mortality rate of 10-30% in developing countries^Footnote 15. Older adults and immunocompromised individuals had a mortality rate of approximately 25%^Footnote 15.

Following vaccine introduction in 1986^Footnote 16, the incidence declined dramatically for all age groups due to vaccine coverage and herd immunity^{Footnote 3Footnote 14}. Globally, the vaccine coverage is 72%^Footnote 14. In Canada, it is estimated that vaccine coverage was 96% in 2019^Footnote 5.

Currently, Hib is more prevalent in developing countries, and more common among young children, the elderly, and indigenous peoples^{Footnote 2Footnote 7Footnote 17}. Adult cases are rare and sickness is usually concomitant with another immunosuppressive state^Footnote 18. A bimodal seasonal pattern of infection, peaking in September/December and March/May has been observed for meningitis^Footnote 19. In 2021, there were three cases of invasive Hib in unvaccinated children residing in Amish communities reported in Pennsylvania^Footnote 20. There was a sharp increase of Hib cases on Vancouver Island in 2022 among individuals experiencing homelessness and substance use^Footnote 21. This outbreak resulted in at least 8 infections and 1 fatality.

Young children, below the age of 5, and adults >65 are predisposed to infection^Footnote 7. Patients with HIV, patients with asplenia, sickle cell disease (SCD), and possibly malignancies are also at a higher risk of developing invasive Hib infections^Footnote 5. The prevalence of Hib is also higher among indigenous populations of North America^Footnote 5. Environmental conditions such as crowding can increase the likelihood of exposure to Hib^Footnote 22.

Host range

Natural host(s)

Hib is a human obligate parasite^Footnote 6.

Other host(s)

Hib has been experimentally inoculated in rats, mice, and rabbits^{Footnote 23 Footnote 24 Footnote 25}.

Infectious dose

Unknown.

Incubation period

The exact incubation period is unknown, but it is estimated to be 2 - 4 days^{Footnote 8Footnote 26}.

Communicability

Hib can be transmitted through inhalation of airborne respiratory secretion droplets from infected individuals, as well as via direct contact with secretions, such as discharge from nose and throat, during infectious periods^{Footnote 7Footnote 27}. The portal of entry is most commonly the nasopharynx^Footnote 27.

Hib is not highly contagious^Footnote 12. Secondary infection may occur in case of particularly close contact with patients. Asymptomatic individuals can have Hib nasopharyngeal carriage and act as a reservoir and source of disease transmission^Footnote 5. It is not communicable 48 hours after initiation of effective antibiotic treatment^Footnote 28.

Section III: Dissemination

Reservoir

Humans are the only known reservoir^Footnote 3.

Zoonosis/Reverse zoonosis

None.

Vectors

None.

Section IV: Stability and viability

Drug susceptibility/resistance

Hib is susceptible to chloramphenicol and third generation cephalosporins^Footnote 3. In cases of Hib meningitis, ceftriaxone, ceftazidime, cefotaxime, ampicillin-sulbactam, fluoroquinolones, and azithromycin are effective antibiotic choices^Footnote 8. Pharmaceutical agents for symptom management can be co-administered. Dexamethason is useful for alleviating inflammation and reducing the likelihood of hearing loss or neurological sequelae. Steroids can also be used but must be started prior to or at the same time as antibiotic administration^Footnote 8.

Resistance has been shown for ampicillin, co-trimoxazole, clarithromycin, tetracycline, chloramphenicol, macrolides (e.g. erythromycin), and rifampicin^{Footnote 8Footnote 29}.

Susceptibility to disinfectants

Phenolic disinfectants, 1% sodium hypochlorite, 70% ethanol, formaldehyde, glutaraldehyde, iodophore, and peracedic acid are effective against Hib^Footnote 30.

Physical inactivation

Hib is inactivated by UV^Footnote 31, microwave ^Footnote 32, and gamma radiation ^Footnote 33, moist heat (121°C for at least 20 min) ^Footnote 34 and dry heat (165-170°C for 2 h).

Survival outside host

Hib does not survive long term in the environment^Footnote 12. H. influenza can persist for approximately 12 days on dry inanimate surfaces^Footnote 35, 18 hours in mucous^Footnote 36, and 12 hours on plastic^Footnote 36.

Section V: First aid/medical

Surveillance

Hib infection can be identified by monitoring for symptoms. Diagnosis is most often confirmed by gram-stain followed by a bacterial culture^{Footnote 3Footnote 8}. For rapid diagnosis, techniques include detection of the PRP polysaccharide by latex agglutination, enzyme-linked immunosorbent assay, or countercurrent immunoelectrophoresis and PCR^{Footnote 3Footnote 8}. Hib associated meningitis can be confirmed through PCR analysis of a cerebrospinal fluid (CSF) obtained through lumbar puncture prior to antibiotic administration^Footnote 8. Pneumonia can be diagnosed through examination of a chest x-ray, then sputum gram-stain and cultures. Invasive procedures such as bronchoscopy and trans-tracheal aspiration may be required to obtain samples^Footnote 8. RT-PCR of respiratory secretions has a high sensitivity and specificity. Multiplex PCR and a line probe assay (LPA) are advanced techniques that can detect Hib^{Footnote 3Footnote 8}. Isothermal nucleic acid amplification test (isothermal NAAT), duplex recombinase polymerase amplification (RPA), and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) are other methods that can aid in rapid species identification with high sensitivity and specificity^{Footnote 3Footnote 8}.

Note: The specific recommendations for surveillance in the laboratory should come from the medical surveillance program, which is based on a local risk assessment of the pathogens and activities being undertaken, as well as an overarching risk assessment of the biosafety program as a whole. More information on medical surveillance is available in the Canadian Biosafety Handbook (CBH).

First aid/treatment

The primary treatment for Hib is appropriate antibiotics and intravenous antibiotics are often required but depending on illness, oral administration may follow for 7-10 days^{Footnote 3Footnote 8}. Hib demonstrates resistance to several antibiotics, thus, it is essential to monitor the response to treatment and alter the antibiotic regimen accordingly^Footnote 8. Additional pharmaceutical treatments can be administered for symptom management. In cases of subdural and pleural effusion, empyema or septic arthritis, surgical intervention may be required^Footnote 8.

Note: The specific recommendations for first aid/treatment in the laboratory should come from the post-exposure response plan, which is developed as part of the medical surveillance program. More information on the post-exposure response plan can be found in the CBH.

Immunization

Several effective vaccines have been developed and are used globally^Footnote 15. Hib vaccines are used most widely in developed countries, but are becoming increasingly applied in developing countries. The estimated global coverage is 72%, with large regional variation^Footnote 15.

In Canada, Haemophilus influenzae type b conjugate (tetanus protein conjugate) vaccines, as well as absorbed combination vaccines containing conjugated Haemophilus influenzae type b vaccine (tetanus toxoid conjugate), diphtheria and tetanus toxoids, acellular pertussis, inactivated poliomyelitis, and recombinant hepatitis B (not present in all combination vaccines) are available for use^Footnote 37. It is estimated that the clinical efficacy is approximately 95% for Hib vaccination. Hib vaccines are recommended for routine infant immunization between 2 months and 5 years of age^Footnote 37. It is also recommended for immunocompromised individuals.

Note: More information on the medical surveillance program can be found in the CBH, and by consulting the Canadian Immunization Guide.

Prophylaxis

Prophylaxis with rifampicin is indicated for direct contacts, when recommended by a doctor^Footnote 3. Rifampicin can eradicate the pharyngeal carriage of Hib in 92-97% of contacts and significantly reduces the risk of secondary disease^Footnote 38. Pregnant and breastfeeding persons should also receive rifampicin prophylaxis if there is a vulnerable individual among household contacts as the benefits outweigh potential risks^Footnote 38.

Note: More information on prophylaxis as part of the medical surveillance program can be found in the CBH.

Section VI: Laboratory hazards

Laboratory-acquired infections

Prior to 2000, there were 5 reported cases of laboratory acquired infections^Footnote 39. Since then, there have been no reported cases of laboratory-acquired Hib infection.

Note: Please consult the Canadian Biosafety Standard (CBS) and CBH for additional details on requirements for reporting exposure incidents. A Canadian biosafety guideline describing notification and reporting procedures is also available.

Sources/specimens

Biological samples can be found in body fluids^Footnote 8. Bacteria may be in the cerebrospinal fluid, serum, urine^Footnote 3, blood, subdermal and pleural fluid, joint fluid, and middle ear aspirates^Footnote 12.

Primary hazards

Most laboratory acquired infections are caused by inhalation of airborne infectious materials^Footnote 39, autoinoculation^Footnote 40, or ingestion.

Special hazards

None.

Section VII: Exposure controls/personal protection

Risk group classification

Haemophilus influenzae is a Risk Group 2 human pathogen and a Risk Group 1 animal pathogen; however, serotype classification may vary^Footnote 41.

Containment requirements

Containment Level 2 facilities, equipment, and operational practices outlined in the CBS for work involving infectious or potentially infectious materials, animals, or cultures.

Protective clothing

The applicable Containment Level 2 requirements for personal protective equipment and clothing outlined in the CBS are to be followed. The personal protective equipment could include the use of a lab coat and dedicated footwear (e.g., boots, shoes) or additional protective footwear (e.g., boot or shoe covers) where floors may be contaminated (e.g., animal cubicles, post mortem rooms), gloves when direct skin contact with infected materials or animals is unavoidable, and eye protection where there is a known or potential risk of exposure to splashes.

Note: A local risk assessment will identify the appropriate hand, foot, head, body, eye/face, and respiratory protection, and the personal protective equipment requirements for the containment zone and work activities must be documented.

Other precautions

A biological safety cabinet (BSC) or other primary containment devices to be used for activities with open vessels, based on the risks associated with the inherent characteristics of the regulated material, the potential to produce infectious aerosols or aerosolized toxins, the handling of high concentrations of regulated materials, or the handling of large volumes of regulated materials.

Use of needles and syringes are to be strictly limited. Bending, shearing, re-capping, or removing needles from syringes to be avoided, and if necessary, performed only as specified in standard operating procedures (SOPs). Additional precautions are required with work involving animals or large scale activities.

Additional information

For diagnostic laboratories handling primary specimens that may contain Hib, the following resources may be consulted:

• Human Diagnostic Activities Biosafety Guideline
• Local Risk Assessment Biosafety Guideline

Section VIII: Handling and storage

Spills

Allow aerosols to settle. Wearing personal protective equipment, gently cover the spill with absorbent paper towel and apply suitable disinfectant, starting at the perimeter and working towards the centre. Allow sufficient contact time with disinfectant before clean up (CBH).

Disposal

All materials/substances that have come in contact with the regulated materials to be completely decontaminated before they are removed from the containment zone or standard operating procedures (SOPs) to be in place to safely and securely move or transport waste material out of the containment zone to a designated decontamination area / third party. This can be achieved by using decontamination technologies and processes that have been demonstrated to be effective against the regulated material, such as chemical disinfectants, autoclaving, irradiation, incineration, an effluent treatment system, or gaseous decontamination (CBH).

Storage

The applicable Containment Level 2 requirements for storage outlined in the CBS are to be followed. Primary containers of regulated materials removed from the containment zone to be labelled, leakproof, impact resistant, and kept either in locked storage equipment or within an area with limited access.

Section IX: Regulatory and other information

Canadian regulatory context

Controlled activities with Haemophilus influenzae type b require a Pathogen and Toxin licence issued by the Public Health Agency of Canada.

The following is a non-exhaustive list of applicable designations, regulations, or legislations:

• Human Pathogen and Toxins Act and Human Pathogens and Toxins Regulations
• Transportation of Dangerous Goods Regulations
• National Notifiable Disease (human)

Updated

March, 2023

Prepared by

Centre for Biosecurity, Public Health Agency of Canada.

Disclaimer

The scientific information, opinions, and recommendations contained in this Pathogen Safety Data Sheet have been developed based on or compiled from trusted sources available at the time of publication. Newly discovered hazards are frequent and this information may not be completely up to date. The Government of Canada accepts no responsibility for the accuracy, sufficiency, or reliability or for any loss or injury resulting from the use of the information.

Persons in Canada are responsible for complying with the relevant laws, including regulations, guidelines and standards applicable to the import, transport, and use of pathogens in Canada set by relevant regulatory authorities, including the Public Health Agency of Canada, Health Canada, Canadian Food Inspection Agency, Environment and Climate Change Canada, and Transport Canada. The risk classification and related regulatory requirements referenced in this Pathogen Safety Data Sheet, such as those found in the Canadian Biosafety Standard, may be incomplete and are specific to the Canadian context. Other jurisdictions will have their own requirements.

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