Haemophilus

Haemophilus is a genus of Gram-negative coccobacilli, all of whose strains require at least 1 of 2 factors for growth (factor V [NAD] and factor X [heme]); therefore, it is most often isolated on chocolate agar, which can supply both factors. The most common pathogenic species is H. influenzae, which is transmitted through respiratory droplets and can cause epiglottitis, meningitis, otitis media, and pneumonia. H. ducreyi is transmitted through sexual contact and is the cause of chancroid, a type of genital ulcer.

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General Characteristics

General characteristics of Haemophilus species:

  • Gram-negative pleiomorphic coccobacilli
  • All 24 members of Haemophilus are usually cultured on chocolate agar plates, as all species require at least 1 of 2 growth factors (provided by chocolate agar but not blood agar): factor V (nicotinamide adenine dinucleotide [NAD]) and factor X (heme)
    • H. influenzae requires both factors
    • May also be grown on blood agar with Staphylococcus aureus, which provides factor NAD in excess of its own needs; heme is released from the red blood cells by the action of staphylococcal hemolysins
  • The H. influenzae species is divided into typeable (encapsulated) and non-typeable (non-encapsulated), strains. In the encapsulated strains, the polysaccharide capsule is used to serotype them into 6 types, a to f, with type b (Hib) being the most virulent and clinically important one.
  • The non-typeable H. influenzae (NTHi) strains also cause disease, especially mucosal diseases of the upper respiratory tract such as otitis media, acute rhinosinusitis, acute bronchitis, acute exacerbations of chronic obstructive pulmonary disease, and non-bacteremic pneumonia, and are usually non-invasive. H. influenzae is also one of the 4 most common causes of bacterial conjunctivitis in the United States (along with Staphylococcus aureus, Streptococcus pneumoniae, and Moraxella catarrhalis)
  • Hib infection is rare in developed countries due to widespread vaccine use.

Virulence factors of Haemophilus species:

  • Capsular antigen (in the encapsulated strains): antiphagocytic
  • Adhesin proteins (e.g., HMW1, HMW2) mediate attachment to the human epithelial cells in the airway.
  • Pili and the major outer membrane P2 protein: bind sialic acid-containing moieties on epithelial cell surfaces
  • IgA1 protease: cleaves immunoglobulin A at the hinge region, preventing agglutination and mechanical clearance of the pathogen
  • Phase variation: The outer surface proteins are modified to adapt to changes in the host environment.
  • In vivo biofilm production is especially important in the pathogenesis of acute otitis media (AOM). (AOM is the most common pediatric bacterial infection, affecting up to 75% of children at some point before the age of 5 years. S. pneumoniae and H. influenzae, especially NTHi, are responsible for up to 80% of bacterial AOM.)

Related videos

Haemophilus influenzae on blood agar

Haemophilus influenzae bacteria cultured on a blood agar plate.

Image: “Haemophilus influenzae 01” by CDC. License: Public Domain

Haemophilus influenzae

The table below summarizes the major clinical manifestations as well as symptoms and at-risk populations for H. influenzae infection.
PathogenPopulation at riskSymptoms
H. influenzaeMeningitis
  • Infants 3–18 months of age
  • Rare due to vaccine
Predominantly caused by strains with the type B capsule
Otitis MediaChildren and adults
  • Preceded by an upper respiratory tract infection
  • Irritability in infants
  • Ear pain
  • Fever
EpiglottitisChildren 2–7 years old
  • Swollen, “cherry-red” epiglottis
  • Inspiratory stridor
  • Drooling
PneumoniaElderly, patients with chronic obstructive pulmonary disease (COPD)Typical presentation:
blood-tinged sputum
  • Transmission: respiratory droplets. Humans are the only reservoir for H. influenzae.
  • Despite the name, H. influenzae does NOT cause influenza, which is exclusively viral.
  • Risk factors
    • Age < 5 years and absent or incomplete Hib immunization
    • Functional or anatomic asplenia, including sickle cell disease
    • Any underlying medical conditions that interfere with immune function
    • Structural lung disease, smoking, alcoholism, pregnancy, older age, lower socioeconomic status
  • Diagnosis
    • Non-invasive respiratory infections: Use clinical signs and symptoms (AOM, conjunctivitis, exacerbation of chronic obstructive pulmonary disease). Detection of H. influenzae in the respiratory tract does not differentiate colonization from infection.
    • Invasive infections: Culture (may lack sensitivity but necessary to understand antibiotic susceptibility; a rapid assay for beta-lactamase production is useful), matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, polymerase chain reaction (PCR)-based assays
  • Vaccine only for type b capsule strain (Hib): available since 1985
    • Polysaccharide vaccine conjugated to the diphtheria toxoid (to get a better response)
    • Administered to infants aged 2–6 months (2 or 3 doses) with a booster dose at age 12 through 15 months. 
    • Even after vaccination, infection still possible, with a peak occurrence at 6 months to 1 year, corresponding to a decline in maternal protective immunoglobulin G (IgG) and inability of the child to generate sufficient antibody against the capsular antigen due to immature immune system
    • Before vaccination, H. influenzae was the leading cause of bacterial meningitis and other serious invasive diseases in children aged < 5 years in the United States; after the introduction of conjugate Hib vaccines in 1987 and 1989, the incidence of invasive Hib disease in children aged < 5 years decreased by 99%.
  • Treatment:
    • Mucosal infections: amoxicillin-clavulanate
    • Meningitis or systemic disease: ceftriaxone
    • Prophylaxis of meningitis for close contacts (if index case had invasive Hib or H. influenzae type a disease): rifampin

To help remember the common clinical manifestations of H. influenzae, use the following mnemonic:

  • “HaEMOPhilus causes…”
    • Epiglottitis
    • Meningitis
    • Otitis media
    • Pneumonia
Pathogenesis of Haemophilus influenzae
The H. influenzae species is divided into typeable (encapsulated) and non-typeable (NTHi), or non-encapsulated, strains. Of the 6 serotypes of encapsulated strains, H. influenzae type b (Hib) is the most virulent type: It invades the respiratory mucosa and spreads throughout the bloodstream to cause systemic diseases. Non-encapsulated H. influenzae strains are usually non-invasive but can defeat the mucosal defenses and cause otitis media, conjunctivitis, and bronchitis.
Image by Lecturio.

Haemophilus ducreyi

  • The cause of chancroid, one of the 5 classic infectious causes of genital ulcer disease (others: Herpes simplex virus [HSV-1 and HSV-2], syphilis [Treponema pallidum], lymphogranuloma venereum [Chlamydia trachomatis L1-L3], granuloma inguinale [“donovanosis,” caused by Klebsiella granulomatis])
  • Also 1 of the causes of non-genital chronic skin ulcers in tropical climates
  • Clinical presentation of chancroid:
    • Incubation: 3 to 10 days
    • Ulcers: painful, sharply circumscribed or irregular with ragged undermined edges
    • Inguinal adenopathy in 50% of cases
    • Males more often symptomatic than females
  • Transmission: direct contact
  • Diagnosis: Difficult, so clinical criteria often used while excluding other more likely causes to arrive at “probable diagnosis”
    • Culture or PCR testing can be used for diagnosis, but not always available.
    • Gram stain may show small gram-negative coccobacilli in chains resembling a school of fish or a railroad track, but has poor sensitivity.
  • Treatment: ceftriaxone or azithromycin

Mnemonic:

Haemophilus ducreyi is so painful that you do cry.

Haemophilus ducreyi

Haemophilus ducreyi bacteria, the causative agent of chancroid, stained with gentian violet.


Image: “Photomicrograph of Haemophilus ducreyi” by CDC Public Health Image Library. License: Public Domain

References

  1. Musher DM. (1996). Haemophilus Species. In Baron S (Ed.). Medical Microbiology, 4th ed. (Chap. 30). Publisher: Univ. Texas Medical Branch at Galveston. ISBN-10: 0-9631172-1-1. Retrieved on Aug. 1, 2020 from: https://www.ncbi.nlm.nih.gov/books/NBK8458/#:~:text=Haemophilus%20influenzae%20requires%20both%20factors,have%20lysed%20red%20blood%20cells.
  2. Levinson W, Chin-Hong P, Joyce EA, Nussbaum J, Schwartz B. (2020). In Review of Medical Microbiology and Immunology, 16th ed, pp 166-168, 215-216. Publisher: McGraw-Hill.
  3. Langereis JD, de Jonge MI. Invasive Disease Caused by Nontypeable Haemophilus influenzae. Emerg Infect Dis. 2015;21(10):1711-1718. doi:10.3201/eid2110.150004
  4. CDC. Haemophilus influenzae Disease (Including Hib). Retrieved on August 1, 2020 from: https://www.cdc.gov/hi-disease/clinicians.html#incidence
  5. Briere, EC, Rubin L, Moro PL, et al. Prevention and Control of Haemophilus influenzae Type b Disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP) Morbidity and Mortality Weekly Report (MMWR). Feb. 28, 2014 / 63(RR01);1-14. Retrieved on Aug. 1, 2020 from: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6301a1.htm?s_cid=rr6301a1_w
  6. Yee ME, Bakshi N, Graciaa SH, et al. Incidence of invasive Haemophilus influenzae infections in children with sickle cell disease. Pediatr Blood Cancer. 2019;66(6):e27642. doi:10.1002/pbc.27642
  7. Monasta L, Ronfani L, Marchetti F, Montico M, Vecchi Brumatti L, Bavcar A, et al. (2012) Burden of Disease Caused by Otitis Media: Systematic Review and Global Estimates. PLoS ONE 7(4): e36226. https://doi.org/10.1371/journal.pone.0036226
  8. Vermee, Q., Cohen, R., Hays, C. et al. Biofilm production by Haemophilus influenzae and Streptococcus pneumoniae isolated from the nasopharynx of children with acute otitis media. BMC Infect Dis 19, 44 (2019). https://doi.org/10.1186/s12879-018-3657-9
  9. das Neves Romanelia MT, Tresoldia AT, Pereiraa RM, et al. Invasive Non-Type B Haemophilus Influenzae Disease: Report of Eight Cases. Revista Paulista de Pediatria. 2019;37(2). Published: Jan. 07, 2019. Retrieved on Aug. 1, 2020 from: https://doi.org/10.1590/1984-0462/;2019;37;2;00006
  10. Yeh S. Epidemiology, clinical manifestations, diagnosis, and treatment of Haemophilus influenzae. In UpToDate Evidence Based Clinical Resource. Retrieved on Aug. 1, 2020 from: https://www.uptodate.com/contents/epidemiology-clinical-manifestations-diagnosis-and-treatment-of-haemophilus-influenzae#H1115106976
  11. Hicks CB. Chancroid. In UpToDate Evidence Based Clinical Resource. Retrieved on Aug. 1, 2020 from: https://www.uptodate.com/contents/chancroid#H3653316944

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