Table of Contents
Definition / general | Essential features | Epidemiology | Sites | Pathophysiology | Clinical features | Diagnosis | Laboratory | Case reports | Treatment | Clinical images | Microscopic (histologic) description | Microscopic (histologic) images | Peripheral smear description | Peripheral smear images | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Cite this page: Amerson-Brown M. Haemophilus influenzae. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/microbiologyhinfluenzae.html. Accessed December 25th, 2024.
Definition / general
- Haemophilus influenzae is a fastidious, opportunistic pathogen of the respiratory tract that can cause invasive infections in susceptible populations
- Primary diagnostic techniques include culture and species differentiation based on growth requirements of hemin (factor X) and NAD+ (factor V)
- Gram negative, coccobacilli shaped bacteria
- Taxonomy (Database (Oxford) 2020;2020:baaa062)
- Kingdom: bacteria
- Phylum: Pseudomonadota
- Class: Gammaproteobacteria
- Order: Pasteurellales
- Family: Pasteurellaceae
- Genus: Haemophilus
- 13 species (Database (Oxford) 2020;2020:baaa062)
- H. influenzae (primary clinical pathogen) belongs to the genus Haemophilus
- Other species include H. aegyptius, H. ducreyi, H. felis, H. haemoglobinophilus, H. haemolyticus, H. parainfluenzae, H. paracuniculus, H. parahaemolyticus, H. paraphrohaemolyticus, H. pittamaniae, H. piscium, H. sputorum (commensal flora and rare clinical pathogens)
Essential features
- Gram negative coccobacilli, oxidase positive, facultative anaerobe
- Fastidious
- Requires both X and V factors for growth (Baron: Medical Microbiology, 4th Edition, 1996)
- Opportunistic pathogen and normal oropharyngeal colonizer
- Causes infection in neonates, immunocompromised persons and patients with chronic respiratory issues (Int J Infect Dis 2024;146:107120)
- 6 different serogroups (StatPearls: Haemophilus influenzae Infection [Accessed 20 August 2024])
- Named A - F
- Serogroup B (Hib) is common in invasive disease
- Nontypeable (NTHi) strains lack capsule
- Named A - F
- Community outbreaks and sporadic infections of invasive disease
Epidemiology
- Children < 5 years old (Pediatr Infect Dis J 2021;40:1028)
- Serious Hib infection most common in this age group
- Carriage > 50%
- Elderly patients with invasive disease have a higher fatality rate than children
- Immunocompromised persons (including stem cell transplant and malignancy) (Pediatr Infect Dis J 2021;40:1028)
- Persons with cystic fibrosis
- Sickle cell disease
- Asplenia
- Complement deficiency
- Nontypeable Haemophilus influenzae (NTHi) most common
Sites
- Respiratory system (community acquired pneumonia and tracheobronchitis)
- Bloodstream, brain and spinal cord (meningitis)
- Epiglottis
- Skin (cellulitis)
- Joint (infectious arthritis)
- Otitis media
- Sinusitis
- References: Sci Rep 2021;11:11, Pneumonia (Nathan) 2015;6:26, J Orthop 2022;31:6, Case Rep Infect Dis 2024;2024:5571104
Pathophysiology
- Normal oropharyngeal flora (BMC Microbiol 2015;15:6)
- Transmitted by respiratory droplets via coughing or sneezing
- Virulence factors (J Med Microbiol 2022;71, Schaechter: Encyclopedia of Microbiology, 3rd Edition, 2009)
- Protein H, Haemophilus surface fibrils (Hsf) and pili aid in adhesion (Infect Immun 2000;68:3362)
- Polyribosyl ribitol phosphate (PRP) capsule is antiphagocytic and helps to evade the host's neutrophil response
- IgA proteases help with evasion of host immune response
- Lipooligosaccharide outer membrane proteins P1, P2, P5 (endotoxin activity)
- Outer membrane protein engages toll-like receptor 2 (TLR2)
- Sialyltransferases and galactosyltransferases (helps evade host immune response)
- Genetic phase variation (helps evade host immune system) (Folia Med 2012;54:19)
- Capsule containing strains can penetrate the epithelium and capillary endothelium
- Spread from mucosa via lymphatic drainage or damaged mucosa
- Invasive infections
- Pneumonia
- Meningitis, which may result in brain damage or hearing loss
- Joint infections
- Sepsis
- Noninvasive infections
- Mucosal infections
- Exacerbation of underlying respiratory disease
Clinical features
- Prophylaxis with rifampin is recommended by the U.S. Centers for Disease Control and Prevention (CDC) for unvaccinated close contacts of someone with invasive Haemophilus influenzae type B disease (CDC: Haemophilus influenzae Disease [Accessed 13 August 2024])
- Risk factor: American Indian and Alaskan native children have a higher incidence (Clin Infect Dis 2021;73:1617)
Diagnosis
- Culture based methods (Baron: Medical Microbiology, 4th Edition, 1996)
- Gold standard
- For serotyping and monitoring antimicrobial susceptibility
- But fastidious growth requirements may reduce sensitivity
- Polymerase chain reaction (PCR) methods on direct specimens (Clin Microbiol Infect 2020;26:281, J Infect Dis 2024;229:214, J Clin Microbiol 2023;61:e0042623)
- Respiratory or cerebrospinal fluid (CSF)
- Enables rapid diagnosis
- For example, FilmArray® multiplex panels by BioFire Diagnostics
- Signs and symptoms for community acquired noninvasive infections
- Otitis media, conjunctivitis, etc.
Laboratory
- Aerobic growth on media containing erythrocyte factors: X (hemin) and V (nicotinamide adenine dinucleotide) containing media at 37 °C (Baron: Medical Microbiology, 4th Edition, 1996)
- Chocolate media
- X and V disks
- Haemophilus ID quad plates
- Small, round or spread, wet tan or yellow colonies
- Oxidase positive
- Indole variable used to differentiate biotypes
- Nitrate reduction positive
- Can satellite on blood agar around colonies that are beta hemolytic
- Wet mouse smell
- Matrix assisted laser desorption / ionization time of flight (MALDI TOF) (J Clin Microbiol 2017;55:2679)
- Serotyping by PCR or whole genome sequencing (WGS) (Genome Med 2022;14:13)
- Molecular syndromic panels for pneumonia and meningitis (Clin Microbiol Infect 2020;26:281, J Infect Dis 2024;229:214, J Clin Microbiol 2023;61:e0042623)
Case reports
- 25 year old man with epiglottitis secondary to SARS-CoV-2 infection (Clin Pract Cases Emerg Med 2023;7:158)
- 32 year old woman with chorioamnionitis (IDCases 2023;32:e01751)
- 50 year old woman with meningitis and bacteremia following conjunctivitis and 75 year old woman with otomastoiditis (Case Rep Infect Dis 2024;2024:5571104)
- 56 year old man with necrotizing fasciitis in the setting of SARS-CoV-2 pneumonia (Int J Surg Case Rep 2023;106:108264)
- 58 year old woman with epiglottitis that led to purpura fulminants (Cureus 2024;16:e55016)
Treatment
- Prevention (HHS: Hib (Haemophilus Influenzae Type B) [Accessed 13 August 2024], CDC: Hib Vaccination [Accessed 13 August 2024])
- Hib vaccine
- Protein conjugate vaccine
- Given to children < 5 years old
- Bone marrow transplant patients
- No vaccine for other serogroups or NTHi
- Hib vaccine
- Treatment
- Beta lactams (ampicillin, second or third generation cephalosporins) (Clin Infect Dis 2011;53:617)
- Beta lactam / beta lactamase inhibitors (amoxicillin clavulanate)
- Fluoroquinolones and tetracycline resistance is low (Can J Infect Dis Med Microbiol 2019;2019:6542919)
- Macrolide and ampicillin resistance is common (J Antimicrob Chemother 2024;79:2194)
- Ampicillin resistance (caused by beta lactamases or alterations in penicillin binding proteins)
- Dexamethasone is often included in treatment regimens for patients with meningitis
- Beta lactams (ampicillin, second or third generation cephalosporins) (Clin Infect Dis 2011;53:617)
Clinical images
Microscopic (histologic) description
- Tiny Gram negative coccobacilli
- Tiny Gram negative rods
Microscopic (histologic) images
Peripheral smear description
- Tiny Gram negative coccobacilli
- Tiny Gram negative rods
Peripheral smear images
Differential diagnosis
- All organisms are able to be differentiated from H. influenzae based on Gram stain results or growth patterns in culture
- Meningitis (Pediatr Rev 2024;45:305):
- Community acquired pneumonia (N Engl J Med 2015;373:415):
- Legionella species
- Mycoplasma pneumoniae
- Streptococcus pneumoniae
- Moraxella catarrhalis
- Chlamydia pneumoniae
- Respiratory viruses
- Joint infections (Pediatr Int 2022;64:e14993):
Additional references
Board review style question #1
A 1 year old child presents to the emergency department with fever, lethargy and positive Kernig sign. A Gram stain of the cerebrospinal fluid (CSF) revealed Gram stain morphology as shown in the figure that only grew on chocolate agar. Which of the following is the most likely causative agent?
- Escherichia coli
- Haemophilus influenzae
- Neisseria gonorrhoeae
- Neisseria meningitidis
Board review style answer #1
B. Haemophilus influenzae. H. influenzae is the only Gram negative coccobacillus organism listed. Answer A is incorrect because Escherichia coli has Gram negative rods. Answers C and D are incorrect because Neisseria meningitidis and N. gonorrhoeae are both Gram negative diplococci. In addition, E. coli, N. meningitidis and N. gonorrhoeae can all grow on blood agar.
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Reference: Haemophilus influenzae
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Reference: Haemophilus influenzae
Board review style question #2
A 65 year old smoker presents to the emergency department with a persistent cough, purulent sputum and fever for > 1 week. Chest Xray reveals a right lower lobe consolidation. The microbiology laboratory reports abundant H. influenzae from the sputum culture. What does H. influenzae require for growth?
- Hemin and NAD+
- Only V factor
- Only X factor
- Red cells and NAD+
Board review style answer #2
A. Hemin and NAD+. H. influenzae requires both the presence of hemin (X factor) and NAD+ (V factor) for growth. Answers B and C are incorrect because only 1 of the 2 necessary factors are listed. Answer D is incorrect because while red cells contain both hemin and NAD+, these nutrients are only available to the bacteria if the red cells are lysed.
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Reference: Haemophilus influenzae
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Reference: Haemophilus influenzae
Board review style question #3
An unvaccinated 8 month old presents to urgent care with fever, otitis media, congestion and purulent nasal discharge. The Gram stain from the sinus wash shows 4+ Gram negative coccobacilli. The patient is discharged on amoxicillin clavulanate. 2 weeks later, the patient is admitted for symptoms of meningitis in which the cerebrospinal fluid grew H. influenzae. Which virulence factor of H. influenzae is primarily responsible for the invasive nature of this child’s disease?
- Capsular polysaccharide
- IgA protease
- Lipopolysaccharide (LPS)
- Pili
Board review style answer #3
A. Capsular polysaccharide. The capsular polysaccharide prevents phagocytosis and allows the organism to cross the epithelial and endothelial barriers and become invasive. Cerebrospinal fluid infection is an invasive infection. Answer B is incorrect because IgA protease leaves IgA to allow for successful colonization. Answer C is incorrect because lipopolysaccharide triggers the inflammatory process. Answer D is incorrect because pili aids in attachment to mucosal epithelia.
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Reference: Haemophilus influenzae
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Reference: Haemophilus influenzae