Haemophilus influenzae

Definitions & Key takeaways

Haemophilus influenzae, or just H. influenzae, is a gram-negative, facultatively anaerobic, non-motile coccobacillus. Haemophilus influenzae bacteria are classified into encapsulated strains and unencapsulated strains. Based on their capsular antigen type, encapsulated strains are further classified into six serotypes (serotypes a, b, c, d, e, and f). Unencapsulated strains are also referred to as nontypable because they lack the polysaccharide capsule, and capsular antigens.

Nontypeable strains of Haemophilus influenzae are known to cause relatively simple mucosal infections, like otitis media, sinusitis, and pneumonia. On the other hand, encapsulated strains such as Haemophilus influenza type b can cause more severe infections such as meningitis and epiglottitis, but such severe infections are not so common nowadays due to vaccination.

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Haemophilus influenzae is a small Gram-negative coccobacillus which can normally colonize the human respiratory tract. There are two major categories of H.
influenzae - encapsulated strains and unencapsulated strains. Encapsulated strains are classified into six serotypes based on their capsular antigens - a, b, c, d, e and f, and unencapsulated strains are called nontypable, because they lack the polysaccharide capsule, and, consequently, capsular antigens.
The strains that cause disease in humans are most often Haemophilus influenzae type b, or Hib for short and Haemophilus influenzae nontypable.Now, Haemophilus influenzae has a thin peptidoglycan layer, so it doesn’t retain the crystal violet dye during Gram staining.
Instead, like any other Gram-negative bacteria, it stains pink with safranin dye. And since it’s a coccobacillus, it’s shaped somewhere between round, like a coccus, and linear, like a bacillus.
Haemophilus influenzae is non-motile, so it doesn’t move, and facultative anaerobic which means it can survive both in aerobic and anaerobic environments.
It’s also catalase and oxidase positive which means it produces both these enzymes.Finally, Haemophilus influenzae can be cultivated on chocolate agar, because this medium contains essential nutrients that Haemophilus influenzae needs to grow, like factor X, also called hemin, and factor V, also called nicotinamide adenine nucleotide.
Another way to grow it is to grow it with Staphylococcus aureus colonies, on blood agar, which provides factor V via red blood cells hemolysis.
On both blood agar and chocolate agar, Haemophilus influenzae grows into convex, smooth, gray or transparent colonies. Now, Haemophilus influenzae has a number of virulence factors, that are like assault weaponry that help it attack and destroy the host cells, and evade the immune system.So first, encapsulated strains of Haemophilus influenzae are covered by a polysaccharide layer called a capsule.
Now, this capsule is a major virulence factor for Haemophilus influenzae because of its antiphagocytic ability, meaning that it protects the bacteria against phagocytosis by macrophages or neutrophils.
This allows Haemophilus influenzae to escape destruction and attach to epithelial cells in the airways. Also, on the capsule, there are pili, which are hair-like extensions, and adhesion proteins such as HMW1 and HMW2 that help the bacteria attach to host cells.Both encapsulated and unencapsulated strains have an outer membrane - which consist of lipooligosaccharides, or LOS.
LOS inhibits mucociliary clearance, or the self-clearing mechanism of the bronchi, that would normally sweep the bacteria out of the respiratory tract.
With the help of LOS, Haemophilus influenzae can colonize the respiratory tract.What is more, both encapsulated and unencapsulated strains make IgA protease, a toxic protein that destroys Immunoglobulin A, or IgA.
IgA is an immune system protein found in the nasopharyngeal mucosa secretions that normally opsonizes invading bacteria, meaning it tags them so neutrophils can recognize and destroy them.
So IgA protease neutralizes the first line of mucosal defense! Interestingly, unencapsulated strains have two other abilities that allow it to evade the immune system.
First, these strains can change the oligosaccharides they express on their outer membrane each time they infect a cell, and this process is called phase variation.
Because of phase variation, the immune system can’t remember the infecting strain, so it can’t mount a quick specific immune response against it when it encounters the same strain in the future.
Finally, unencapsulated strains have the ability to produce biofilms. A biofilm is basically a layer of goop-like material made of exopolysaccharides or EPS, within which Haemophilus influenzae bacteria live and reproduce.
Comparing a biofilm to strawberry jam, the seeds would be the bacteria and the rest of the jam would be the EPS. The bacteria in the biofilm hide from the host's immune system and antibiotics.Ok, now, encapsulated strains tend to cause more invasive disease on account of their capsule.
One way is to spread directly from the nasopharynx to the epiglottis, causing epiglottitis, or to the soft skin tissues in the face, causing cellulitis.
Encapsulated strains can also breach through the epithelium of the nasopharynx and invade the blood capillaries directly, causing bacteremia.
From the bloodstream, it can spread to distant sites, like the meninges, causing meningitis, the bones, causing osteomyelitis or the joints, causing septic arthritis.Nonencapsulated strains of Haemophilus influenzae, on the other hand, are less invasive, and they mostly cause mucosal infections by direct extension.
For example, they may go up the eustachian tubes and reach the middle ear, causing otitis media. If they spread to the paranasal sinuses, they cause sinusitis.
Finally, if they go down the respiratory tract, they may cause bronchitis, which is the inflammation of the bronchi, or pneumonia, which is the inflammation of the lungs.
Now, nonencapsulated strains of Haemophilus influenzae colonize the nasopharynx of 40 to 80% of children and adults, whereas encapsulated strains, such as Hib, colonizes 3 to 5% of children aged 2 to 5 years.
Either way, Haemophilus influenzae is mostly transmitted via respiratory droplets and respiratory secretions. Risk factors vary depending on the infecting strain.
Haemophilus influenzae type b typically causes disease in children, and in people with spleen issues, since the spleen plays an important role in immunity against encapsulated bacteria.
This group includes those who have undergone a splenectomy, which is when the spleen is removed, or those with sickle cell disease, who have functional asplenia, and in people with malignancies or congenital deficiencies of complement components.
Also, people with an acute viral infection, especially with influenza virus, are at risk for a possibly fatal bacterial superinfection with Haemophilus influenzae - even if their spleen is working just fine.Haemophilus influenzae nontypable mostly causes disease in children and people with immunocompromising conditions, like diabetes, malignancy, or an HIV infection.
After a viral infection, it can cause postviral pneumonia. Other risk factors include an underlying lung condition, such as chronic obstructive pulmonary disease or cystic fibrosis.
In people with chronic obstructive pulmonary disease, Haemophilus influenzae nontypable causes a type of pneumonia called bronchopneumonia.Now, symptoms depend on the disease.
First, infections caused by Haemophilus influenzae type B. With epiglottitis, there’s fever, sore throat, difficulty speaking and dyspnea.
With meningitis, there’s fever, lethargy, irritability, vomiting, sore neck and altered mental status, cellulitis develops with fever and a warm, tender area of erythema on cheek or periorbital area.
With bacteremia there may be fever, chills, hypotension and tachycardia, with septic arthritis there may be fever, pain, swelling and tenderness of affected joint and with osteomyelitis there is fever, bone pain and weakness.
Now for infections caused by Haemophilus influenzae nontypable. Otitis media associates fever, ear pain and otorrhea, which is when there’s discharge coming out of the ear.
With sinusitis, there’s fever, tenderness in the area of the affected sinus and persistent, purulent nasal discharge. With bronchopneumonia, there’s fever, chills, chest pain, cough and shortness of breath.
Finally, with conjunctivitis, there’s eye redness, pain and burning in the eye.Diagnosis can be done by identifying Haemophilus influenzae in a culture from a biological sample, like blood, CSF, synovial fluid, pleural fluid, fluid obtained by sinus aspiration, tympanocentesis, tracheal or lung aspiration, bronchoscopy or bronchoalveolar lavage.
Alternatively serological methods such as latex agglutination, enzyme immunoassay or coagglutination can be used to detect antibodies against Haemophilus influenzae.
For epiglottitis, a laryngoscopy can be done, which shows a cherry red, swollen epiglottis and an X-ray which shows a thumbprint sign on epiglottis.
When bronchopneumonia is suspected, a chest X-ray can be done, and it shows ground-glass opacities, bronchial wall thickening and confluent areas of consolidation.
Now, infections with Haemophilus influenzae type B, especially meningitis, are treated with ceftriaxone and chloramphenicol.
On the other hand, mucosal infections with Haemophilus influenzae nontypable are treated with amoxicillin +/- clavulanate as a first-line, and with third and second generation cephalosporins, macrolides or fluoroquinolones as an alternative.Finally, there is a vaccine for Haemophilus influenzae type B which is recommended between 2 and 18 months of age.
This vaccine contains type B capsular polysaccharide conjugated to a diphtheria toxoid component and its use has greatly decreased the incidence of Haemophilus influenzae meningitis.
So today, cases of Haemophilus influenzae meningitis are almost exclusively seen in unimmunized children. Finally, contacts of children with Haemophilus influenzae type B infections may be treated with chemoprophylaxis by using rifampin.Alright, as a quick recap.
Haemophilus influenzae is a Gram-negative coccobacillus that is non-motile, facultatively anaerobic, catalase and oxidase positive, and grows on chocolate agar with factors V and X.
There are two types of Haemophilus influenzae - encapsulated strains and unencapsulated strains. Both encapsulated and unencapsulated strains have an outer membrane with LOS, and they secrete IgA protease, but only encapsulated strains have, well, a capsule with pilli and adhesion proteins.
On the other hand, only non-encapsulated strains possess the skills of phase variation and biofilm formation. Encapsulated strains causes invasive diseases such as epiglottitis, meningitis, cellulitis, bacteremia, septic arthritis and osteomyelitis.
Unencapsulated strains cause mucosal infections like otitis media, conjunctivitis, sinusitis and bronchitis and bronchopneumonia.
Diagnosis can be done by identifying bacteria in a culture from blood, CSF, synovial fluid or pleural fluid, or with serological methods such as latex agglutination, enzyme immunoassay or coagglutination.
Treatment is done with amoxicillin +/- clavulanate for Haemophilus influenzae nontypable, and with ceftriaxone for Haemophilus influenzae type B.
Prevention can be done using a vaccine for Haemophilus influenzae type B. done with Amoxicillin with or without clavulanate for him.
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