Non-typeable H Influenzae- An Overview

Introduction

Hemophilus influenzae (H. influenzae) is a bacterium. Typeable H. influenzae is encapsulated. On the other hand, non-typeable H. influenzae (NTHi) is non-encapsulated. It naturally resides in the human pharynx (throat) as a typical inhabitant. However, it can cause a wide range of infections. NTHi-induced respiratory tract infections in adults are a significant cause of death and disability in both developing and developed nations.

What Is the Pathogenesis of Non-typeable H. Influenzae?

NTHi is very successful in colonization. It is because of the antigenic variation of its proteins and enzymes. NTHi is an extracellular (outside the cell) pathogen. The disease mechanisms through which it persists in the human pharynx are:

1. Adhesion: The ability of NTHi to attach to the mucous membranes is essential to allow the organism to multiply. It depends on the receptors, bacterial ligands (binding molecules), tissue microenvironment, and other microorganisms colonizing that area. Further, NTHi strains express proteins to bind the surface structures. It also helps the bacteria invade subepithelial tissues.

2. Increased Mucin Production: Mucin (a slimy substance) is produced by the outermost cells of the epithelium. Studies report that NTHi attaches to the damaged epithelium. NTHi also increases mucin production. NTHi also persists as a biofilm (an assembly of microorganisms). Biofilms characterize live bacteria adhering to a surface and dividing. They further form an aggregation of live bacteria, host cells, and dead bacteria.

3. Evasion of Host Defenses: Immunoglobulin A (IgA) is essential in mucous membrane immunity. It is the dominant antibody in the human upper respiratory tract. NTHi expresses IgA protease (an antibody-cleaving enzyme) that breaks down the IgA and facilitates adhesion.

4. Epithelial Cell Entry: NTHi is usually non-invasive. However, to evade the immune system, it may enter the host cell and cause invasive disease. It is a dynamic interaction. It is because of adherence and invasion of the NTHi increase over time. NTHi enters the cell by binding the high-molecular-weight (HMW) proteins on the bacterial surface.

5. Antigenic Variation: NTHi can adapt by varying the proteins found in its outer membrane. Hence, it can avoid or adapt to evolving host defenses. A predominant strain of NTHi colonizes the oropharyngeal area. However, many strains can be concomitantly present.

6. Inflammasome Activation: Inflammasomes are protein complexes that detect viral and bacterial exposure. They are also able to respond to pathogen-associated and damage-associated molecular patterns. NTHi activates inflammasomes and evades host response.

What Are the Predisposing Factors for Non-typeable H. Influenzae Infection?

The mechanisms by which NTHi establishes itself need to be better recognized. Mucus undergoes alterations in conditions such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis due to NTHi. Various predisposing factors for NTHi infections include:

1. Inhalational Corticosteroids (ICs): ICs contain cortisone-like medicine (steroid). ICs prevent asthma symptoms. The primary treatment for chronic asthma is ICs. It is because of their broad range of anti-inflammatory actions. However, long-term steroid therapy leads to impaired antimicrobial defense. Studies report lymphocyte (immune cell) suppression by ICs.

2. Cigarette Smoking: Cigarette smoke impairs bacterial clearance. It is because of a decrease in ciliary movement. Cilia are hair-like projections on the air passage cells that move microbes and debris out of the airways. Smoking is also associated with an increased expression of intracellular cell adhesion molecule 1 (ICAM-1). ICAM-1 is a surface protein NTHi uses as an adhesion factor.

What Are the Diseases Caused by Non-typeable H. Influenzae?

NTHi is a respiratory tract pathogen. It causes:

1. Lower Respiratory Tract Infections (LRTI): Acute bronchitis, pneumonia, and episodes of worsening symptoms in individuals with chronic obstructive pulmonary disease (COPD) are known as acute exacerbations, and asthma is all included within the category of lower respiratory tract infections (LRTIs).

• Asthma: Worldwide, approximately 350 million individuals are impacted by asthma, which is a chronic respiratory condition. NTHi is isolated more from the airways of asthma patients than healthy patients. It affects patients already suffering from COPD and asthma. Nasopharyngeal colonization with NTHi is common in children by the second year of their lives. Infants and elderly individuals are the most susceptible to severe invasive NTHi infections.
• COPD: COPD is an inflammatory disease with airway obstruction. NTHi strains during COPD exacerbations induce more airway inflammation. Furthermore, it causes exacerbations in COPD patients. The strains affecting COPD patients have more virulence (severity) than others.

2. Cystic Fibrosis (CF): CF is a genetic disorder that affects the lungs, digestive system, and other body organs. NTHi frequently infects the respiratory tract of cystic fibrosis patients.

3. Otitis Media: Otitis media is a term used for middle ear infections. NTHi is responsible for many otitis media cases in children. Up to 100 percent of children in developing countries and 62 percent in developed countries have their first episode of otitis media within one year. Otitis media presents in infants with fever, irritability, and ear pulling. On the contrary, older patients report typical ear pain.

4. Other Infections: The parasitic nature of NTHi results in most infections of the middle ear, conjunctiva, sinuses, and lower respiratory tract. NTHi colonization of the genitourinary tract (GUT) also predisposes prepubertal females to infection.

How Is Non-typeable H. Influenzae Isolated?

Doctors usually diagnose NTHi infections with one or more laboratory tests.

1. Gram Staining: It reveals pleomorphic (more than one form) Gram-negative coccobacillus.

2. Blood Culture: Cultures of blood and body fluids confirm the organism.

3. Nasopharyngeal Swab: This type of nasal swab can be used for NTHi respiratory infections.

4. Polymerase Chain Reaction (PCR): PCR isolates the DNA of NTHi. It can also differentiate between different strains of the bacterium.

For rapid diagnosis, methods used are immunoelectrophoresis, latex particle agglutination (LPA), and enzyme-linked immunosorbent assay (ELISA).

• Immunoelectrophoresis measures the blood antibodies to H. influenzae.

• LPA measures the influenza patient's antigen-antibody reaction.

• ELISA enables rapid diagnosis of various influenza strains, including the non-typeable H. influenzae.

Imaging helps view the extent of the disease.

What Is the Management of Non-typeable H. Influenzae?

1. Oral Antibiotics: The mainstay of NTHi treatment is oral antibiotics.

• The drug of choice is high-dose Amoxicillin. The dose is 80 to 90 milligrams (mg)/kilograms (kg)/day twice daily.

• The second line of treatment is Amoxicillin or Clavulanate.

• In a patient allergic to Penicillin, Erythromycin-Sulfisoxazole is prescribed. Cefaclor is a second-generation cephalosporin (antibiotic group) used in the same.

The age of the children and disease severity determine the length of treatment. Children younger than two years with severe infections are treated for ten days. Further, two to five-year-olds with mild to moderate otitis media are treated for a week. Finally, five to seven days of treatment are given for children older than six years with mild to moderate symptoms.

2. Parenteral Antibiotics: Invasive NTHi disease is treated by intravenous (into the vein) antibiotics.

3. Vaccines: Various vaccine candidates are under randomized controlled trials in humans.

Conclusion

NTHi is one of the most significant causes of acute otitis media in children and respiratory diseases in adults. Invasive infections caused by NTHi strains have spread to many countries. Hence, parents or guardians of the affected children in schools or daycare must be alerted to the development of the disease. This may ensure timely treatment of the same.