Haemophilus influenzae

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Haemophilus influenzae
Haemophilus influenzae.jpg
H. influenzae on a Chocolate agar plate.
Scientific classification
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H. influenzae
Binomial name
Haemophilus influenzae
(Lehmann & Neumann 1896)
Winslow et al. 1917
Haemophilus influenzae satelliting colonies (pin point) near Staphylococcus aureus (yellow) on blood agar plate. Hinfluenzae satillite.jpg
Haemophilus influenzae satelliting colonies (pin point) near Staphylococcus aureus (yellow) on blood agar plate.

Haemophilus influenzae (formerly called Pfeiffer's bacillus or Bacillus influenzae) is a Gram-negative, coccobacillary, facultatively anaerobic pathogenic bacterium belonging to the Pasteurellaceae family. H. influenzae was first described in 1892 by Richard Pfeiffer during an influenza pandemic. [1]

Coccobacillus

A coccobacillus is a type of bacterium with a shape intermediate between cocci and bacilli. Coccobacilli, then, are very short rods which may be mistaken for cocci.

Facultative anaerobic organism organism that makes ATP by aerobic respiration if oxygen is present

A facultative anaerobe is an organism that makes ATP by aerobic respiration if oxygen is present, but is capable of switching to fermentation if oxygen is absent.

Pasteurellaceae family of bacteria

The Pasteurellaceae comprise a large family of Gram-negative bacteria. Most members live as commensals on mucosal surfaces of birds and mammals, especially in the upper respiratory tract. Pasteurellaceae are typically rod-shaped, and are a notable group of facultative anaerobes. Their biochemical characteristics can be distinguished from the related Enterobacteriaceae by the presence of oxidase, and from most other similar bacteria by the absence of flagella.

Contents

The bacterium was mistakenly considered to be the cause of influenza until 1933, when the viral cause of influenza became apparent, and is still colloquially known as bacterial influenza. H. influenzae is responsible for a wide range of localized and invasive infections. This species was the first free-living organism to have its entire genome sequenced. [2]

Influenza infectious disease

Influenza, commonly known as the flu, is an infectious disease caused by an influenza virus. Symptoms can be mild to severe. The most common symptoms include: high fever, runny nose, sore throat, muscle pains, headache, coughing, sneezing, and feeling tired. These symptoms typically begin two days after exposure to the virus and most last less than a week. The cough, however, may last for more than two weeks. In children, there may be diarrhea and vomiting, but these are not common in adults. Diarrhea and vomiting occur more commonly in gastroenteritis, which is an unrelated disease and sometimes inaccurately referred to as "stomach flu" or the "24-hour flu". Complications of influenza may include viral pneumonia, secondary bacterial pneumonia, sinus infections, and worsening of previous health problems such as asthma or heart failure.

Genome entirety of an organisms hereditary information; genome of organism (encoded by the genomic DNA) is the (biological) information of heredity which is passed from one generation of organism to the next; is transcribed to produce various RNAs

In the fields of molecular biology and genetics, a genome is the genetic material of an organism. It consists of DNA. The genome includes both the genes and the noncoding DNA, as well as mitochondrial DNA and chloroplast DNA. The study of the genome is called genomics.

Serotypes

In 1930, two major categories of H. influenzae were defined: the unencapsulated strains and the encapsulated strains. Encapsulated strains were classified on the basis of their distinct capsular antigens. The six generally recognized types of encapsulated H. influenzae are: a, b, c, d, e, and f. [3] Genetic diversity among unencapsulated strains is greater than within the encapsulated group. Unencapsulated strains are termed nontypable (NTHi) because they lack capsular serotypes; however, they can be classified by multilocus sequence typing. The pathogenesis of H. influenzae infections is not completely understood, although the presence of the capsule in encapsulated type b (Hib), a serotype causing conditions such as epiglottitis, is known to be a major factor in virulence. Their capsule allows them to resist phagocytosis and complement-mediated lysis in the nonimmune host. The unencapsulated strains are almost always less invasive; they can, however, produce an inflammatory response in humans, which can lead to many symptoms. Vaccination with Hib conjugate vaccine is effective in preventing Hib infection, but does not prevent infection with NTHi strains. [4]

The pathogenesis of a disease is the biological mechanism progress of disease showing its morphological features or that leads to the diseased state. The term can also describe the origin and development of the disease, and whether it is acute, chronic, or recurrent. The word comes from the Greek πάθος pathos and γένεσις genesis ("creation").

Epiglottitis inflammation of the epiglottis

Epiglottitis is inflammation of the epiglottis—the flap at the base of the tongue that keeps food from going into the trachea (windpipe). Symptoms are usually rapid in onset and include trouble swallowing which can result in drooling, changes to the voice, fever, and an increased breathing rate. As the epiglottis is in the upper airway, swelling can interfere with breathing. People may lean forward in an effort to open the airway. As the condition worsens stridor and bluish skin may occur.

Phagocytosis An endocytosis process that results in the engulfment of external particulate material by phagocytes. The particles are initially contained within phagocytic vacuoles (phagosomes), which then fuse with primary lysosomes to effect digestion of the par

Phagocytosis is the process by which a cell uses its plasma membrane to engulf a large particle, giving rise to an internal compartment called the phagosome. It is one type of endocytosis.

Diseases

Haemophilus influenzae infection
Specialty Infectious disease

Most strains of H. influenzae are opportunistic pathogens; that is, they usually live in their host without causing disease, but cause problems only when other factors (such as a viral infection, reduced immune function or chronically inflamed tissues, e.g. from allergies) create an opportunity. They infect the host by sticking to the host cell using trimeric autotransporter adhesins.

Trimeric autotransporter adhesin

In molecular biology, trimeric autotransporter adhesins (TAAs), are proteins found on the outer membrane of Gram-negative bacteria. Bacteria use TAAs in order to infect their host cells via a process called cell adhesion. TAAs also go by another name, oligomeric coiled-coil adhesins, which is shortened to OCAs. In essence, they are virulence factors, factors that make the bacteria harmful and infective to the host organism.

Naturally acquired disease caused by H. influenzae seems to occur in humans only. In infants and young children, H. influenzae type b (Hib) causes bacteremia, pneumonia, epiglottitis and acute bacterial meningitis. On occasion, it causes cellulitis, osteomyelitis, and infectious arthritis. It is one cause of neonatal infection. [5]

Bacteremia is the presence of bacteria in the blood. Blood is normally a sterile environment, so the detection of bacteria in the blood is always abnormal. It is distinct from sepsis, which is the host response to the bacteria.

Pneumonia Infection of the lungs

Pneumonia is an inflammatory condition of the lung affecting primarily the small air sacs known as alveoli. Typically symptoms include some combination of productive or dry cough, chest pain, fever, and trouble breathing. Severity is variable.

Meningitis inflammation of membranes around the brain and spinal cord

Meningitis is an acute inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The most common symptoms are fever, headache, and neck stiffness. Other symptoms include confusion or altered consciousness, vomiting, and an inability to tolerate light or loud noises. Young children often exhibit only nonspecific symptoms, such as irritability, drowsiness, or poor feeding. If a rash is present, it may indicate a particular cause of meningitis; for instance, meningitis caused by meningococcal bacteria may be accompanied by a characteristic rash.

Due to routine use of the Hib conjugate vaccine in the U.S. since 1990, the incidence of invasive Hib disease has decreased to 1.3/100,000 in children. However, Hib remains a major cause of lower respiratory tract infections in infants and children in developing countries where the vaccine is not widely used. Unencapsulated H. influenzae strains are unaffected by the Hib vaccine and cause ear infections (otitis media), eye infections (conjunctivitis), and sinusitis in children, and are associated with pneumonia.

Otitis media otitis which involves inflammation of the middle ear

Otitis media is a group of inflammatory diseases of the middle ear. The two main types are acute otitis media (AOM) and otitis media with effusion (OME). AOM is an infection of rapid onset that usually presents with ear pain. In young children this may result in pulling at the ear, increased crying, and poor sleep. Decreased eating and a fever may also be present. OME is typically not associated with symptoms. Occasionally a feeling of fullness is described. It is defined as the presence of non-infectious fluid in the middle ear for more than three months. Chronic suppurative otitis media (CSOM) is middle ear inflammation of greater than two weeks that results in episodes of discharge from the ear. It may be a complication of acute otitis media. Pain is rarely present. All three may be associated with hearing loss. The hearing loss in OME, due to its chronic nature, may affect a child's ability to learn.

Conjunctivitis inflammation of the outermost layer of the eye and the inner surface of the eyelids

Conjunctivitis, also known as pink eye, is inflammation of the outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may occur. The affected eye may have increased tears or be "stuck shut" in the morning. Swelling of the white part of the eye may also occur. Itching is more common in cases due to allergies. Conjunctivitis can affect one or both eyes.

Sinusitis inflammation of the mucous membrane that lines the sinuses resulting in symptoms

Sinusitis, also known as a sinus infection or rhinosinusitis, is inflammation of the mucous membrane that lines the sinuses resulting in symptoms. Common symptoms include thick nasal mucus, a plugged nose, and facial pain. Other signs and symptoms may include fever, headaches, poor sense of smell, sore throat, and cough. The cough is often worse at night. Serious complications are rare. It is defined as acute sinusitis if it lasts less than 4 weeks, and as chronic sinusitis if it lasts for more than 12 weeks.

Diagnosis

Sputum Gram stain at 1000x magnification. The sputum is from a person with Haemophilus influenzae pneumonia, and the Gram negative coccobacilli are visible with a background of neutrophils. Haemophilus influenzae sputum 1000x edited.jpg
Sputum Gram stain at 1000x magnification. The sputum is from a person with Haemophilus influenzae pneumonia, and the Gram negative coccobacilli are visible with a background of neutrophils.
Haemophilus influenzae requires X and V factors for growth. In this culture, Haemophilus has only grown around the paper disc that has been impregnated with X and V factors. No bacterial growth is seen around the discs that only contain either X or V factor. H. influenzae XV.jpg
Haemophilus influenzae requires X and V factors for growth. In this culture, Haemophilus has only grown around the paper disc that has been impregnated with X and V factors. No bacterial growth is seen around the discs that only contain either X or V factor.
Chest X-ray of a case of Haemophilus influenzae, presumably as a secondary infection from influenza. It shows patchy consolidations, mainly in the right upper lobe (arrow). Chest radiograph in influensa and H influenzae, posteroanterior, annotated.jpg
Chest X-ray of a case of Haemophilus influenzae, presumably as a secondary infection from influenza. It shows patchy consolidations, mainly in the right upper lobe (arrow).
Chest X-ray in a case of COPD exacerbation where a nasopharyngeal swab detected Haemophilus influenzae: Opacities (on the patient's right side) can be seen in other types of pneumonia, as well. X-ray of COPD exacerbation - anteroposterior view.jpg
Chest X-ray in a case of COPD exacerbation where a nasopharyngeal swab detected Haemophilus influenzae: Opacities (on the patient's right side) can be seen in other types of pneumonia, as well.

Clinical features may include initial symptoms of an upper respiratory tract infection mimicking a viral infection, usually associated with fevers, often low-grade. This may progress to the lower respiratory tract in a few days, with features often resembling those of a wheezy bronchitis. Sputum may be difficult to expectorate and is often grey or creamy in color. The cough may persist for weeks without appropriate treatment. Many cases are diagnosed after presenting chest infections that do not respond to penicillins or first-generation cephalosporins. A chest X-ray can identify alveolar consolidation. [6]

Clinical diagnosis of H. influenzae is typically performed by bacterial culture or latex particle agglutinations. Diagnosis is considered confirmed when the organism is isolated from a sterile body site. In this respect, H. influenzae cultured from the nasopharyngeal cavity or sputum would not indicate H. influenzae disease, because these sites are colonized in disease-free individuals. [7] However, H. influenzae isolated from cerebrospinal fluid or blood would indicate H. influenzae infection.

Culture

Bacterial culture of H. influenzae is performed on agar plates, the preferable one being chocolate agar, with added X (hemin) and V (nicotinamide adenine dinucleotide) factors at 37 °C in a CO2-enriched incubator. [8] Blood agar growth is only achieved as a satellite phenomenon around other bacteria. Colonies of H. influenzae appear as convex, smooth, pale, grey, or transparent colonies.

Gram stained and microscopic observation of a specimen of H. influenzae will show Gram-negative coccobacillus. The cultured organism can be further characterized using catalase and oxidase tests, both of which should be positive. Further serological testing is necessary to distinguish the capsular polysaccharide and differentiate between H. influenzae b and nonencapsulated species.

Although highly specific, bacterial culture of H. influenzae lacks sensitivity. Use of antibiotics prior to sample collection greatly reduces the isolation rate by killing the bacteria before identification is possible. [9] Beyond this, H. influenzae is a finicky bacterium to culture, and any modification of culture procedures can greatly reduce isolation rates. Poor quality of laboratories in developing countries has resulted in poor isolation rates of H. influenzae.

H. influenzae will grow in the hemolytic zone of Staphylococcus aureus on blood agar plates; the hemolysis of cells by S. aureus releases factor V which is needed for its growth. H. influenzae will not grow outside the hemolytic zone of S. aureus due to the lack of nutrients such as factor V in these areas. Fildes agar is best for isolation. In Levinthal medium, capsulated strains show distinctive iridescence.

Latex particle agglutination

The latex particle agglutination test (LAT) is a more sensitive method to detect H. influenzae than is culture. [10] Because the method relies on antigen rather than viable bacteria, the results are not disrupted by prior antibiotic use. It also has the added benefit of being much quicker than culture methods. However, antibiotic sensitivity testing is not possible with LAT alone, so a parallel culture is necessary.

Molecular methods

Polymerase chain reaction (PCR) assays have been proven to be more sensitive than either LAT or culture tests, and highly specific. [10] However, PCR assays have not yet become routine in clinical settings. Countercurrent immunoelectrophoresis has been shown to be an effective research diagnostic method, but has been largely supplanted by PCR.

Interaction with Streptococcus pneumoniae

Both H. influenzae and S. pneumoniae can be found in the upper respiratory system of humans. In an in vitro study of competition, S. pneumoniae always overpowered H. influenzae by attacking it with hydrogen peroxide and stripping off the surface molecules H. influenzae needs for survival. [11]

When both bacteria are placed together into a nasal cavity, within 2 weeks, only H. influenzae survives. When either is placed separately into a nasal cavity, each one survives. Upon examining the upper respiratory tissue from mice exposed to both bacteria species, an extraordinarily large number of neutrophils (immune cells) was found. In mice exposed to only one of the species, the neutrophils were not present.

Lab tests showed neutrophils exposed to dead H. influenzae were more aggressive in attacking S. pneumoniae than unexposed neutrophils. Exposure to dead H. influenzae had no effect on live H. influenzae.

Two scenarios may be responsible for this response:

  1. When H. influenzae is attacked by S. pneumoniae, it signals the immune system to attack the S. pneumoniae
  2. The combination of the two species triggers an immune system response that is not set off by either species individually.

It is unclear why H. influenzae is not affected by the immune response. [12]

Signs and symptoms

Pneumonia occurs when the lungs become infected, causing inflammation (swelling). Symptoms of pneumonia usually include: [13]

Treatment

Haemophilus influenzae produces beta-lactamases, and it is also able to modify its penicillin-binding proteins, so it has gained resistance to the penicillin family of antibiotics. In severe cases, cefotaxime and ceftriaxone delivered directly into the bloodstream are the elected antibiotics, and, for the less severe cases, an association of ampicillin and sulbactam, cephalosporins of the second and third generation, or fluoroquinolones are preferred. (Fluoroquinolone-resistant Haemophilus influenzae have been observed.) [14]

Macrolide antibiotics (e.g., clarithromycin) may be used in patients with a history of allergy to beta-lactam antibiotics.[ citation needed ] Macrolide resistance has also been observed. [15]

Serious complications

The serious complications of HiB are brain damage, hearing loss, and even death. [16]

Prevention

ActHIB (Hib-vaccine) Act-HIb.jpg
ActHIB (Hib-vaccine)

Effective vaccines for Haemophilus influenzae Type B have been available since the early 1990s, and are recommended for children under age 5 and asplenic patients. The World Health Organization recommends a pentavalent vaccine, combining vaccines against diphtheria, tetanus, pertussis, hepatitis B and Hib. There is not yet sufficient evidence on how effective this pentavalent vaccine is in relation to the individual vaccines. [17]

Hib vaccines cost about seven times the total cost of vaccines against measles, polio, tuberculosis, diphtheria, tetanus, and pertussis. Consequently, whereas 92% of the populations of developed countries were vaccinated against Hib as of 2003, vaccination coverage was 42% for developing countries, and only 8% for least-developed countries. [18]

The Hib vaccines do not provide cross-protection to any other Haemophilus influenzae serotypes like Hia, Hic, Hid, Hie or Hif. [19]

An oral vaccination has been developed for non-typeable Haemophilus influenzae (NTHi) for patients with chronic bronchitis but it has not shown to be effective in reducing the number and severity of COPD exacerbations. [20]

Sequencing

H. influenzae was the first free-living organism to have its entire genome sequenced. Completed by Craig Venter and his team at The Institute for Genomic Research - one of the institutes now part of the J. Craig Venter Institute. Haemophilus was chosen because one of the project leaders, Nobel laureate Hamilton Smith, had been working on it for decades and was able to provide high-quality DNA libraries. The genome consists of 1,830,140 base pairs of DNA in a single circular chromosome that contains 1740 protein-coding genes, 2 transfer RNA genes, and 18 other RNA genes. The sequencing method used was whole-genome shotgun, which was completed and published in Science in 1995. [21]

Likely protective role of transformation

Unencapsulated H. influenzae is often observed in the airways of patients with chronic obstructive pulmonary disease (COPD). Neutrophils are also observed in large numbers in sputum from patients with COPD. The neutrophils phagocytize H. influenzae, thereby activating an oxidative respiratory burst. [22] However instead of killing the bacteria the neutrophils are themselves killed (though such an oxidative burst likely causes DNA damage in the H. influenzae cells). The lack of killing of the H. influenzae appears to explain the persistence of infection in COPD. [22]

H. influenzae mutants defective in the rec1 gene (a homolog of recA ) are very sensitive to killing by the oxidizing agent hydrogen peroxide. [23] This finding suggests that rec1 expression is important for H. influenzae survival under conditions of oxidative stress. Since it is a homolog of recA, rec1 likely plays a key role in recombinational repair of DNA damage. Thus H. influenzae may protect its genome against the reactive oxygen species produced by the host’s phagocytic cells through recombinational repair of oxidative DNA damages. [24] Recombinational repair of a damaged site of a chromosome requires, in addition to rec1, a second homologous undamaged DNA molecule. Individual H. influenzae cells are capable of taking up homologous DNA from other cells by the process of transformation. Transformation in H. influenzae involves at least 15 gene products, [21] and is likely an adaptation for repairing DNA damages in the resident chromosome (as suggested in Transformation (genetics)#Transformation, as an adaptation for DNA repair).

Vaccines that target unencapsulated H. influenzae serotypes are in development. [25]

See also

Related Research Articles

Sputum mucus that is coughed up from the lower airways

Sputum is mucus and is the name used for the coughed-up material (phlegm) from the lower airways. In medicine, sputum samples are usually used for naked eye exam, microbiological investigations of respiratory infections, and cytological investigations of respiratory systems. It is critical that the patient not give a specimen that includes any mucoid material from the interior of the nose. Naked eye exam of sputum can be done at home by a patient in order to note the various colors. Any hint of yellow color suggests an airway infection. Such color hints are best detected when the sputum is viewed on a very white background such as white paper, a white pot, or a white sink surface. The more intense the yellow color, the more likely it is a bacterial infection.

Acute bronchitis short-term inflammation of the bronchi (large and medium-sized airways) of the lungs

Acute bronchitis, also known as a chest cold, is short-term inflammation of the bronchi of the lungs. The most common symptom is a cough. Other symptoms include coughing up mucus, wheezing, shortness of breath, fever, and chest discomfort. The infection may last from a few to ten days. The cough may persist for several weeks afterward with the total duration of symptoms usually around three weeks. Some have symptoms for up to six weeks.

Atypical pneumonia, also known as walking pneumonia, is the type of pneumonia not caused by one of the pathogens most commonly associated with the disease. Its clinical presentation contrasts to that of "typical" pneumonia. A variety of microorganisms can cause it. When it develops independently from another disease it is called primary atypical pneumonia (PAP).

The HACEK organisms are a group of fastidious gram-negative bacteria that are an unusual cause of infective endocarditis, which is an inflammation of the heart due to bacterial infection. HACEK is an abbreviation of the initials of the genera of this group of bacteria: Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella. The HACEK organisms are a normal part of the human microbiota, living in the oral-pharyngeal region.

<i>Streptococcus pneumoniae</i> species of bacterium

Streptococcus pneumoniae, or pneumococcus, is a Gram-positive, alpha-hemolytic or beta-hemolytic, facultative anaerobic member of the genus Streptococcus. They are usually found in pairs (diplococci) and do not form spores and are nonmotile. As a significant human pathogenic bacterium S. pneumoniae was recognized as a major cause of pneumonia in the late 19th century, and is the subject of many humoral immunity studies.

Asplenia refers to the absence of normal spleen function and is associated with some serious infection risks. Hyposplenism is used to describe reduced ('hypo-') splenic functioning, but not as severely affected as with asplenism.

Lower respiratory tract infection

Lower respiratory tract infection (LRTI), while often used as a synonym for pneumonia, can also be applied to other types of infection including lung abscess and acute bronchitis. Symptoms include shortness of breath, weakness, fever, coughing and fatigue.

Bacterial pneumonia is a type of pneumonia caused by bacterial infection.

Bacterial capsule

The bacterial capsule is a very large structure of many bacteria. It is a polysaccharide layer that lies outside the cell envelope, and is thus deemed part of the outer envelope of a bacterial cell. It is a well-organized layer, not easily washed off, and it can be the cause of various diseases.

<i>Neisseria meningitidis</i> species of bacterium

Neisseria meningitidis, often referred to as meningococcus, is a Gram-negative bacterium that can cause meningitis and other forms of meningococcal disease such as meningococcemia, a life-threatening sepsis. It has also been reported to be transmitted through oral sex and cause urethritis in men. The bacterium is referred to as a coccus because it is round, and more specifically, diplococcus because of its tendency to form pairs. About 10% of adults are carriers of the bacteria in their nasopharynx. As an exclusively human pathogen it is the main cause of bacterial meningitis in children and young adults, causing developmental impairment and death in about 10% of cases. It causes the only form of bacterial meningitis known to occur epidemically, mainly Africa and Asia. It occurs worldwide in both epidemic and endemic form. N. meningitidis is spread through saliva and respiratory secretions during coughing, sneezing, kissing, chewing on toys and even through sharing a source of fresh water. It infects its host cells by sticking to them with long thin extensions called pili and the surface-exposed proteins Opa and Opc and has several virulence factors.

Moraxella catarrhalis is a fastidious, nonmotile, Gram-negative, aerobic, oxidase-positive diplococcus that can cause infections of the respiratory system, middle ear, eye, central nervous system, and joints of humans. It causes the infection of the host cell by sticking to the host cell using trimeric autotransporter adhesins.

Sultamicillin chemical compound

Sultamicillin, sold under the brand name Unasyn among others, is an oral form of the antibiotic combination ampicillin/sulbactam. It contains esterified ampicillin and sulbactam.

Gemifloxacin chemical compound

Gemifloxacin mesylate is an oral broad-spectrum quinolone antibacterial agent used in the treatment of acute bacterial exacerbation of chronic bronchitis and mild-to-moderate pneumonia. Vansen Pharma Inc. has licensed the active ingredient from LG Life Sciences of Korea.

The Haemophilus influenzae type B vaccine, often called Hib vaccine, is a vaccine used to prevent Haemophilus influenzae type b (Hib) infection. In countries that include it as a routine vaccine, rates of severe Hib infections have decreased more than 90%. It has therefore resulted in a decrease in the rate of meningitis, pneumonia, and epiglottitis.

A pneumococcal infection is an infection caused by the bacterium Streptococcus pneumoniae, which is also called the pneumococcus. S. pneumoniae is a common member of the bacterial flora colonizing the nose and throat of 5–10% of healthy adults and 20–40% of healthy children. However, it is also a cause of significant disease, being a leading cause of pneumonia, bacterial meningitis, and sepsis. The World Health Organization estimate that in 2005 pneumococcal infections were responsible for the death of 1.6 million children worldwide.

Haemophilus meningitis is a form of bacterial meningitis caused by the Haemophilus influenzae bacteria. It is usually associated with Haemophilus influenzae type b. Meningitis involves the inflammation of the protective membranes that cover the brain and spinal cord. Haemophilus meningitis is characterized by symptoms including fever, nausea, sensitivity to light, headaches, stiff neck, anorexia, and seizures. Haemophilus meningitis can be deadly, but antibiotics are effective in treating the infection, especially when cases are caught early enough that the inflammation has not done a great deal of damage. Before the introduction of the Hib vaccine in 1985, Haemophilus meningitis was the leading cause of bacterial meningitis in children under the age of five. However, since the creation of the Hib vaccine, only two in every 100,000 children contract this type of meningitis. Five to ten percent of cases can be fatal, although the average mortality rate in developing nations is seventeen percent, mostly due to lack of access to vaccination as well as lack of access to medical care needed to combat the meningitis.

Acute exacerbation of chronic obstructive pulmonary disease

Acute exacerbation of COPD is a sudden worsening of COPD symptoms that typically lasts for several days. It may be triggered by an infection with bacteria or viruses or by environmental pollutants. Typically, infections cause 75% or more of the exacerbations; bacteria can roughly be found in 25% of cases, viruses in another 25%, and both viruses and bacteria in another 25%. Airway inflammation is increased during the exacerbation resulting in increased hyperinflation, reduced expiratory air flow and decreased gas exchange.

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Classification
D
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