Pneumococcal infection
Encyclopedia
Pathogenesis
S. pneumoniae is normally found in the nasopharynxNasopharynx
The nasopharynx is the uppermost part of the pharynx. It extends from the base of the skull to the upper surface of the soft palate; it differs from the oral and laryngeal parts of the pharynx in that its cavity always remains patent .-Lateral:On its lateral wall is the pharyngeal ostium of the...
of 5-10% of healthy adults, and 20-40% of healthy children. It can be found in higher amounts in certain environments, especially those where people are spending a great deal of time in close proximity to each other (day care centers, military barracks). It attaches to nasopharyngeal cells through interaction of bacterial surface adhesin
Adhesin
Adhesins are cell-surface components or appendages of bacteria that facilitate bacterial adhesion or adherence to other cells or to inanimate surfaces. Adhesins are a type of virulence factor....
s. This normal colonization can become infectious if the organisms are carried into areas such as the Eustachian tube
Eustachian tube
The Eustachian tube is a tube that links the nasopharynx to the middle ear. It is a part of the middle ear. In adult humans the Eustachian tube is approximately 35 mm long. It is named after the sixteenth-century anatomist Bartolomeo Eustachi...
or nasal sinuses where it can cause otitis media
Otitis media
Otitis media is inflammation of the middle ear, or a middle ear infection.It occurs in the area between the tympanic membrane and the inner ear, including a duct known as the eustachian tube. It is one of the two categories of ear inflammation that can underlie what is commonly called an earache,...
and sinusitis
Sinusitis
Sinusitis is inflammation of the paranasal sinuses, which may be due to infection, allergy, or autoimmune issues. Most cases are due to a viral infection and resolve over the course of 10 days...
, respectively. Pneumonia occurs if the organisms are inhaled into the lungs and not cleared (again, viral infection, or smoking
Tobacco smoking
Tobacco smoking is the practice where tobacco is burned and the resulting smoke is inhaled. The practice may have begun as early as 5000–3000 BCE. Tobacco was introduced to Eurasia in the late 16th century where it followed common trade routes...
-induced ciliary paralysis might be contributing factors). The organism's polysaccharide
Polysaccharide
Polysaccharides are long carbohydrate molecules, of repeated monomer units joined together by glycosidic bonds. They range in structure from linear to highly branched. Polysaccharides are often quite heterogeneous, containing slight modifications of the repeating unit. Depending on the structure,...
capsule makes it resistant to phagocytosis, and if there is no pre-existing anticapsular antibody, alveolar macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s cannot adequately kill the pneumococci. The organism spreads to the blood stream (where it can cause bacteremia
Bacteremia
Bacteremia is the presence of bacteria in the blood. The blood is normally a sterile environment, so the detection of bacteria in the blood is always abnormal....
) and is carried to the meninges
Meninges
The meninges is the system of membranes which envelopes the central nervous system. The meninges consist of three layers: the dura mater, the arachnoid mater, and the pia mater. The primary function of the meninges and of the cerebrospinal fluid is to protect the central nervous system.-Dura...
, joint spaces, bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
s, and peritoneal cavity
Peritoneal cavity
The peritoneal cavity is a potential space between the parietal peritoneum and visceral peritoneum, that is, the two membranes that separate the organs in the abdominal cavity from the abdominal wall...
, and may result in meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
, brain abscess
Brain abscess
Brain abscess is an abscess caused by inflammation and collection of infected material, coming from local or remote infectious sources, within the brain tissue...
, septic arthritis
Septic arthritis
Septic arthritis is the purulent invasion of a joint by an infectious agent which produces arthritis. People with artificial joints are more at risk than the general population but have slightly different symptoms, are infected with different organisms and require different treatment. Septic...
, or osteomyelitis
Osteomyelitis
Osteomyelitis simply means an infection of the bone or bone marrow...
.
S. pneumoniae has several virulence factor
Virulence factor
Virulence factors are molecules expressed and secreted by pathogens that enable them to achieve the following:* colonization of a niche in the host...
s, including the polysaccharide capsule mentioned earlier, that help it evade a host's immune system. It has pneumococcal surface proteins that inhibit complement-mediated opsonization, and it secretes IgA1 protease that will destroy secretory IgA produced by the body and mediates its attachment to respiratory mucosa.
The risk of pneumococcal infection is much increased in persons with impaired IgG synthesis, impaired phagocytosis, or defective clearance of pneumococci. In particular, the absence of a functional spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
, through congenital asplenia, splenectomy
Splenectomy
A splenectomy is a surgical procedure that partially or completely removes the spleen.-Indications:The spleen, similar in structure to a large lymph node, acts as a blood filter. Current knowledge of its purpose includes the removal of old red blood cells and platelets, and the detection and fight...
, or sickle-cell disease
Sickle-cell disease
Sickle-cell disease , or sickle-cell anaemia or drepanocytosis, is an autosomal recessive genetic blood disorder with overdominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various...
predisposes one to a more severe course of infection (Overwhelming post-splenectomy infection
Overwhelming post-splenectomy infection
An overwhelming post-splenectomy infection is a rare but rapidly fatal infection occurring in individuals following removal of the spleen...
) and prevention measures are indicated (see asplenia
Asplenia
Asplenia refers to the absence of normal spleen function and is associated with some serious infection risks. Hyposplenism is used to describe reduced splenic functioning, but not as severely affected as with asplenism.-Congenital:...
).
People whose immune system is compromised, such as those living with HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
, are also at higher risk of pneumococcal disease. In HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
patients with access to treatment, the risk of invasive pneumoccal disease is 0.2%-1% per year and has a fatality rate of 8%.
There is an association between pneumococcal pneumonia and influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
. Damage to the lining of the airways (respiratory epithelium) caused by influenza may facilitate pneumococcal entry and infection.
Other risk factors include smoking
Smoking
Smoking is a practice in which a substance, most commonly tobacco or cannabis, is burned and the smoke is tasted or inhaled. This is primarily practised as a route of administration for recreational drug use, as combustion releases the active substances in drugs such as nicotine and makes them...
, injection drug use, Hepatitis C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
, and COPD.
Virulence factors
S. pneumoniae expresses different virulence factors on its cell surface and inside the organism. These virulence factors contribute to some of the clinical manifestations during infection with S. pneumoniae.- Polysaccharide capsule -prevents phagocytosis by host immune cells by inhibiting C3b opsonization of the bacterial cells
- PneumolysinPneumolysinPneumolysin is a putative virulence factor of the gram positive bacteria Streptococcus pneumoniae.It is a 53 kDa pore forming toxin composed of 471 amino acids...
(Ply) -a 53-kDa pore forming protein that can cause lysis of host cells and activate complement - Autolysin (LytA) -activation of this protein lyses the bacteria releasing its internal contents (i.e. pneumolysin)
- Hydrogen peroxideHydrogen peroxideHydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...
- causes damage to host cells (can cause apoptosis in neuronal cells during meningitis) and has bactericidal effects against competing bacteria (Haemophilus influenzaeHaemophilus influenzaeHaemophilus influenzae, formerly called Pfeiffer's bacillus or Bacillus influenzae, Gram-negative, rod-shaped bacterium first described in 1892 by Richard Pfeiffer during an influenza pandemic. A member of the Pasteurellaceae family, it is generally aerobic, but can grow as a facultative anaerobe. H...
, Neisseria meningitidisNeisseria meningitidisNeisseria meningitidis, often referred to as meningococcus, is a bacterium that can cause meningitis and other forms of meningococcal disease such as meningococcemia, a life threatening sepsis. N. meningitidis is a major cause of morbidity and mortality during childhood in industrialized countries...
, Staphylococcus aureusStaphylococcus aureusStaphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
) - PiliPilusright|thumb|350px|Schematic drawing of bacterial conjugation. 1- Donor cell produces pilus. 2- Pilus attaches to recipient cell, brings the two cells together. 3- The mobile plasmid is nicked and a single strand of DNA is then transferred to the recipient cell...
- hair-like structures that extend from the surface of many strains of S. pneumoniae. They contribute to colonization of upper respiratory tract and increase the formation of large amounts of TNFTumor necrosis factorsTumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...
by the immune system during sepsisSepsisSepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
, raising the possibility of septic shockSeptic shockSeptic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome and death... - Choline binding protein A/Pneumococcal surface protein A (CbpA/PspA) -an adhesin that can interact with carbohydrates on the cell surface of pulmonary epithelial cells and can inhibit complement-mediated opsonization of pneumococci
Humoral immunity
In the 19th century, it was demonstrated that immunization of rabbitRabbit
Rabbits are small mammals in the family Leporidae of the order Lagomorpha, found in several parts of the world...
s with killed pneumococci protected them against subsequent challenge with viable pneumococci. Serum
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
from immunized rabbits or from humans who had recovered from pneumococcal pneumonia also conferred protection. In the 20th century, the efficacy of immunization was demonstrated in South Africa
South Africa
The Republic of South Africa is a country in southern Africa. Located at the southern tip of Africa, it is divided into nine provinces, with of coastline on the Atlantic and Indian oceans...
n miners.
It was discovered that the pneumococcus's capsule made it resistant to phagocytosis, and in the 1920s it was shown that an antibody specific for capsular polysaccharide aided the killing of S. pneumoniae. In 1936, a pneumococcal capsular polysaccharide vaccine was used to abort an epidemic of pneumococcal pneumonia. In the 1940s, experiments on capsular transformation by pneumococci first identified DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
as the material that carries genetic information.
In 1900, it was recognized that different serovars of pneumococci exist, and that immunization with a given serovar did not protect against infection with other serovars. Since then over ninety serovars have been discovered, each with a unique polysaccharide capsule which can be identified by the quellung reaction
Quellung reaction
The Quellung reaction is a biochemical reaction in which antibodies bind to the Bacterial capsule of Streptococcus pneumoniae, Klebsiella pneumoniae, Neisseria meningitidis and Haemophilus influenzae and thus allow them to be visualized under a microscope...
. Because some of these serovars cause disease more commonly than others, it is possible to provide reasonable protection by immunizing with less than 90 serovars; the current vaccine contains 23 serovars (i.e., it is "23-valent").
The serovars are numbered according to two systems: the American system, which numbers them in the order in which they were discovered, and the Danish system which groups them according to antigenic similarities.
Diagnosis
Depending on the nature of infection, an appropriate sample is collected for laboratory identification. Pneumococci are typically gram positive, cocci, seen in pairs or chains. When cultured on blood agar plates with added optochinOptochin
Optochin is a chemical used in cell culture techniques for the presumptive identification of Streptococcus pneumoniae, which is optochin-sensitive, from other alpha-hemolytic streptococci such as Streptococcus viridans which are resistant...
antibiotic disk, they show alpha-hemolytic
Hemolysis (microbiology)
Hemolysis is the breakdown of red blood cells. The ability of bacterial colonies to induce hemolysis when grown on blood agar is used to classify certain microorganisms. This is particularly useful in classifying streptococcal species...
colonies and a clear zone of inhibition around the disk meaning they're sensitive to the antibiotic. Pneumococci are also bile soluble. Just like other streptococci, they are catalase
Catalase
Catalase is a common enzyme found in nearly all living organisms that are exposed to oxygen, where it catalyzes the decomposition of hydrogen peroxide to water and oxygen...
negative. A Quellung test can identify specific capsular polysaccharides.
Pneumococcal antigen (cell wall C polysaccharide) may be detected in various body fluids. Older detection kits, based on latex agglutination, added little value above Gram staining and were occasionally false-positive
Type I and type II errors
In statistical test theory the notion of statistical error is an integral part of hypothesis testing. The test requires an unambiguous statement of a null hypothesis, which usually corresponds to a default "state of nature", for example "this person is healthy", "this accused is not guilty" or...
. Better results are achieved with rapid immunochromatography, which has a sensitivity
Sensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...
(identifies the cause) of 70-80% and >90% specificity (when positive identifies the actual cause) in pneumococcal infections. The test was initially validated on urine samples, but has been applied successfully to other body fluids. Chest x-rays can also be conducted to confirm an infection.
Treatment
Historically, treatment relied primarily on β-lactam antibiotics. In the 1960s, nearly all strains of S. pneumoniae were susceptible to penicillinPenicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
, but since that time, there has been an increasing prevalence of penicillin resistance
Antibiotic resistance
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...
, especially in areas of high antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
use. A varying proportion of strains may also be resistant to cephalosporin
Cephalosporin
The cephalosporins are a class of β-lactam antibiotics originally derived from Acremonium, which was previously known as "Cephalosporium".Together with cephamycins they constitute a subgroup of β-lactam antibiotics called cephems.-Medical use:...
s, macrolide
Macrolide
The macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered...
s (such as erythromycin), tetracycline, clindamycin
Clindamycin
Clindamycin rINN is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria...
and the quinolone
Quinolone
The quinolones are a family of synthetic broad-spectrum antibiotics. The term quinolone refers to potent synthetic chemotherapeutic antibacterials....
s. Penicillin-resistant strains are more likely to be resistant to other antibiotics. Most isolates remain susceptible to vancomycin
Vancomycin
Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
, though its use in a β-lactam-susceptible isolate is less desirable because of tissue distribution of the drug and concerns of development of vancomycin resistance. More advanced beta-lactam antibiotics (cephalosporins) are commonly used in combination with other drugs to treat meningitis and community-acquired pneumonia. In adults, recently developed fluoroquinolones such as levofloxacin
Levofloxacin
Levofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class and is used to treat severe or life-threatening bacterial infections or bacterial infections that have failed to respond to other antibiotic classes. It is sold under various brand names, such as Levaquin and...
and moxifloxacin
Moxifloxacin
Moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent developed by Bayer AG . It is marketed worldwide under the brand names Avelox, Avalox, and Avelon for oral treatment. In most countries, the drug is also available in parenteral form for intravenous infusion...
are often used to provide empiric coverage for patients with pneumonia, but in parts of the world where these drugs are used to treat tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
, resistance has been described.
Susceptibility testing should be routine, with empiric antibiotic treatment guided by resistance patterns in the community in which the organism was acquired, pending the results. There is currently debate as to how relevant the results of susceptibility testing are to clinical outcome. There is slight clinical evidence that penicillins may act synergistically with macrolides to improve outcomes.
Prevention
Vaccines against Streptococcus pneumoniaeStreptococcus pneumoniae
Streptococcus pneumoniae, or pneumococcus, is Gram-positive, alpha-hemolytic, aerotolerant anaerobic member of the genus Streptococcus. A significant human pathogenic bacterium, S...
are available.