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Indian Journal for the Practising Doctor

Streptococcal Infection

Author(s): Bashir Gaash

Vol. 2, No. 1 (2005-03 - 2005-04)

Streptococci were first demonstrated in patients with erysipelas by Billroth in 1874, and isolated in 1883 by Fehleisen, but it was Rosenbach who, in 1884, applied the designation to the group. The name ‘streptococcus’ is derived from the Greek ‘streptos’ signifying a chain formed of links or a necklace of beads; ‘coccus’ meaning a berry. The organisms may occur in pairs or in chains of varying length. There are two main types: haemolytic & non-haemolytic. The haemolytic ones are further divided on whether they lead to alpha, beta or gamma hemolysis. In beta-haemolysis, a colony of organisms grown on blood agar is surrounded by a clear zone, 2-4 mm in diameter, within which the RBC are completely lysed.

Strep. pyogenes and other streptococci that show a similar phenotype are called β-haemolytic streptococci. They are pathogenic in man. In contrast, species that are typically part of the normal throat flora are either non-haemolytic, or they produce α-haemolysis, characterized by a zone of incomplete, often greenish clearing around colonies grown on blood agar.

The β-hemolytic streptococci grow poorly on ordinary nutrient agar but more readily on blood agar: the zones of beta-hemolysis are fully developed after 18 hours’ growth and very little enlargement occurs thereafter. The colonies do not exceed 1 mm in size. Although the organisms grow both aerobically & anaerobically, β-haemolysis develops more readily anaerobically. Although the growth is possible over a wider range of temperatures, the optimum temperature is 37°C.

Virulence Factors & Toxins

a) Extracellular products:

Haemolysins (Streptolysins): Two types of haemolysins, O & S, which are at peak 8 hours after incubation at 37°C, are produced in broth culture. The O-haemolysin is readily oxidized (derives its name from oxygen-liability) while the S-hemolysin is oxygen-stable, (derives its S from being produced by streptococci growing in the presence of serum). The former is produced by all streptococci while as the latter is only produced by group A, C & G.

Streptolysin O & S are the proteins responsible for beta-haemolysis. They lyse RBC & WBC by making holes in their cell membrane. Streptolysins are toxic to the body; streptolysin O is antigenic and leads to production of antibodies (antistreptolysin O) while streptolysin S is either non-antigenic or too weakly antigenic. Antistreptolysin O (ASO) is a true antibody which rises as a result of streptococcal infection. That is why practitioners want to know its titre. It is an exceedingly useful indicator of recent streptococcal infection.

Anti-streptolysin ‘O’ is toxic to a variety of cells and cell fractions including polymorphonuclear leukocytes, platelets, lysosomes etc. Previously it was thought that a separate haemolysin , leucocidin, destroyed white blood cells. Now we know that it is identical with streptolysin O.

Several extracellular factors serve to facilitate liquefaction of pus and the spreading of streptococci through tissue planes. Four antigenically different DNAses (A, B, C & D) participate in the degradation of deoxyribonucleic acid. Previously, de-oxyribonuclease used to be called Streptodornase. Streptokinase, another toxic product of GAS, leads to dissolution of clots by catalyzing the conversion of plasminogen into plasmin. Proteinase is another factor liberated by GAS. A spreading factor, hyaluronidase, is also found in streptococcal filtrates. These enzymes degrade the tissue and enhance the spread of infection. The tissue destruction in turn leads to inflammatory response which leads to various symptoms and signs.

Streptococcal pyrogenic exotoxins (SPEs) are a family of genetically similar exotoxins that cause severe streptococcal disease unrelated to strep throat. These diseases include scarlet fever, streptococcal toxic shock syndrome, and ‘flesh eating’ necrotizing fasciitis. These exotoxins are superantigens, which can lead to massive activation of T cells. The resulting uncontrolled release of cytokines is responsible for the seriousness of these infections. Erythrogenic (Dick) toxin belongs to this group. It is an SPE released from the infection site which enters the bloodstream, circulates throughout the body and leads to a redness of skin and whitish coating of the tongue.

Antibodies to five of extracellular products are used in the serodiagnosis of streptococcal infection. These are ASO, anti-DNase, antihyaluronidase, antinicotinamine adenine dinucleotidase, and antistreptokinase.

b) Somatic Antigens:

In addition to elaborating various toxins, Group A streptococci (GAS) posses different somatic protein antigens, which enable GAS to be further divided. This typing is of great value in the study of outbreaks of streptococcal infection. M protein causes the degradation of complement component C3b, an opsonin that would otherwise promote phagocytosis of the bacteria. M protein is essential for the virulence of GAS, because antibody to it prevents infection from occurring. Organisms which do not have M protein are avirulent. More than 90 different kinds of M protein exist and, unfortunately, antibody to one type does not prevent infection by a strain that has another kind of M protein.

Another protein antigen closely related to the M protein is the serum opacity-factor (OF). This is itself antigenic and type-specfic; it is useful as an epidemiological marker in typifying GAS when they are not identifiable on the basis of M antigen. It has been found that immune response to M-protein is generally weaker after pharyngeal infection with OF-positive than with OF-negative strains.

Protein F of the cell wall mediates attachments of GAS to the throat by adhering to a protein found on the surface of the epitheloid cells. Another cell wall constituent, lipoteichoic acid, plays a similar role in the first step in colonization ie adherence of GAS to fibronectin on the surface of human epithelial cells.

Protein G of the bacterium binds to the Fc segment of immunoglobulin G. The effect is to prevent phagocytosis mediated by specific antibody against the bacterium. There are other multifunctional surface proteins which have the ability to bind to host proteins, including immunonoglobulin G & A.

C5a peptidase is an enzyme released by GAS, which destroys the C5a component of the complement system, which normally attracts phagocytes to the site of a bacterial infection. This cell-bound peptidase cleaves the C5a component of the complement and inhibits neutrophil chemotaxis.

Both, M antigen and the capsule, which contains mucopolysaccharide hyaluronic acid, are related to the virulence of the strain. M protein is the major somatic virulence factor, while hyaluronic acid capsule is an accessory virulence factor. Both retard phagocytosis of the microorganism by polymorphonuclear leukocytes's and strains containing this, being resistant to phagocytosis, multiply rapidly in body and initiate disease.

Streptococcal Pharyngitis (Strep throat)

Streptococcal sore throat is one of the most common complaints in childhood.

Virulent factors of Streptococcus pyogenes (GAS)

C5a peptidase: Inhibits attraction of phagocytes by destroying C5a

Hyaluronic acid capsule: Inhibits phagocytosis; aids penetration of epithelium

M protein: Interferes with phagocytosis by causing breakdown of C3b opsonin

Protein F: Responsible for attachment to host cells

Protein G: Interferes with phagocytosis by binding Fc segment of IgG SPEs

Superantigens responsible for scarlet fever, toxic shock, ‘flesh-eating’ fascitis

Streptolysin O & S: Lyse leukocytes and erythrocytes

Tissue degrading enzymes: Enhance spread of bacteria by breaking down DNA, proteins, blood clots, tissue hyaluronic acid.

Epidemiology: More than 95% of streptococcal infections in man are caused by group A streptococcus (GAS), which, based on the presence of M antigen, has more than 90 subtypes. Immunity is type-specific; a patient exposed to one subtype develops immunity to that type, but remains susceptible to other subtypes. Thus, he may continue to get repeated sore throat. Other serotypes as C & G are occasionally involved.

The disease occurs primarily in children aged 5-15 years old, with the peak incidence in first few years of the school. However, all age groups are susceptible, and children getting infection in school may infect any family member. There is no sex predilection, and thus boys and girls are equally susceptible.

Infection is spread from person to person. Nasal carriers are much more infectious than throat carriers. Streptococci are present in large numbers in the saliva of patients for only about a week after the onset of the illness, though the organisms may remain on the throat for many weeks longer. Coughing, yelling, & dribbling by salivary carriers, and sneezing by nasal carriers, lead to dispersal of streptococci in the moist state. Nasal & salivary carriers are thus much more infectious than faucial carriers.

Wet handkerchiefs & wet swabs can transmit infection. When dried, streptococci lose their capability to infect.

More than the profuseness of bacilli in the throat or nose of carriers, it is the age and closeness of contact which determine spread of infection.

Overcrowding, as occurs in schools, refugee camps and military or police barracks favours person-to-person spread, and also may enhance the virulence of organisms by natural selection. This is also an underlying cause for increased incidence in colder areas and colder months of the year.

Explosive food - and waterborne infections are well documented. A person preparing food may cough or sneeze on food (especially which is eaten raw) and infect the food. Outbreak consequent to use of salad has also been recorded. Infrequently, a human carrier may infect the milk, and lead to a milk-borne spread. Rarely a human carrier may lead to mastitis in cow, which in turn may lead to infection of milk. Outbreaks of tonsillitis and scarlet fever have been reported from consumption of cream.

Fomites have no significant role to play.

Carriers: GAS frequently colonizes the throats of asymptomatic persons. Pharyngeal carrier rates in normal children vary in different populations, at different seasons and in different conditions and geographical locations. A rate of between 6 & 8% is normally found in populations living in temperate climates; in school-going children these rates have mostly been found to be 15-20%, but may be as high as 50%. In adults, carriage rate is lower. No direct relationship has been observed between carrier rates and outbreaks of illness.

During convalescence GAS rapidly disappear from nose, and the number and virulence of organisms from throat declines. Thus, risk of infection from convalescent carrier is lesser than that from the acutely ill patient.

Clinical features

The usual incubation period is 2-4 days; the organisms multiply in tonsillo-pharyngeal region, and are present in large numbers in both the nose and throat. There is sudden onset of sore throat with malaise, fever (101°F or higher), and headache. Nausea, vomiting and abdominal pain are common in children. On examination, the posterior part of pharynx is red and oedematous and shows lymphoid hyperplasia. Hyperemic tonsils are studded with grayish-white exudate. Lymph nodes at the angles of mandible are enlarged or tender.

Streprococcal Serogroups Most Frequently Involved in Human Disease

Serogroup Group specific Cell Wall Antigen Usual Clinical Features
A Rhamnose-N-acetyl polysaccharide Pharyngitis, tonsillitis, otitis media, sinusitis, scarlet fever, erysipelas, cellulites, impetigo, pneumonia, endometritis, septicemia.
Delayed non-suppurative sequelae: acute rheumatic fever, acute glomerulonephritis,
B Rhamnose-glucosamine polysaccharide Chorioamnionitis, peuperal sepsis, neonatal sepsis, meningitis
C Rhamnose-N-acetylgalatosamine polysaccharide Upper respiratory infections
D Glycerol teichnoic acid Genitourinary tract infections, wound infections, endocarditis
G Rhamnose-galactosamine polysaccharide Upper respiratory infection, cellulites, septicemia, deep-tissue infections.

Total leucocyte count may exceed 12000/cmm with increased numbers of neutrophils. The level of C-reactive protein (CRP) is usually elevated. Throat culture is positive for β-hemolytic streptococci.

All patients don’t exhibit such full-blown syndrome. All don’t show tonsillar or pharyngeal exudates. Those who have undergone tonsillectomy experience a milder syndrome. Infants exhibit less localization to faucial areas, but instead get a generalized infection with rhonorrhea, suppurative complications, low-grade fever, and a more protracted course. Exudative pharyngitis in children younger than 3 years rarely is streptococcal.

Fever abates within 3-5 days; all acute signs and symptoms subside within a week. It takes several weeks for tonsils and lymph nodes to return their normal size.

In untreated infection, organisms persist for many weeks in the throat. During convalescence the organisms decrease in number and disappear sooner from the nares than the throat. The M-protein content of streptococci, and thus their virulence, gradually decreases. In untreated cases, the organisms have been found die down within 18 days. Penicillin shortens the period of fever, toxicity and infectivity. This is readily appreciated if the drug is started within first 24 hours.

In patients who don’t receive drugs, type-specific antibodies are detectable in serum between 4 and 8 weeks. These antibodies protect the patient from subsequent attack with the same M-typable organism but not from others.

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