Streptococcus pyogenes

Streptococcus pyogenes is a Gram-positive, aerobic to facultatively anaerobic, immobile and unencapsulated, beta-hemolytic bacterium of Lancefield group A and is therefore also known as group A streptococcus (GAS). Microscopically, S. pyogenes appears mostly in chains, more rarely in pairs. The pathogen contains (but is not limited to) the C-polysaccharide antigen of group A (Lancefield classification). A-streptococci are tentatively identified by specific antisera (detection of cell wall antigens) and uniquely identified by molecular biology, mass spectrometry, or biochemical techniques.

S. pyogenes is primarily an extracellular bacterium. In recent years, increasing evidence has been found that streptococci are also intracellular pathogens. They can survive in macrophages, neutrophil granulocytes, and various epithelial cells, analogous to a Trojan horse, and thus disseminate in the host.

The only reservoir for S. pyogenes is humans, who transmit the germs directly by smear infection, less frequently by droplet infection. Colonization of domestic animals (dogs, cats) occurs in very close contact with their S. pyogenes-carrying owner.

S. pyogenes cannot multiply in the inanimate environment. However, the pathogen can survive for up to several months, especially on dry surfaces in mucus or blood debris, and remain infectious. However, this route of transmission is rare (Hof H 2019).

The number of asymptomatic carriers is associated with age and varies seasonally in temperate climates. School children are colonized with Streptococcus pyogenes in 20%. Adults only 1-2%. Transmission of Streptococcus pyogenes usually occurs through direct contact with saliva or nasal secretions, rarely through contaminated food and water. The incubation period is 1-3 days, rarely longer.

Streptococcus pyogenes causes 700 million infections worldwide annually. In about 1% of infected patients, it is an invasive infection with a mortality of up to 25%.

Streptococcus pyogenes can cause a variety of clinical pictures, important groups are:

• local purulent infections of the throat or skin
• generalized or toxin-mediated clinical pictures
• immunologically caused secondary diseases

On the bacterial genetic level, different virulence genes are responsible for the various diseases. Different S. pyogenes strains carry these genes in different combinations in their genome - mainly due tobacteriophage transduction. The encoded virulence factors determine the tissue tropism of the bacteria, their invasiveness in typically sterile anatomical compartments as well as their resistance to defense mechanisms and allow manipulation of host defenses in the sense of enhancing the consequences of infection. The virulence factors are largely molecularly and functionally characterized. The same is true for many aspects of specific host defenses.

Diseases induced by S. pyogenes:

• Tonsillo pharyngitis: The most common manifestation of S. pyogenes infection is (tonsillo-)pharyngitis, which primarily affects school children but can occur in all age groups. The number of acute streptococcal pharyngitis cases in Germany is estimated to be 1 to 1.5 million per year. In temperate climates, the majority of streptococcal pharyngitis occurs in winter and spring.
• Scarlet fe ver: When Streptococcus pyogenes produces pyrogenic toxins such as SpeA, SpeC or SSA, the clinical picture of scarlet fever may occur. In this case, in addition to the typical symptoms of pharyngitis, a maculopapular exanthema occurs, often beginning in the groin and axilla and then spreading to the upper body and extremities. Perioral pallor and palmar and plantar recess are typical. After the exanthema fades, desquamation occurs, some of which is pronounced. By means of a rapid streptococcus test, the throat swab is applied to a test cassette containing antibodies against S. pyogenes. If S. pyogenes are present in the swab, precipitates form and the positive signal can be read as a band. In contrast to culture, which takes about two days, the result of the rapid streptococcal test is available after only a few minutes. Culture is the gold standard, but in special cases with a high pre-test probability of streptococcal tonsillitis and negative RADT, it can also be useful.
• Streptococcal-induced skin infections: Pyoderma occurs preferentially in tropical and subtropical climates and is most common in young children. The prevalence of these diseases is highly dependent on personal hygiene and associated with socioeconomic status.
• Impetigo contagiosa: Impetigo contagiosa is a superficial skin infection that commonly occurs on the face (especially around the mouth and nose) and on the legs. Pustular efflorescences form, which break open and lead to crusting. Fever does not occur in impetigo and the patient does not make a sick impression.
• Erysipelas: Streptococcus pyogenes is the most common causative agent, accounting for 20-40% of erysipelas, which presents as a sharply demarcated, reddened, hyperthermic, and painful lesion.
• Necrotizing fasciitis: Necrotizing fasciitis is a soft tissue infection that spreads rapidly along muscle fascia and typically occurs after minor trauma. Injured muscle tissue is thought to express vimentin, which is used by circulating S. pyogenes (e.g., during passive bacteremia in tonsillitis) to adhere to and invade the tissue. Despite adequate therapy, the mortality of necrotizing fasciitis is still very high at up to 36%.
• Streptococcal-associated toxic shock syndrome: This condition is a rare and severe clinical picture with high mortality. The membrane-bound M protein and the expression of exotoxins, which act as superantigens, lead to excessive activation of the immune system. In addition, the exotoxins induce the expression of TLR2 and TLR4, which further activates the immune system and leads to significantly higher vascular permeability. Due to rapid fluid loss into the third space, hypotension with decreased organ perfusion and rapid progression to septic shock with multiple organ failure occur. Even despite immediately initiated therapy, the mortality of STSS remains very high at up to 50%.
• Scarlet fever

Non-suppurative complications:

• Acute rheumatic fever (ARF).
• Acute poststreptococcal glomerulonephritis (APSGN).

Both conditions are immune-mediated diseases that can occur after noninvasive and invasive infections with certain strains of S. pyogenes (M type1, 3, 5, 6, 11, 12, 14, 17, 18, 19, 24, 27, 29, 30, 32, 41).

Acuterheumatic fever: Acute rheumatic fever secondary to S. pyogenes tonsillopharyngitis is very rare in Europe and North America and affects mainly children aged 5-15 years. In the acute clinical picture, the first ARF symptoms are fever, migratory arthritides mainly of the large joints (in 80% of cases), somewhat later carditis (50% of cases), Sydenham's chorea minor in up to 20%, rheumatoid nodules in 2%, and erythema marginatum.

Acute poststreptococcal glomerulonephritis (APSGN): One to four weeks after S. pyogenes infection, nephritic symptoms such as mild arterial hypertension, hematuria, proteinuria and edema, and renal failure may occur. This is caused by the deposition of immune complexes of certain strains of S. pyogenes (M types 1, 4, 12, 49, 55, 57, 60) known as "nephritogenic", which are deposited in the glomeruli and thus lead to renal damage. The diagnosis is made on the basis of the clinical picture of nephritis with the typical renal findings and a documented previous streptococcal infection (culture, rapid streptococcal test or antistreptolysin titer) and confirmed by renal biopsy. The prognosis of APSGN is good in children, in contrast to older patients, in whom mortality of up to 25% has been described.

Duration of contagiousness: Patients with acute streptococcal infection who have not received specific treatment may be contagious for up to 3 weeks, and those with purulent excretions for longer. After initiation of effective antibiotic therapy, contagiousness for pharyngeal infections ceases after 24 hours. There are no corresponding data for soft tissue infections, but a similar time period seems plausible.

Obsessive-compulsive disorders (OCDs) such as athetoses and chorea minor.

Infectious disease societies, particularly in the English-speaking world, regularly issue evaluation criteria and recommendations for outpatients regarding diagnostic tests for S. pyogenes in the context of respiratory diseases. In general, such detection is recommended only for children older than 3 years with sore throat, severely swollen cervical lymph nodes, and fever, but not for children younger than 3 years or adults or any person with predominant signs of viral respiratory infection (rhinitis, hoarseness, cough, enoral ulceration). No comparable recommendations exist for the investigation of skin and soft tissue infections.

Good preanalytics is of decisive importance for a meaningful examination result. Suitable samples for the detection of pharyngeal infections are swabs with flocked or polyurethane swabs. For the detection of skin and soft tissue infections, punctates and biopsies are more suitable than swabs with the above-mentioned swabs, whereby the wound environment must be disinfected before taking the sample. If systemic infections are suspected, blood cultures must also be obtained. Special transport media are not necessary if transport times of less than 2 hours can be maintained. Biopsies are protected from drying out by adding small amounts of sterile physiological saline solution or phosphate buffer. In the diagnostic laboratory, microscopic, culture-linked, serological and molecular biological examination procedures are possible.

Themicroscopic detection of gram-positive chain cocci in the examination material is indicative in the case of a typical clinic, but is not very specific, since morphologically there is no difference to other streptococci. However, chain lengths of more than two cocci are indicative of β-hemolytic streptococci. The method of choice is the cultural detection of S. pyogenes on sheep blood agar, if no mass spectrometric differentiation is possible, in combination with serogroup determination. Further typing is reserved for special epidemiological or scientific questions (special laboratories, reference centres). In the case of chronic recurrent infections, the examination of the

In the case of chronic recurrent infections, the examination of the sample material by means of specific PCR has a higher sensitivity than culture because of the storage of the metabolically altered bacteria in biofilms or within eukaryotic cells.

In the context of pharyngitis clarification, it can be useful in the outpatient setting to first perform a rapid antigen test, whereby the rapid tests currently available on the basis of antigen detection are very specific, but not to the same extent sensitive. Molecular point-of-care detection methods, which can also be carried out in a comparatively short time, do not have these disadvantages, but are not widely used for cost reasons. If the test result is positive, an infection with streptococci of serogroup A can be assumed and the patients should be treated. If the test result is negative or inconclusive, on the other hand, a cultural or, if necessary, molecular biological examination of a throat swab should be performed in order to determine the further course of action and, if necessary, to avoid unnecessary antibiotic treatment.

Antibody detection is only useful if a secondary streptococcal disease is suspected. It is particularly important to detect anti-streptolysin O antibodies and anti-DNase B antibodies to detect a previous S. pyogenes infection. Selectively elevated anti-DNase-B levels indicate a previous skin infection with S. pyogenes.

Very sensitive and specific molecular biological tests are available in principle, but are rarely used to date for economic reasons.

In multiplex format, these can help to rapidly differentiate S. pyogenes-related infections from clinically indistinguishable purulent infections caused by other bacteria or viruses, or to quickly identify S. pyogenes as the causative agent of sepsis.

emm typing, superantigen determination etc. of S. pyogenes isolates are carried out in the NRZ for Streptococci in case of corresponding questions (outbreaks etc.).

So far, no resistance of S. pyogenes to β-lactams is known worldwide. The therapy of choice for pharyngeal and skin infections with S. pyogenes is therefore the 10-day administration of penicillin or amoxicillin or ampicillin (orally or parenterally). Some publications recommend shorter durations of therapy. A regimen shortened to 5 days with oral cephalosporins is equivalent for children.

For penicillin allergy , oral therapy with erythromycin or other macrolides for a duration of 5 to 10 days shows similarly good results. However, resistance rates for macrolides vary regionally from 10 to more than 30%, so resistance testing is ideally strongly indicated before administration of these antibiotics.

Cotrimoxazole and quinolones other than moxifloxacin do not work reliably.

In severe systemic infections(sepsis, STSS, fasciitis necroticans), administration of clindamycin as well as immunoglobulin preparations is recommended in addition to parenteral penicillin G therapy.

Patients with rheumatic fever should receive relapse prophylaxis with penicillin. There is no consensus regarding the duration of prophylaxis. It should be given for at least 5 years, and after a relapse for life.

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