Group A Strep (GAS) Infection

• Streptococcus pyogenes, also known as group A beta-hemolytic Streptococcus, or group A strep (GAS) is a gram-positive coccus (spherical bacteria) that is ubiquitous, highly communicable, and spread primarily through person-to-person (skin-to-skin) contact and via respiratory droplets, as the human skin and mucous membranes are the only known reservoir for GAS.
• Infections of the upper respiratory tract (pharyngitis) and infections of the skin (cellulitis) with GAS are among the most common bacterial infections.
• GAS infection can be complicated by potentially life-threatening complications, including acute rheumatic fever (ARF), acute glomerulonephritis, pediatric autoimmune neuropsychiatric disorders (PANDAS), and streptococcal toxic shock syndrome (STSS).
• GAS is associated with toxic shock syndrome and with life-threatening skin and soft-tissue infections, most notably necrotizing fasciitis, each of which is associated with an incredibly high morbidity and mortality.
• Antibiotics and anti-microbials (both naturally occurring and synthetically derived substances) are drugs used to treat and/or to prevent infection by bacteria and other organisms. Antibiotics target a number of bacterial processes, namely inhibition of cell-wall biosynthesis, inhibition of protein synthesis, and inhibition of DNA replication or repair, in an effort to kill bacteria (bactericidal) or to stop bacteria from growing (bacteriostatic).

According to the U.S. Centers for Disease Control and Prevention (CDC), more than 10 million cases of noninvasive GAS infections occur in the United States annually, and the majority of these infections are throat and superficial skin infection. Approximately 9,000-11,500 cases of invasive GAS infections occur annually, and their occurrence appears to be increasing, perhaps due to increased abilities of the organism to cause disease.

GAS is highly communicable and primarily spread through person-to-person contact. Respiratory droplet spread represents the major route for transmission of GAS strains associated with upper respiratory tract infection. Epidemiological studies of invasive GAS infection have identified several risk factors for sporadic infection, including advanced age, HIV infection, diabetes mellitus, varicella infection, cancer, heart disease, injection drug use, and steroid use. The only risk factor consistently associated with mortality due to sporadic invasive GAS infection, however, is being greater than or equal to 65 years of age.

With respect to GAS pharyngitis, several factors are associated with increased risk of infection: namely, young age and the time of year. GAS pharyngitis occurs most commonly in children between the ages of 5 and 15. Although GAS pharyngitis can occur at any time of the year, late fall and early spring tend to be the times when GAS pharyngitis circulates most commonly. GAS flourish whenever groups of people are in close contact and that is why GAS infection spreads easily among family members, in schools, and in child-care settings.

Signs and symptoms of GAS tonsillopharyngitis include:

• sore throat,
• fever,
• enlarged lymph nodes in the neck,
• enlarged tonsils,
• rash,
• pus collections on the tonsils,
• tiny red spots on the palate,
• headache,
• abdominal pain.

GAS produces different kinds of skin diseases, including impetigo, erysipelas, and necrotizing fasciitis. The classical finding associated with GAS impetigo is a blistering or purulent lesion, the destruction or irritation of which results in the development of a coating described as honey crusting. It is this honey crusting that is the clinical hallmark of GAS impetigo.

Erysipelas is a form of GAS-induced skin disease characterized by redness, hardening, tenderness, a raised, sharply demarcated border, and a consistency often compared to that of an orange peel.

Necrotizing fasciitis, unlike impetigo and erysipelas, is a skin infection whose invasion through the superficial tissues results in marked tissue destruction in the deep fascial layers of the skin. Host factors, such as decreased blood and oxygen supplies to tissues, immunocompromised states, chronic illnesses, burns, trauma, and surgery, predispose someone to the spread of the organisms into the deep fascial layers of tissue and leads to rapid tissue death. Unlike impetigo and erysipelas, necrotizing fasciitis often appears with instability of vitals signs (such as blood pressure and heart rate) or evidence suggestive of a more widespread infection rather than an infection localized to the superficial tissues.

Several clinical scores for the diagnosis of streptococcal pharyngitis exist, including the Centor score, the FeverPAIN score, the Steinhoff score, and the Joachim score. These clinical decision tools take into consideration patient age, symptoms, and absence of symptoms that would suggest an alternate diagnosis; namely, conjunctivitis, cough, diarrhea, rash, and rhinitis.

Studies suggest, however, that clinical findings alone are insufficient to diagnose streptococcal pharyngitis in children, unlike in adults, and that the use of clinical findings alone, without confirmatory laboratory testing (either a rapid strep test or a throat culture) leads to unnecessary prescription of antibiotics. GAS tonsillopharyngitis may also be diagnosed by a blood test known as the antistreptolysin O antibody titer, which is elevated or increasing in GAS infection.

Rapid antigen diagnostic testing (RADT) for GAS is a practical method for the detection of GAS that can be done in the practitioner’s office. It allows for rapid antibiotic prescription for confirmed cases of GAS tonsillopharyngitis. RADT is highly sensitive and specific for the diagnosis of GAS pharyngeal infection and allows for more rapid management of GAS pharyngitis previously delayed by waiting for throat culture results. This rapid test exhibited a good correlation with the results of throat culture. Pediatric practice guidelines, however, recommend that all negative rapid antigen tests in the face of overt clinical symptoms need to be supported by a throat culture.

Erysipelas and impetigo are diagnosed based almost entirely on clinical manifestations of the diseases. Unlike cellulitis, a raised, sharply demarcated border of the affected area differentiates erysipelas from cellulitis. The characteristic honey crusting suggests the diagnosis of impetigo. Blood cultures are helpful in determining sepsis and bacteremia (spread of the bacteria to the bloodstream) but are not helpful in the diagnosis of erysipelas or impetigo.

The diagnosis of necrotizing fasciitis, in the early stages of the disease process, may not be easily diagnosed. Prompt treatment is essential if this diagnosis is suspected. Treatment approaches should include administration of fluids, treatment of electrolyte and acid-base imbalances, antibiotic therapy, early and aggressive surgical consultation, and support of failing organ systems, to treat the disease. Blood and tissue cultures will help definitively establish the diagnosis, and clinicians can use this information to tailor antibiotic therapy.

Tonsillopharyngitis

Antibiotic therapy is recommended for the treatment of symptomatic tonsillopharyngitis in confirmed infections with GAS identified in the laboratory either by rapid antigen detection or by culture. Treatment with antibiotics is also recommended for the prevention of acute rheumatic fever.

Treatment options include:

• penicillins (penicillin V potassium, ampicillin, amoxicillin),
• cephalosporins,
• macrolides,
• and clindamycin.

While the only agent shown to prevent initial attacks of rheumatic fever has been intramuscular penicillin, other antimicrobial medications have been effective in treating upper respiratory tract infections caused by GAS.

Skin and soft-tissue infections

Antibiotic therapy for skin and soft tissue infections is based upon the clinical presentation. Class 1 infections are uncomplicated infections localized to a particular area and without signs or symptoms of systemic infection (for example, impetigo and erysipelas). Broad-spectrum oral antibiotics are the mainstay of therapy for class 1 infections in general and include amoxicillin/clavulanic acid, clindamycin, quinolones, and linezolid. Antibiotic therapy may be tailored to the specific organism once culture and sensitivity data are available.

Complicated infections include:

• those in which the patient is febrile and ill-appearing (class 2);
• those in which the patient appears toxic or has at least one unstable comorbid condition such as diabetes, decreased mobility, obesity, or prior surgery (class 3);
• and those in which the patient demonstrates signs of sepsis syndrome or a life-threatening infection (class 4) (for example, necrotizing fasciitis).

Complicated infections may be treated with intravenous beta-lactams, with or without beta-lactamase inhibitors, broad-spectrum cephalosporins, carbapenem, and linezolid.

Updated guidelines from the Infectious Disease Society of America base the approach to treatment of skin and soft-tissue infections on whether or not the infection is nonpurulent (not producing pus, such as necrotizing infection/cellulitis/erysipelas) or purulent (pus-producing, such as furuncle/carbuncle/abscess) and the degree of illness (mild, moderate, and severe):

• Purulent infections:
  • mild purulent infections may be treated with incision and drainage alone;
  • moderate infections require incision and drainage, culture and sensitivity, and oral antibiotic therapy based upon the expected drugs that will be effective, with attention to methicillin-resistant Staphylococcus aureus (MRSA), prior to the availability of culture and antibiotic sensitivity results from the lab;
  • severe infections require incision and drainage, culture and sensitivity, and empiric intravenous antibiotic therapy, again with attention to MRSA pending results of culture and sensitivity tests.
• Nonpurulent infections:
  • mild nonpurulent infections of the skin and soft tissues may be treated with oral antibiotics;
  • moderate infections may be treated with intravenous antibiotics followed by oral antibiotics;
  • severe infections may be treated with broad-spectrum empiric antibiotics, culture and sensitivity, and immediate surgical consultation for consideration of debridement.

Treatment of necrotizing skin and soft-tissue infections begins with broad-spectrum antibiotic therapy that can be modified later once culture information is available and the patient stabilizes. Antibiotic choices include combination therapy with piperacillin-tazobactam, clindamycin, quinolones, penicillin, linezolid, or vancomycin, or single-drug therapy with imipenem-cilstatin or meropenem. Antibiotics, in addition to aggressive fluid resuscitation, management of electrolyte and acid-base abnormalities, surgical debridement of necrotic tissue, and support of failing organ systems are the mainstays of therapy.

Bacteremia refers to the presence of bacteria in the bloodstream. GAS bacteremia is believed to be responsible for 3.3% of cases of bacteremia in children and 0.6% of cases of bacteremia in adults. Risk factors for GAS bacteremia include:

• burns,
• varicella virus infection,
• cancer,
• immunosuppression from corticosteroid use,
• immunocompromised status,
• intravenous drug use,
• HIV infection,
• post-influenza GAS pneumonia,
• surgery,
• trauma,
• diabetes,
• peripheral vascular disease, and
• cardiac disease.

Despite the relatively low frequency, GAS nevertheless remains a serious infection whose mortality (death rate) for adults ranges from 25%-48% and for children, approximately 8%. The mortality for those patients who develop shock is higher, and this may be the most important predictor of mortality.

Scarlet fever is characterized by the development of a diffuse, fine rash coincident with acute GAS pharyngitis.

A form of kidney inflammation known as glomerulonephritis may be a complication of GAS infection. Glomerulonephritis that occurs secondary to GAS infection, likely mediated by the body's immunologic response to acute GAS infection, typically occurs 1-2 weeks following an initial infection.

Acute rheumatic fever (ARF), another potential complication of GAS infection, typically occurs 2-4 weeks following acute GAS tonsillopharyngitis. ARF is an inflammatory disease that may occur following inadequately treated GAS infection. Symptoms vary and can include:

• fever,
• joint pain and swelling,
• small nodules beneath the skin,
• rash,
• heart murmur, and
• neurologic changes like abnormal body movements (chorea) or unusual behavior.

ARF can cause permanent damage to the heart. Rheumatic heart disease, a spectrum of progressive valvular heart disease and carditis that occurs as a late sequel of acute rheumatic fever, typically occurs 10-20 years following the initial infectious process.

Treatment of potentially life-threatening complications of GAS infections includes not only eradication of the organism from normally sterile sites throughout the body but also management of secondary problems:

• hypotension,
• tachycardia, and
• end organ system failure, typical hepatic and renal, that occur in streptococcal toxic shock syndrome.

The diagnosis of STSS is made by isolating the organism in a culture sent to the laboratory from a normally sterile site (skin, throat, vagina) and by the observation of hypotension along with two or more of the following: renal dysfunction; blood-clotting disturbances; liver dysfunction; acute respiratory distress syndrome; a diffuse, red, flat rash and/or soft-tissue necrosis. Other conditions that may cause similar symptoms must also be ruled out, such as staphylococcal toxic shock syndrome, typhoid fever, Rocky Mountain spotted fever, meningococcemia, infection with S. pneumonia, leptospirosis, and heat stroke.

Pediatric autoimmune neuropsychiatric disorder associated with group A streptococci (PANDAS) is a controversial entity observed in a small subset of pediatric patients. It is believed that GAS infection triggers a heightened immunologic response with subsequent central nervous system manifestations, including abrupt and episodic onset of obsessive-compulsive disorder (OCD) and/or tic disorder and other neurological abnormalities involving abnormal motor activity. Demonstration of a temporal relationship between an acute GAS infection and the development of neuropsychiatric symptoms is essential for the diagnosis of PANDAS.

Tonsillopharyngitis and uncomplicated skin and soft-tissue infections caused by GAS have a good prognosis. Patients who are long-term carriers may develop multiple episodes of infection, but these individuals are unlikely to spread the organism to close contacts and are at very low risk for developing complications.

The most serious complication of acute rheumatic fever is cardiac involvement, and congestive heart failure, cerebrovascular accidents, and endocarditis are common among individuals with rheumatic heart disease. About 1.5% of people with rheumatic carditis die of the disease annually. Morbidity and mortality rates have demonstrated steady improvement, a decline which is likely attributable to careful disease surveillance and initiation of prompt aggressive therapy.

Glomerulonephritis following acute streptococcal infection carries a very good prognosis -- 95% of patients recover spontaneously within 3-4 weeks without long-term sequelae (effects).

STSS has a case-fatality rate of 30%-60%.

Necrotizing skin and soft-tissue infections carry a mortality rate as high as 35% even with prompt aggressive medical and surgical management.

The long-term outcome for children who meet the diagnostic criteria for PANDAS is not known, but it is believed that unrecognized and untreated PANDAS may result in an increased for progression to lifelong neuropsychiatric complications including obsessive-compulsive disorder and tic disorders.