Introduction

Streptococcus pyogenes is a major human-specific bacterial pathogen that causes a wide array of manifestations ranging from mild localized infections to life-threatening invasive infections.[1] Ineffective treatment of S  pyogenes infections can result in postinfectious sequelae such as acute rheumatic fever and post-streptococcal glomerulonephritis. Moreover, it causes invasive infections like necrotizing fasciitis and toxic shock syndrome, which are associated with high morbidity and mortality.

Streptococci are gram-positive, catalase-negative, coagulase-negative cocci that occur in pairs or chains. They are divided into 3 groups based on hemolysis on blood agar: beta-hemolytic (complete lysis of red blood cells), alpha-hemolytic (green hemolysis), and gamma-hemolytic (no hemolysis). Beta-hemolytic streptococci are classified into group A (Streptococcus pyogenes) and group B (Streptococcus agalactiae).

Etiology

S pyogenes is a gram-positive, catalase-negative, oxidase-negative, β-hemolytic streptococci. The organism is a facultative anaerobe that grows best in 5% to 10% carbon dioxide and forms pinpoint colonies on blood agar plates. The Lancefield serological grouping system is used to differentiate group A streptococci (GAS) from other streptococci.

The type A antigen of S pyogenes is a polysaccharide that comprises N-acetylglucosamine attached to a rhamnose polymer backbone.[2] M protein is the major surface protein present on the S pyogenes cell wall, and GAS strains are further divided into different serotypes based on the antigenic characteristics of the M protein. More than 80 different serotypes have been identified on the basis of the M protein.[2]. Depending upon the postinfectious sequelae, S pyogenes is categorized into 2 classes: Class I and Class II. Class I strains cause rheumatic fever, while class II strains result in acute glomerulonephritis.[3]

S pyogenes usually colonizes the pharynx, anus, and genital mucosa. Infections caused by S pyogenes are highly contagious. Transmission can occur through airborne droplets, hand contact with nasal discharge or with objects or surfaces contaminated with bacteria, skin contact with contaminated lesions, or contaminated food sources. GAS strains may gain access to the skin through abrasions and lesions, which may lead to erysipelas or cellulitis.[2] GAS can cause infection in muscle and fascia, resulting in myositis and necrotizing fasciitis, usually following a mild trauma, and can result in toxic shock syndrome. 

S pyogenes can cause the infection of the vaginal mucosa and uterus causing septicemia.[2] Skin lesions have been identified as the most common predisposing factor for severe S pyogenes infections.[4] Crowded settings like military camps, nursing homes, and schools cause ease of transmission of the organism and result in epidemics of group A streptococci infection.

Epidemiology

The frequency of S pyogenes infections varies across regions worldwide, depending on the clinical manifestations. GAS has always been associated with serious diseases that result in high morbidity and mortality. GAS infections declined by the mid-20th century. However, by the end of 1980, severe GAS infections reemerged.[5] 

Over the last 2 decades, nonsuppurative and suppurative complications of the S pyogenes infection have increased. This increase in disease burden can be attributed to a multitude of factors, including changes in virulence and antibiotic resistance.[6][7] GAS infections and their complications vary between poorly developed and well-developed countries. In underdeveloped countries, the prevalence of rheumatic heart disease (RHD) and the incidence of deaths associated with RHD are high. Conversely, in well-developed countries, the incidence of deaths due to invasive GAS infection is high.

The global burden of severe S pyogenes infections is 18.1 million cases, with 1.78 million new cases per year. The worldwide prevalence of RHD is at least 15.6 million cases, with the incidence of 282,000 new cases per year. Approximately 233,000 deaths per year are attributed to RHD.

Each year, approximately 663,000 new cases of invasive GAS disease are reported, with 163,000 deaths per year.[8] There are 616 million cases of sore throat infection worldwide per year, which can be attributed to S pyogenes; also, 111 million cases of skin infection in children of developing countries.[1] In the United States, 15% to 30% of cases of pharyngitis in children and 5% to 20% pharyngitis cases per year in adults are due to S pyogenes. Moreover, the resurgence of cases of ARF in the children of middle c­lass families of the United States has been observed.[9]

Throat infection is more common in temperate areas, and its incidence increases in late winter and early spring. Impetigo is more prevalent in children in humid climates. The severity of invasive skin infections caused by GAS has been observed to increase from January to April and correlates with the host's susceptibility to serious infection.[10]

Toxicokinetics

Multiple virulence factors contribute to the clinical manifestations of S pyogenes. The bacterial capsule, which consists of hyaluronic acid, provides protection against phagocytosis. M protein, lipoteichoic acid, and protein F are responsible for bacterial attachment to host cells. M protein is also responsible for inhibiting opsonization by binding to complement regulators and to fibrinogen. 

M protein is the most important virulence factor of S pyogenes, as experiments have shown that M mutants cannot survive in phagocyte-containing human blood.[11] S pyogenes also produces exotoxins, such as a pyrogenic (erythrogenic) toxin, which is responsible for the rash of scarlet fever and for toxic shock syndrome. Other virulence factors include streptokinase, streptodornase, hyaluronidase, and streptolysins, which facilitate tissue invasion.

History and Physical

History and physical findings will vary depending on the type of infection acquired; nonetheless, an accurate history and proper clinical evaluation are required to reach a clinical diagnosis of S pyogenes infection. A sore throat is usually a major complaint in streptococcal pharyngitis. The most common clinical findings in Streptococcal pharyngitis include sudden-onset fever, malaise, pharyngeal exudate, tender cervical lymphadenopathy, and enlarged tonsils.[12] 

In children, impetigo is one of the most common skin infections. S pyogenes causes nonbullous impetigo. Typically, the itchy, reddish rash appears around the mouth or nose and later becomes a fluid-filled blister. Blisters rupture easily and are covered with honey-colored crust. The lesions are usually well localized and affect exposed areas of the body, such as the face and lower extremities. There are typically no systemic manifestations of the impetigo.

A patient with scarlet fever usually presents with high-grade fever, sore throat, strawberry-like tongue, and a blanchable, papular, non-confluent rash. The rash typically lasts for 7 to 10 weeks, followed by desquamation. Desquamation can only be observed on the palms and soles.[13] Soft-tissue invasive infections due to S pyogenes mostly present with shock and multiorgan failure.

Necrotizing fasciitis due to group A streptococcus (S pyogenes) is a deep-seated infection of the subcutaneous tissue that causes rapid destruction of fascia and fat. Systemically or locally immunocompromised individuals are at increased risk for developing necrotizing fasciitis. Other risk factors include surgical procedures, burns, blunt trauma, minor lacerations, and childbirth. Localized pain, necrosis of the infected skin lesion, swelling, redness, edema, increased heart rate, and fever are the typical manifestations of necrotizing fasciitis. In the advanced stage of the disease, a picture of septic shock can be present.[14]

Evaluation

Streptococcus pyogenes, also known as GAS, is a leading cause of pharyngitis in children and adolescents. Clinicians should use clinical and epidemiological findings to determine the likelihood of GAS pharyngitis. The Infectious Diseases Society of America (IDSA) recommends that a rapid antigen detection test (RADT) be used as the first-line test to assist clinicians in diagnosing GAS pharyngitis. Obtaining throat cultures in children with negative RADT results is recommended to prevent the development of complications.[15] A combined approach using validated clinical criteria, such as the modified Centor score or the FeverPAIN score, along with RADT, is an effective strategy to reduce unnecessary testing and unwarranted antibiotic use.

The gold-standard test for detecting GAS is throat culture; however, it is not cost-effective and can delay treatment.[16] The pyrrolidinyl arylamidase (PYR) test is used to distinguish S pyogenes from other beta-hemolytic streptococci and to detect the presence of the enzyme pyrrolidinyl aminopeptidase. Anti-streptolysin O (ASO) and anti-DNase B (ADB) titers indicate prior streptococcal infection and can be used to diagnose post-streptococcal complications.

Treatment / Management

The drug of choice for the treatment of bacterial pharyngitis is oral penicillin for 10 days or intramuscular benzathine penicillin. This treatment is cost-effective and has a narrow spectrum of activity. In patients with penicillin allergy, macrolides and first-generation cephalosporins can be used.[17][18] However, some strains of S pyogenes have developed resistance to macrolides, which are used as the third-line treatment for Streptococcal throat infection.[19] Severe invasive S pyogenes infections can be treated with vancomycin or clindamycin.[20] Intravenous antibiotic therapy and surgery to remove necrotic tissue are recommended for soft-tissue skin infection caused by S pyogenes. 

Differential Diagnosis

Streptococcal pharyngitis should be differentiated from throat infections due to parainfluenza virus, rhinovirus, coxsackievirus, adenovirus, Mycoplasma species, Corynebacterium diphtheria, and Epstein-Barr virus. Scarlet fever can be confused with measles and rubella. However, the absence of symptoms of upper respiratory tract infection and confluent rash in measles can help to differentiate these diseases. Impetigo caused by S pyogenes needs to be differentiated from impetigo caused by Staphylococcus aureus. S pyogenes causes nonbullous impetigo while S aureus leads to bullous impetigo. 

Prognosis

According to a report of the World Health Organization (WHO) GAS is the ninth leading infectious etiology of human mortality. The majority of deaths are due to invasive infections and RHD, especially in third world countries.[8] Severe GAS infections are high in affluent countries ranging from 14% to 19%.[21] Streptococcal pharyngitis typically resolves in 7 to 10 days. However, poor compliance with treatment can result in post-infection complications. 

Complications

Complications of S pyogenes infections can be divided into suppurative and nonsuppurative. Suppurative complications include peritonsillar abscess, peritonsillar cellulitis, retropharyngeal abscess, otitis media and sinusitis, uvulitis, cervical lymphadenitis, meningitis, brain abscess, arthritis, endocarditis, osteomyelitis, and liver abscess. Nonsuppurative complications are rheumatic fever, post-streptococcal glomerulonephritis, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections), Sydenham chorea, and other autoimmune movement disorders.[19]

Deterrence and Patient Education

Patients must be counseled about the importance of completing the course of antibiotics. They should be advised to follow up with a health care provider and to maintain personal hygiene. The act of handwashing can severely decrease the chance of acquiring skin infections due to S pyogenes.

Pearls and Other Issues

Ineffective treatment of skin or pharyngeal infection with group A streptococcus leads to acute rheumatic fever. Prevention of recurrent episodes of ARF and the development of potential serious outcomes of rheumatic heart disease require secondarily prophylaxis of penicillin. Secondary prophylaxis is the most effective method of reducing the incidence of ARF and RHD. Nevertheless, primary prophylaxis is gaining popularity throughout the globe. Primary prevention comprises of prompt treatment of streptococcal throat or skin infection via a single injection of benzathine penicillin or oral penicillin for 10 days after confirmation of S pyogenes infection. Not only does prompt antibiotic treatment reduce the burden of ARF, but it also reduces the incidence of suppurative complications like otitis media. 

Enhancing Healthcare Team Outcomes

While the general clinician is almost always involved in the care of patients with streptococcal infection, caring for those with severe streptococcal disease requires consultation with an interprofessional team of specialists, including a general surgeon, plastic surgeon, radiologist, infectious disease specialist, and specialty-trained nurses. Necrotizing fasciitis is a life-threatening condition, and due to the complexity of this disease, a team approach is required. Since necrotizing fasciitis is a surgical emergency, it is required that the patient be admitted to a surgical intensive care unit, where the medical staff is skilled in performing debridement and, if needed, reconstructive surgery.

Emergent surgical consultation is required to explore and debride the necrotic tissue. In addition, surgical exploration identifies the etiology and extent of necrosis. Computed tomography and MRI may help locate the primary foci of infection. Hemodynamic stability should be maintained.

In patients with toxic shock syndrome, monitoring of cardiac output is important. Due to the high incidence of acute respiratory distress syndrome (55%) in patients with severe Streptococcal soft tissue infection, intubation and ventilatory support are needed. Greater than 50% of patients with severe soft tissue infections can develop acute renal failure; hence, dialysis may be needed.

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Disclosure: Sidrah Kanwal declares no relevant financial relationships with ineligible companies.

Disclosure: Pradeep Vaitla declares no relevant financial relationships with ineligible companies.