key: cord-0709005-5ehrztvj
authors: Snelling, Thomas L; Carapetis, Jonathan R
title: Group A Streptococcus
date: 2012-11-28
journal: Hunter's Tropical Medicine and Emerging Infectious Disease
DOI: 10.1016/b978-1-4160-4390-4.00036-9
sha: 1261328de947c33bdf10c6183ecc65162b58fa16
doc_id: 709005
cord_uid: 5ehrztvj

nan

Group A Streptococcus causes a diverse spectrum of disease, ranging from benign and self-limited infection of the throat or skin, to lethal soft tissue infections accompanied by multi-organ failure. Until the advent of the antibiotic era, Group A Streptococcus was a major cause of death in industrialized countries as a result of sepsis, rheumatic heart disease and fatal epidemics of scarlet fever [1, 2] . The 1980s saw an increase in rheumatic fever cases in the Rocky Mountain states of the USA, along with an apparent resurgence in severe Group A Streptococcus disease in industrialized countries. The resultant increased attention paid to Group A Streptococcus disease in recent years has also brought to focus the continuing high burden of Group A Streptococcus disease in developing countries, particularly those in tropical regions [3] .

The burden of all Group A Streptococcus infections is highest in resource-limited settings, most of which are in tropical regions. It is assumed that the major reasons for this relate to poverty, overcrowded living conditions and limited access to medical care, although geography and climate may also play a role. The estimated number of cases and deaths of Group A Streptococcus diseases is shown in Table 36-1. Of the more severe diseases, 79% of rheumatic heart disease cases, 95% of acute rheumatic fever cases, 97% of acute post-streptococcal glomerulonephritis cases and 97% of invasive Group A Streptococcus cases come from less developed countries [3] .

Pharyngitis is the most common manifestation of Group A Streptococcus disease-its incidence is highest in school-aged children. One episode occurs every 1-2 child years in some resource-limited settings, while only 1 episode every 7-8 child years has been observed in developed urban settings. Limited data on the incidence of Group A Streptococcus pharyngitis in tropical areas suggest significant variability, with rates comparable to temperate climates in some settings but, in others, the documented rate is considerably lower. Transmission is higher in winter months. Impetigo is common in childhood; transmission occurs readily in school and preschool care settings, especially in the summer months. In tropical settings where the burden is particularly high, the majority of children in some communities have impetigo at any one time.

Cellulitis and erysipelas are the most frequent manifestations of invasive Group A Streptococcus infection and, in contrast to pharyngitis and impetigo, incidence increases with age. In the mid-1980s, reports emerged from industrialized countries of both increasing numbers of severe necrotizing Group A Streptococcus infections and of streptococcal toxic shock syndrome [4] . Group A Streptococcus strains belonging to emm types 1 and 3, in particular, have been implicated in this rise. Most cases of severe invasive Group A Streptococcus disease are sporadic, but secondary cases and case clusters have been reported. Limited data suggest that both the incidence and case-fatality of invasive Group A Streptococcus disease in resource-limited countries is several-fold higher than in industrialized countries.

Acute rheumatic fever and rheumatic heart disease continue to result in a substantial component of Group A Streptococcus-related morbidity and mortality in resource-limited settings. Of the 517,000 Group A Streptococcus-related deaths each year, it is estimated that two thirds are caused by rheumatic heart disease or its complications [3] . The true prevalence of rheumatic heart disease remains uncertain, with estimates of at least 1.3 per 1000 school-aged children in developing countries based on auscultatory screening, while estimates based on echocardiography suggest the true prevalence may be more than 10 times higher [5] . Acute rheumatic fever has become uncommon in industrialized settings, although the incidence remains high among indigenous populations in Australia and New Zealand.

The incidence of acute post-streptococcal glomerulonephritis appears to be declining in industrialized settings, but sporadic cases still occur. Acute post-streptococcal glomerulonephritis continues to occur both sporadically and in epidemics in tropical climates (where Group A Streptococcus pyoderma is also common); limited data suggest that acute mortality and chronic morbidity from acute post-streptococcal glomerulonephritis may be higher in developing settings.

The oropharynx and the skin of humans are the only recognized ecologic niches for Group A Streptococcus and they represent the major entry sites for both local and invasive infection [6] (see Fig. 36 .1). Up to 20% of school-aged children may be colonized in the oropharynx in temperate and some tropical regions, although in many tropical settings, less than 5% of children carry Group A Streptococcus (with groups C and G streptococci being more common). Surface proteins facilitate specific adhesion of Group A Streptococcus to either the mucosal epithelium of the throat or to the skin (or both). A number of additional cellular products appear to facilitate direct spread of the invading organism through tissue planes and bacteremia can result in hematogenous dissemination. Some strains have the capacity to elaborate pyrogenic exotoxins that may act as "superantigens", leading to polyclonal proliferation of subsets of T lymphocytes, massive cytokine production and shock [7] .

Antibodies against Group A Streptococcus proteins (in particular antibodies against serotype-specific epitopes on the M protein) are important in providing protection against subsequent infection. However, aberrant immune responses to otherwise benign Group A Streptococcus pharyngitis or impetigo can result in the immune-mediated manifestations, acute rheumatic fever and acute post-streptococcal glomerulonephritis. In acute rheumatic fever, cross-reactive antibodies are thought to arise in genetically predisposed individuals infected with rheumatogenic Group A Streptococcus strains. These strains elicit immune responses to antigens with a similarity between epitopes on the M protein and certain host proteins contained within endocardial, synovium and neural tissues.

Group A Streptococcus pharyngitis may be mild or associated with high fever, tender anterior cervical lymphadenopathy, tonsillar exudates and raised peripheral white cell count. Symptoms usually resolve after 3-5 days, although suppurative complications (which are now uncommon in industrialized settings) include peritonsillar and retropharyngeal abscess, suppurative lymphadenitis, otitis media, mastoiditis and meningitis. Non-suppurative complications include scarlet fever, acute rheumatic fever or acute post-streptococcal glomerulonephritis. Scarlet fever is characterized by a diffuse blanching rash that spreads from the chest to the abdomen and extremities leaving a sandpaper-like texture to the skin. Desquamation of the fingers, toes, groin and axilla occurs one or more weeks later. The tongue is frequently coated in a white film (white strawberry tongue) that eventually gives way to a beefy red appearance (red strawberry tongue). While most cases are benign, scarlet fever was often lethal in the preantibiotic era. Many cases likely represented what would be regarded today as streptococcal toxic shock syndrome (STSS).

In simple impetigo, infection is confined to the epidermis with the formation of superficial crusted lesions on the face or other exposed body parts. In tropical and impoverished settings "pyodermatous" lesions may be pustular and ulcerative. Children are usually afebrile and otherwise well, although resolution of pyoderma may take many days and result in scarring. Erysipelas, which typically affects the face or an extremity, is a painful infection of the dermis resulting in a clearly demarcated red and raised area of inflammation and often formation of superficial bullae. Cellulitis involves the deeper subcutaneous tissues causing a more diffuse and less clearly demarcated area of inflammation. Infection of the draining lymphatic tracts (lymphangitis) results in tender linear streaks extending from the site of infection. Unlike impetigo, cellulitis and erysipelas are usually associated with fever and systemic toxicity.

Necrotizing fasciitis is a rapidly progressing infection of the subcutaneous fat, the superficial fascia and deeper structures, including muscle. Shock, multi-organ failure and death may ensue within hours a pre-existing focus of Group A Streptococcus infection (e.g. pharyngitis, otitis media) or with other risk factors (e.g. skull defect or postcranial surgery) [10] . Puerperal sepsis caused by Group A Streptococcus was a frequent cause of death in the pre-antibiotic era with outbreaks resulting from nosocomial transmission. A study in four tropical developing countries (Papua New Guinea, Ethiopia, The Gambia and The Philippines) during the 1990s found that Group A Streptococcus was one of the three leading causes of bacteremia in children aged <90 days, suggesting that Group A Streptococcus puerperal sepsis and septic abortion remain common in less developed, tropical countries [11] . Unlike Group B Streptococcus, Group A Streptococcus more commonly affects the mother than the infant, manifesting as post-partum endometritis, peritonitis, septic thrombophlebitis or bacteremia without focus [12] . However, chorioamnionitis and neonatal sepsis are also reported.

Acute rheumatic fever is characterized by various combinations of fever, polyarthritis or arthralgias, carditis, characteristic rash (erythema marginatum), chorea and subcutaneous nodules [13] (Table 36-3) . Chorea and insidious carditis can occur as a manifestation of acute rheumatic fever in the absence of other features. Severe or recurrent episodes of acute rheumatic fever may result in progressive damage to the mitral valve (and sometimes the aortic valve) resulting in incompetence and progressive heart failure (rheumatic heart disease). Over several years, the valve may eventually become stenotic. Acute post-streptococcal glomerulonephritis can occur 1-2 weeks after or days of onset. Initially, the overlying skin is relatively spared and severe escalating pain may be disproportionate to clinical findings. The skin subsequently becomes violaceous and bullae may form and then slough. STSS is characteristically associated with Group A Streptococcus necrotizing fasciitis, although it may arise in the setting of other invasive Group A Streptococcus infections. The case definition of STSS requires the confirmation of Group A Streptococcus infection, along with hypotension and two or more features of multi-organ involvement: rash, coagulopathy, respiratory distress syndrome, renal failure or hepatic impairment [8] .

Otitis media, retropharyngeal and peritonsillar abscess, sinusitis, meningitis, pneumonia, bacteremia and endocarditis may arise either as a complication of tonsillopharyngitis, following surgery or trauma (including burns), following varicella infection, or without apparent antecedent. Historically, outbreaks of Group A Streptococcus pneumonia were reported among previously healthy adults, although more recent reports have described the highest risk amongst the elderly and those with underlying medical conditions; infection in these individuals is often associated with high case fatality [9] . A viral prodrome is often reported, although the onset of fever, chest pain and dyspnea is characteristically rapid. Group A Streptococcus pneumonia may be necrotizing with pleural effusions frequently present early and early complications include lung abscess formation, mediastinitis and pericarditis. Group A Streptococcus is an uncommon cause of meningitis in children and adults, with most reports arising in individuals with throat infection or a few weeks after Group A Streptococcus skin infection. The features are hematuria (microscopic or gross), edema (which may be most evident peri-orbitally) and hypertension. Severe cases can also be complicated by encephalopathy. The illness is generally benign in childhood, but there may be an appreciable mortality among adults as a result of renal and congestive cardiac failure. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a term used to describe some children with tic or obsessive compulsive disorders in whom symptoms appear to develop or worsen following Group A Streptococcus infection. The existence of PANDAS is controversial [14] . Post-streptococcal reactive arthritis describes a syndrome of polyarthritis that differs from acute rheumatic fever by affecting a range of smaller joints, being relatively resistant to anti-inflammatory treatment and not being associated with carditis, although cases of acute rheumatic fever have been misdiagnosed as post-streptococcal reactive arthritis [15, 16] .

Viruses account for most episodes of acute pharyngitis in all age groups. Group A Streptococcus is isolated in only 20-40% of cases of exudative pharyngitis in school-aged children and an even lower proportion of cases in younger children and adults. Recovery of the organism may not represent infection, but colonization. The distinguishing features of Group A Streptococcus pharyngitis and scarlet fever, and differential diagnoses, are detailed in Invasive infections resulting from trauma or bites, exposure to water or soil, or involving immunocompromised hosts (including diabetic foot infections) may be caused by a more expanded array of pathogens and therefore require broader empirical therapy and heightened efforts to obtain a microbiologic diagnosis [17] .

The arthritis of acute rheumatic fever may be mistaken for septic arthritis (e.g. the polyarthritis of disseminated gonococcosis or multifocal S. aureus infection), rheumatologic causes of polyarthritis, including juvenile rheumatoid arthritis, and post-streptococcal reactive arthritis (see Table 36 -2). Acute rheumatic fever is the most common cause of chorea in most populations with a high incidence of acute rheumatic fever-particularly those in tropical, lessdeveloped countries-and can occur in the absence of other features of acute rheumatic fever or serologic evidence of Group A Streptococcus infection. However, chorea may also be a manifestation of systemic lupus erythematosus, neurovascular disease, drugs, thyrotoxicosis, Wilson's disease and a number of genetic neurodegenerative diseases that must be considered, especially where acute rheumatic fever is uncommon. Measles is associated with prodromal conjunctivitis and coryzal symptoms and Koplik spots. Rubella is associated with post-auricular lymphadenopathy l Parvovirus "fifth disease or erythema infectiosum" associated with distinctive "slapped cheek" rash of face and reticular rash of limbs appearing after fever resolution l Roseola rash associated with defervescence and affects younger children (infants) more than scarlet fever l Kawasaki disease (KD) and Still's disease (SD; systemic-onset juvenile rheumatoid arthritis) associated with multiple symptoms and prolonged fever (>5 days). KD is also associated with conjunctivitis, edema of the hands and feet, and stomatitis. SD is associated with transient or "evanescent" rash, lymphadenopathy, hepatosplenomegaly, uveitis, PSRA associated with small joints and absence of other clinical features of acute rheumatic fever or a propensity to rheumatic heart disease. A diagnosis of PSRA should rarely be made in populations with a high incidence of acute rheumatic fever, and all cases should be given at least 12 months of penicillin prophylaxis before re-evaluation l Neisseria gonorrhoeae may be multifocal and migratory, and must be considered if sexually active. Also associated with cutaneous lesions in disseminated disease. Culture of joint fluid is frequently negative The diagnosis of a primary episode of acute rheumatic fever is based on the most recent version of the Jones' criteria-currently the 1992 version (Table 36-3) . These clinical and investigational criteria have been repeatedly revised since the original 1944 version to maintain their positive predictive value in settings where incidence is decreasing. As a result, some high-burden settings have chosen to modify the revised criteria to retain their sensitivity and negative predictive value [18] .

In acute post-streptococcal glomerulonephritis, activation of the alternative complement pathway results in a depressed C3 level (usually with a normal C4) that resolves after several weeks. Diagnosis generally rests on the presence of signs and symptoms, together with serologic evidence of recent Group A Streptococcus infection and a compatible complement profile. Biopsy is reserved for atypical features, such as anuria or failure of renal function, hypertension or depressed complement that does not improve after several weeks.

instances where alternative antibiotics may be preferred because of differing mechanisms of action, they are generally used as an adjunct to-rather than in replacement of-penicillin therapy. Erythromycin and the newer macrolides have been used for Group A Streptococcus disease where individuals have immediate hypersensitivity to penicillin. Macrolide resistance is common in some settings and can arise abruptly, apparently related to the population level of macrolide consumption. Some mutations confer resistance to both macrolides and clindamycin, but these remain uncommon.

The use of antibiotics for the routine treatment of Group A Streptococcus pharyngitis is contentious because of the usually self-limiting nature of the illness. Studies suggest that treatment reduces the average duration of sore throat by 16 hours and decreases the risk of rheumatic fever and otitis media by around 70%, and the risk of peritonsillar abscess by around 85% [20] . In low-incidence settings, the numbers needed to treat to prevent complications is likely to be very large, so the main aim of antibiotic treatment, if chosen to be used, is alleviation of symptoms and shortening of the duration of illness. However, antibiotic treatment of Group A Streptococcus pharyngitis is essential in populations with a high incidence of acute rheumatic fever and, if diagnostic facilities are limited, empirical treatment of all sore throat cases may be justified. There is little evidence that antibiotics reduce the risk of subsequent acute poststreptococcal glomerulonephritis.

Treatment recommendations are detailed in Table 36 -4. Ten days of twice-daily oral penicillin V or a single dose of intramuscular benzathine pencillin G are the preferred treatment for Group A Streptococcus pharyngitis, although once-daily oral amoxicillin appears to be effective for symptom resolution and Group A Streptococcus eradication [21] . Short courses (up to 5 days) of macrolides and some cephalosporins have been shown to have equivalent clinical and short-term microbiologic cure rates, but the risk of late microbiologic failure may be higher. There are insufficient data regarding the efficacy of shortcourse or non-penicillin regimens in preventing acute rheumatic fever. Treatment of impetigo may be with oral or topical antibioticsoptions are given in Table 36-4 .

Penicillin is the treatment of choice for invasive infection where Group A Streptococcus is confirmed or highly likely (e.g. erysipelas or perianal cellulitis). Because of the narrow spectrum of penicillin, empirical treatment prior to microbiologic confirmation is generally with one or more alternative antimicrobials. For example, an anti-staphylococcal penicillin or a first-generation cephalosporin is required to cover both Group A Streptococcus and S. aureus in cellulitis (see Table 36 -4). Where methicillin-resistant S. aureus (MRSA) is prevalent, clindamycin may be an acceptable alternative if prevailing MRSA strains are susceptible. Suppurative diseases frequently seen as complications of Group A Streptococcus infection (e.g. peritonsillar abscess) may also be caused by organisms other than Group A Streptococcus.

As necrotizing soft tissue infections may be polymicrobial, broadspectrum cover (e.g. with a carbapenem) is recommended until the microbiologic cause is confirmed.

Urgent and aggressive debridement of nonviable tissues has been the cornerstone of management of Group A Streptococcus necrotizing fasciitis, along with intensive supportive care and antibiotics. However, some authorities have suggested that a less aggressive approach may be acceptable if antibiotics and adjunctive therapy with intravenous immunoglobulin (IVIG) are instituted early [22] . Clindamycin is recommended as an adjunct to penicillin for the treatment of severe invasive Group A Streptococcus disease, including necrotizing infections, during the first few days of treatment-this is supported by the superior activity of clindamycin over penicillin in animal models [19] . However, penicillin should always be given unless there is a history of hypersensitivity. Although supportive data are limited, administration of 1 or 2 doses of IVIG early in the course of STSS is widely recommended. A multicenter, randomized, controlled trial revealed a trend toward a reduction in mortality among recipients, but the study was terminated early because of slow recruitment [23] . IVIG is also recommended by some as adjunctive treatment in severe invasive Group A Streptococcus infections, even in the absence of toxic shock. Management of acute rheumatic fever is primarily symptomatic. Penicillin is generally given to eradicate colonization, although acute infection has usually passed by the time symptoms of acute rheumatic fever develop. Salicylates are used to relieve fever and the pain from arthritis that is often severe. Where necessary, cardiac failure is managed with diuretics and angiotensin-converting enzyme (ACE) inhibitors. Steroids are sometimes used in cases of severe carditis, although there is no evidence that they improve the long-term outcome in RHD. Mitral valve repair, balloon valvuloplasty, or valve replacement may be required to manage patients with severe valve disease in rheumatic heart disease.

Management of acute post-streptococcal glomerulonephritis is based on control of hypertension with fluid restriction and use of a loop diuretic such as furosemide. ACE inhibitors may also be needed as an adjunct. Dialysis is occasionally required to manage severe hyperkalemia or symptomatic uremia.

Contacts of patients with Group A Streptococcus infection may be colonized with the same Group A Streptococcus strain, but primary prophylaxis of contacts is rarely indicated for simple Group A Streptococcus pharyngitis. Even for contacts of severe invasive infections, it is estimated that around 2000 contacts would need to receive prophylaxis in order to avoid a single, severe infectionopinion on the value of treating contacts is divided [24] . If prophylactic treatment of contacts is attempted, regimens combining rifampin with penicillin, or using alternative antibiotics such as cephalosporins or azithromycin, are usually recommended as a result of the increasing failures of penicillin alone in eradicating carriage.

However, regular secondary prophylaxis is recommended for all children and adults with previous acute rheumatic fever or established rheumatic heart disease. Monthly intramuscular benzathine penicillin G is central to the management of children and adults with acute rheumatic fever and rheumatic heart disease (see Table 36 -4).

During outbreaks of acute post-streptococcal glomerulonephritis secondary to Group A Streptococcus pyoderma, community-based treatment of infected individuals and their contacts with benzathine penicillin G appears to decrease the transmission of acute poststreptococcal glomerulonephritis-producing Group A Streptococcus strains. In addition to treating infected individuals, reducing the transmission of Group A Streptococcus pyoderma in resource-limited settings is likely to require skin hygiene measures, including the control of scabies.

After a century of research, the development of a vaccine against Group A Streptococcus disease is at last showing promise. The most advanced of the current candidates is a multivalent vaccine including 26 of the most common Group A Streptococcus emm types encountered in North America and Europe. Unfortunately, there is a limited match of these strains with prevalent emm types in Africa and the Pacific, where emm types are more variable [25] . Other candidate vaccines, containing antigens conserved among most, or all, Group A Streptococcus strains, are approaching clinical trials.

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