Dennis L. Stevens PhD, MD
Essentials of Diagnosis
Similarly, 90% of cases of scarlet fever occur in children 2 to 8 years old, and, like pharyngitis, it is most common in temperate regions during the winter months. An experiment of nature in the Faroe Islands suggested that susceptibility to scarlet fever is not dependent on young age per se. Scarlet fever had disappeared from that isolated island for several decades until it was reintroduced by a visitor with unsuspected scarlet fever. An epidemic of scarlet fever ensued, with significant attack rates in all age groups, suggesting that other factors (such as the lack of protective antibody against scarlatina toxin or the introduction of a new strain) rather than age, predisposed those individuals to clinical illness.
In contrast to pharyngitis, impetigo, and scarlet fever, bacteremia has had the highest age-specific attack rate in the elderly and in neonates. Between 1986 and 1988, the prevalence of bacteremia increased 800–1000% in adolescents and adults in Western countries. Although some of this increase is attributable to IV drug abuse and puerperal sepsis, most of the increase is owing to cases of streptococcal toxic shock syndrome (strepTSS).
Human mucus membranes and skin serve as the natural reservoirs of Streptococcus pyogenes. Pharyngeal and cutaneous acquisition is spread person to person via aerosolized microdroplets and direct contact, respectively. Epidemics of pharyngitis and scarlet fever have also resulted from ingestion of contaminated nonpasteurized milk or food. Epidemics of impetigo have been reported, in tropical areas, day care centers, and among underprivileged children. Group A streptococcal infections in hospitalized patients occur during child delivery (puerperal sepsis), times of war (epidemic gangrene), surgical convalescence (surgical wound infection, surgical scarlet fever), or as a result of burns (burn wound sepsis). Thus, in most clinical streptococcal infections, the mode of transmission and portal of entry are easily ascertained. In contrast, among patients with strepTSS, the portal of entry is obvious in only 50% of cases.
Within the tissues, streptococci may evade opsonphagocytosis by destroying or inactivating complement-derived chemoattractants and opsonins (C5a peptidase) and by binding immunoglobulins. Expression of M-protein, in the absence of type-specific antibody, also protects the organism from phagocytosis by polymorphonuclear leukocytes and monocytes.
BOX 48-1 Streptococcal Infections
Bacterial Cell Structure & Extracellular Products
Although all strains of Group A streptococci are endowed with genes for streptococcal pyrogenic exotoxin B, not all strains produce it, and even among producing strains, the quantity of toxin synthesized varies greatly from strain to strain.
Pyrogenic exotoxin C, like streptococcal pyrogenic exotoxin A, is bacteriophage-mediated, and expression is likewise highly variable. Recently, mild cases of scarlet fever in England and the United States have been associated with streptococcal pyrogenic exotoxin C positive strains.
PHARYNGITIS & THE ASYMPTOMATIC CARRIER
Patients with streptococcal pharyngitis have abrupt onset of sore throat, submandibular adenopathy, fever, and chilliness but usually not frank rigors. Cough and hoarseness are rare, but pain on swallowing is characteristic. The uvula is edematous, the tonsils are hypertrophied, and the pharynx is erythematous with exudates, which may be punctate or confluent. Acute pharyngitis is sufficient to induce antibody against M-protein, Streptolysin O, DNase and hyaluronidase, and, if present, pyrogenic exotoxins. Depending on the infecting strain, pharyngitis may progress to scarlet fever, bacteremia, suppurative head and neck infections, rheumatic fever, post-streptococcal glomerulonephritis, or strepTSS. Pharyngitis is usually self-limited and pain, swelling, and fever resolve spontaneously in 3–4 days even without treatment (Boxes 48-2 and 48-3).
BOX 48-2 Treatment of Impetigo1
Definitive diagnosis is difficult when based only on clinical parameters, especially in infants, among which rhinorrhea may be the dominant manifestation. Even in older children with all of the above physical findings, the correct clinical diagnosis is made in only 75% of patients. Absence of any one of the classic signs greatly reduces the specificity. Rapid antigen detection tests in the office setting have a sensitivity and specificity of 40–90%. A popular approach in clinical practice is to obtain two throat swab samples from the posterior pharynx or tonsillar surface. A rapid strep test is performed on the first, and, if positive, the patient is treated with antibiotics and the second swab discarded. If the rapid strep test is negative, the second is sent for culture, and treatment is withheld, pending a positive culture.
BOX 48-3 Treatment of Recurrent Streptococcal Pharyngitis and Tonsillitis
During the last 30–40 years, outbreaks of scarlet fever in the Western world have been infrequent and notably mild, and the illness has been referred to as pharyngitis with a rash or benign scarlet fever (Table 48-1). In contrast, in the latter half of the 19th century, mortalities of 25–35% were common in the United States, Western Europe, and Scandinavia. The fatal or malignant forms of scarlet fever have been described as either septic or toxic. Septic scarlet fever refers to patients who develop local invasion of the soft tissues of the neck and complications such as upper-airway obstruction, otitis media with perforation, meningitis, mastoiditis, invasion of the jugular vein or carotid artery, and bronchopneumonia.
Toxic scarlet fever is rare today, but, historically, patients initially developed severe sore throat, marked fever, delirium, skin rash, and painful cervical lymph nodes. In severe toxic cases, fevers of 107°F, pulses of 130–160 beats per minute, severe headache, delirium, convulsions, little if any skin rash, and death within 24 hours were common. These cases occurred before the advent of antibiotics, antipyretics, and anticonvulsants, and deaths were acutely the result of uncontrolled seizures and hyperpyrexia. In contrast, children with septic scarlet fever had prolonged courses and succumbed 2–3 weeks after the onset of pharyngitis. Complications of streptococcal pharyngitis and malignant forms of scarlet fever have been less common in the antibiotic era. Even before antibiotics became available, necrotizing fasciitis and myositis were not described in association with scarlet fever.
STREPTOCOCCAL PYODERMA (Impetigo contagiosa)
Impetigo is most common in patients with poor hygiene or malnutrition. Colonization of the unbroken skin occurs first, then intradermal inoculation is initiated by minor abrasions, insect bites, etc. Single or multiple thick-crusted, golden-yellow lesions develop within 10–14 days. Penicillin orally or parenterally, or bacitracin or mupiricin topically, are effective treatments for impetigo and also reduce transmission of streptococci to susceptible individuals (see Box 48-2). None of these treatments, including penicillin, prevents post-streptococcal glomerulonephritis.
Erysipelas is caused exclusively by S pyogenes and is characterized by an abrupt onset of fiery red swelling of the face or extremities. Distinctive features are well-defined margins, particularly along the nasolabial fold, scarlet or salmon red rash, rapid progression, and intense pain. Flaccid bullae may develop during the second to third day of illness, yet extension to deeper soft tissues is rare. Surgical débridement is not necessary, and treatment with penicillin is effective (Box 48-4). Swelling may progress despite treatment, although fever, pain, and the intense redness diminish. Desquamation of the involved skin occurs 5–10 days into the illness. Infants and elderly adults are most commonly afflicted, and, historically, erysipelas, like scarlet fever, was more severe before the turn of the century.
Table 48-1. Characteristics of Scarlet Fever.
Group A streptococci are the most common cause of cellulitis; however, alternative diagnoses may be obvious when associated with a primary focus, such as an abscess or boil (Staphylococcus aureus), dog bite (Capnocytophagia), cat bite (Pasteurella multocida), freshwater injury (Aeromonas hydrophila), seawater injury (Vibrio vulnifica), animal carcasses, Erysipelothrix rhusiopathia, and so on. Clinical clues to the etiologic diagnosis are important because aspiration of the leading edge and punch biopsy yield a causative organism in only 15% and 40% of cases, respectively. Patients with lymphedema of any cause, such as lymphoma, filariasis, or postsurgical regional lymph node dissection (eg, mastectomy, carcinoma of the prostate), are predisposed to developing streptococcal cellulitis, as are patients with chronic venous stasis. Recently, recurrent saphenous vein donor site cellulitis has been attributed to Group A, C, or G streptococci.
Group A streptococci may invade the epidermis and subcutaneous tissues, resulting in local swelling, erythema, and pain. The skin becomes indurated and, unlike the brilliant redness of erysipelas, is a pinkish color. If fever, pain, or swelling increase, if bluish or violet bullae or discoloration appear, or if signs of systemic toxicity develop, a deeper infection, such as necrotizing fasciitis or myositis, should be considered (see below). An elevated serum creatinine phosphokinase suggests deeper infection, and prompt surgical inspection and débridement should be performed (see Box 48-4).
BOX 48-4 Treatment of Cellulitis and Erysipelas
Cutaneous infection with bright red streaks ascending proximally is invariably caused by Group A streptococcus. Prompt parenteral antibiotic treatment is mandatory since bacteremia and systemic toxicity develop rapidly once streptococci reach the bloodstream via the thoracic duct.
Necrotizing fasciitis, originally called streptococcal gangrene, is a deep-seated infection of the subcutaneous tissue that results in progressive destruction of fascia and fat but may spare the skin itself. Necrotizing fasciitis has become the preferred term since Clostridium perfringens, Clostridium septicum, and S aureus can produce a similar pathologic process. Infection may begin at the site of trivial or unapparent trauma. Within the first 24 hours, swelling, heat, erythema, and tenderness develop and rapidly spread proximally and distally from the original focus.
During the next 24–48 hours, the erythema darkens, changing from red to purple and then to blue, and blisters and bullae form that contain clear yellow fluid. On the fourth or fifth day, the purple areas become frankly gangrenous. From the seventh to the tenth day, the line of demarcation becomes sharply defined, and the dead skin begins to reveal extensive necrosis of the subcutaneous tissue. Patients become increasingly prostrated and emaciated and may become unresponsive, mentally cloudy, or even delirious. Historically, aggressive fasciotomy and débridement (bearclaw fasciotomy) and irrigations with Dakan's solution (hypochlorous acid) achieved mortalities as low as 20%, even before antibiotics were available (Box 48-5). The time course of progression of necrotizing fasciitis is more rapid, and mortalities have been higher in the 1980–1990s, suggesting increased virulence of streptococci.
Historically, streptococcal myositis has been an extremely uncommon infection, only 21 cases being documented from 1900 to 1985. Recently, the prevalence of streptococcal myositis has increased in the United States, Norway, and Sweden. Translocation of streptococci from the pharynx to the deep site of trauma (muscle) likely occurs hematogenously. Symptomatic pharyngitis or penetrating trauma is uncommon. Severe pain may be the only presenting symptom; swelling and erythema may be the only signs of infection. In most cases, a single muscle group is involved; however, because patients are frequently bacteremic, multiple sites of myositis or abscess can occur.
Distinguishing streptococcal myositis from spontaneous gas gangrene caused by C perfringens or C septicum may be difficult, although the presence of crepitus or gas in the tissue would favor clostridial infection. Myositis is easily distinguished from necrotizing fasciitis anatomically by surgical exploration or incisional biopsy, although clinical features of both conditions overlap and both necrotizing fasciitis and myonecrosis may occur together.
BOX 48-5 Treatment of Necrotizing Fasciitis/Myositis and Streptococcal TSS
In published reports, the case-fatality rate of necrotizing fasciitis is between 20 and 50%, whereas that of streptococcal myositis is between 80 and 100%. Aggressive surgical débridement is extremely important because of the poor efficacy of penicillin described in human cases as well as in experimental models of streptococcal myositis (see Box 48-5).
Pneumonia caused by Group A streptococcus is most common in women in the second and third decades of life and causes large pleural effusions and empyema. Several liters of pleural fluid may accumulate within hours. Chest tube drainage is mandatory, although management is complicated by multiple loculations and fibrinous effusions, resulting in restrictive lung disease.
STREPTOCOCCAL TOXIC SHOCK SYNDROME
In the late 1980s, invasive GAS infections occurred in North America and Europe in previously healthy individuals of all ages. This illness is associated with bacteremia, deep soft-tissue infection, shock, multi-organ failure, and death in 30% of cases. StrepTSS occurs sporadically, although minor epidemics have been reported. Most patients present with a viral-like prodrome, history of minor trauma, recent surgery, or varicella infection. The prodrome may be caused by a viral illness that predisposed to strepTSS, or these vague early symptoms may be related to the evolving infection. In cases associated with necrotizing fasciitis, the infection may begin deep in the soft tissue at a site of minor trauma that frequently does not result in a break in the skin. Although surgical procedures and viral infections such as varicella and influenza may provide portals of entry, no portal can be ascertained in 45% of cases. Preceding symptomatic pharyngitis is rare. Shock and organ failure are related to the production of cytokines by monocytes and lymphocytes stimulated with exotoxins, including pyrogenic exotoxins A, B, and C.
Fever is the most common presenting sign, although some patients present with profound hypothermia secondary to shock. Confusion is present in over half of the patients and may progress to coma or combativeness. On admission, 80% of patients have tachycardia, and over half will have systolic blood pressure of <110 mm Hg. Of those with normal blood pressure on admission, most become hypotensive within 4 hours. Soft-tissue infection evolves to necrotizing fasciitis or myositis in 50–70% of patients, and these require emergent surgical débridement, fasciotomy, or amputation. An ominous sign is progression of soft-tissue swelling to violaceous or bluish vesicles or bullae (see section on necrotizing fasciitis).
Many other clinical presentations may be associated with strepTSS, including endophthalmitis, myositis, perihepatitis, peritonitis, myocarditis, meningitis, septic arthritis, and overwhelming sepsis. Patients with shock and multiorgan failure without signs or symptoms of local infections have a worse prognosis since definitive diagnosis and surgical débridement may be delayed.
The initial hematologic studies demonstrate only mild leukocytosis, but a dramatic left shift (43% of white blood cells may be band forms, metamyelocytes, and myelocytes). The mean platelet count is normal on admission but may drop rapidly by 48 hours, even in the absence of criteria for disseminated intravascular coagulopathy.
Group A streptococcus is isolated from blood in 60% of cases and from deep tissue specimens in 95% of cases. M types 1, 3, 12, and 28 are the most common strains isolated. Pyrogenic exotoxins A and/or B have been found in isolates from the majority of patients with severe infection. Infections in Norway, Sweden, and Great Britain have been primarily caused by M type 1 strains that produce pyrogenic exotoxin B. Other novel pyrogenic exotoxins are being described that may also explain the recent enhanced virulence of Group A streptococcus.
The nonsuppurative complications of S pyogenes infection are acute rheumatic fever and acute glomerulonephritis.
In addition, a resurgence of ARF has occurred predominantly among U.S. military recruits and white middle-class civilians. A particularly frightening aspect of these recent civilian cases was the low incidence of symptomatic pharyngitis (24–78%). Thus our modern primary prevention strategy (diagnosis of acute GAS pharyngitis with penicillin treatment within 10 days) would not have prevented ARF in these cases (Box 48-6).
The clinical manifestations of acute rheumatic fever are multiple, and because each is not specific for ARF, several criteria must be met to establish a definitive diagnosis. Simply put, two major manifestations or one major and two minor manifestations plus, in either case, evidence of an antecedent GAS infection are required for definitive diagnosis. The major manifestations and the frequency with which they occur during first attacks of ARF are as follows: arthritis (75%), carditis (40–50%), chorea (15%), and subcutaneous nodules (<10%). The minor manifestations are fever, arthralgia, heart block, presence of acute-phase reactants in the blood (C-reactive protein, leukocytosis, and elevated erythrocyte sedimentation rate), and prior history of ARF or rheumatic heart disease.
Carditis, when present, occurs during the first 3 weeks of illness and may involve pericardium, myocardium, and endocardium. Patients with pericarditis may have chest pain or pericardial effusion, whereas those with myocarditis may have intractable heart failure. Manifestations of acute endocarditis involve the development of new murmurs of mitral regurgitation, or aortic regurgitation, the latter being sometimes associated with a low-pitched apical middiastolic flow murmur (Carey Coombs murmur). Murmurs of mitral stenosis and aortic stenosis are not detected acutely during first attacks of ARF but are chronic manifestations of rheumatic heart disease. Migratory arthritis involves several joints, most frequently the knees, ankles, elbows, and wrists, in more than 50% of patients. Each involved joint has evidence of inflammation that characteristically resolves within 2–3 weeks with no progression to chronic arthritis or articular damage.
Subcutaneous nodules occur several weeks into the course of ARF and are found over bony surfaces or tendons. They last only 1–2 weeks and have in some cases been associated with severe carditis. Erythema marginatum is an evanescent, nonpainful erythematous eruption occurring on the trunk or proximal extremities. Individual lesions can develop and disappear within minutes, but the process may wax and wane over several weeks or months. Syndenham's chorea often occurs later in the course than other manifestations of ARF and is characterized by rapid nonpurposeful choreiform movements of the face, hands, and feet. Attacks usually disappear during sleep but may persist for 2–4 months.
Evidence of glomerular damage by renal biopsy has been documented in nearly 50% of contacts of siblings with AGN, suggesting that, as in ARF, subclinical disease is not uncommon after infection with certain strains of GAS. Unlike rheumatic fever, but similar to scarlet fever, glomerulonephritis occurs most commonly in children between 2 and 6 years of age. Like ARF and scarlet fever, AGN may affect several members of the same family. Recurrences or secondary attacks occur only rarely, and there is little to suggest that AGN progresses to chronic renal failure.
The differential diagnosis of post-streptococcal AGN must include Henoch-Schénlein disease, polyarteritis nodosa, idiopathic nephrotic syndrome, leptospirosis, hemolytic uremic syndrome (Escherichia coli 0157:H7), and malignant hypertension. The diagnosis is simpler if there is a recent history of symptomatic GAS pharyngitis, impetigo, or scarlet fever. Elevated or rising antibody titers to streptococcal antigens such as ASO, anti-DNase A or B, and/or antihyaluronidase are helpful, although ASO concentration may be low in patients with pyoderma. A careful urinalysis to document proteinuria and hematuria should be performed, but it is mandatory to demonstrate red blood cell casts because the latter is the hallmark of glomerular injury. The blood urea nitrogen and creatinine values are elevated and if nephrotic syndrome is present the serum cholesterol level is elevated and serum albumin concentration is low. Twenty-four-hour excretion of protein is usually less than 3 g, and total hemolytic complement and C3 levels are markedly reduced.
BOX 48-6 Prophylaxis for Rheumatic Fever
Treatment of Group A Infections
During epidemics, particularly when rheumatic fever or a post-streptococcal glomerulonephritis are prevalent, treatment of asymptomatic carriers may be necessary. Studies by the U.S. military have shown that monthly injections of benzathine penicillin greatly reduce the incidence of streptococcal pharyngitis and rheumatic fever in young soldiers living in crowded conditions.
Erythromycin resistance of S pyogenes is currently 4% in Western countries; however, in Japan in 1974, the rate reached 72%. Sulfonamide resistance currently is reported in <1% of GAS isolates.
Resistance to penicillin has not been described, yet in some settings there is a lack of in vivo efficacy despite in vitro susceptibility to penicillin. Three mechanisms may explain this lack of efficacy.
Penicillin failure in pharyngitis, tonsillitis, or mixed infections may be caused by inactivation of penicillin in situ by beta lactamases produced by cocolonizing organisms such as Bacteroides fragilis, Haemophilus influenzae, or S aureus. For example, the failure rate of penicillin treatment of GAS pharyngitis may approach 25%, and, if such patients are treated with a second course of penicillin, the failure rate may approach 80%, perhaps owing to selection of beta-lactamase–producing bacteria. In contrast, cures of 90% have been achieved when treatment consisted of amoxicillin plus clavulanate, oral cephalosporin, or clindamycin.
Streptococcal cellulitis responds quickly to penicillin, although, in some cases in which staphylococcus is of concern, nafcillin or oxacillin may be a better choice. For treatment of streptococcal pneumonia, prolonged penicillin therapy, thoracoscopy, and decortication of the pleura may be necessary.
Bisno AL: Group A streptococcal infections and acute rheumatic fever. N Engl J Med 1991;325:783. (An excellent review article about Group A streptococcus. The emphasis of this chapter is on rheumatic fever but there are excellent sections on virulence factors, epidemiology, and streptococcal infections in general.)
Cone LA, Woodard DR, Schlievert PM, et al: Clinical and bacteriologic observations of a toxic-shock like syndrome due to Streptococcus pyogenes. N Engl J Med 1987;317:146. (Case report of an early case of streptococcal toxic shock syndrome.)
Martin PR, Hoiby EA: Streptococcal serogroup A epidemic in Norway 1987–1988. Scand J Infect Dis 1990;22:421. (An excellent population-based study demonstrating a remarkable recent increase in Group A streptococcal bacteremia in age groups from 18 to 50 years of age.)
Schwartz B, Facklam RR, Breiman RF: Changing epidemiology of Group A streptococcal infection in the USA. Lancet 1990;336:1167. (A survey of Group A streptococcal isolates sent to the CDC over the last decade. A clear indication that invasive infections are currently associated with M types 1 and 3.)
Stevens DL: Invasive Group A streptococcus infections. Clin Infect Dis 1992;14:2. (A review article describing the changing epidemiology of scarlet fever, necrotizing fasciitis, myositis, bacteremia, and the streptococcal toxic shock syndrome.)
Stevens DL, Bryant-Gibbons AE, Bergstrom R, Winn V: The Eagle effect revisited: Efficacy of clindamycin, erythromycin, and penicillin in the treatment of streptococcal myositis. J Infect Dis 1988;158:23. (This article demonstrates the remarkable efficacy of clindamycin but failure of penicillin in an animal model of streptococcal necrotizing fasciitis and myonecrosis.)
Stevens DL, Bryant AE, Hackett SP: Sepsis syndromes and toxic shock syndromes: Concepts in pathogenesis and a perspective of future treatment strategies. Curr Opin Infect Dis 1993;6:374. (A comparative review of the cellular basis of cytokine and lymphokine mediated shock caused by gram-negative and gram-positive bacteria.)
Stevens DL, Tanner MH, Winship J, et al: Severe Group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N Engl J Med 1989;321:1. (A report of the clinical, laboratory, and systemic complications associated with 20 patients with streptococcal toxic shock syndrome. An analysis of strains reveals that most were M types 1 and 3 and most strains produced pyrogenic exotoxin type A.)