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.
Clinical Findings
Signs and Symptoms
The abrupt onset of severe pain is a common initial symptom of strepTSS. The pain most commonly involves an extremity but may also mimic peritonitis, pelvic inflammatory disease, acute myocardial infarction, or pericarditis. Treatment with nonsteroidal anti-inflammatory agents may mask the presenting symptoms or predispose to more severe complications, such as shock.
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 debridement, 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 debridement may be delayed.
Laboratory Findings
Hemoglobinuria is present and serum creatinine is elevated in most patients at the time of admission. Serum albumin concentrations are moderately low (3.3 grams/dl) on admission and drop progressively over 48-72 hours. Hypocalcemia, including ionized hypocalcemia, is detectable early in the hospital course. The serum creatine kinase level is a useful test to detect deeper soft-tissue infections, such as necrotizing fasciitis or myositis.
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.
Course
Shock is apparent early in the course, and fluid management is complicated by profound capillary leak. Adult respiratory distress syndrome occurs frequently (55%), and renal dysfunction, which precedes hypotension in many patients, may progress despite treatment. In patients who survive, serum creatinine levels return to normal within 4-6 weeks, although many will require dialysis. The recommended antibiotic therapy for strepTSS is shown in Box 48-5. Overall, 30% of patients die despite aggressive treatment including IV fluids, colloid, pressors, mechanical ventilation, and surgical interventions, such as fasciotomy, debridement, exploratory laparotomy, intraocular aspiration, amputation, and hysterectomy.
Nonsuppurative Complications
The nonsuppurative complications of S pyogenes infection are acute rheumatic fever and acute glomerulonephritis.
Rheumatic Fever
The prevalence of acute rheumatic fever (ARF) in the Western world decreased dramatically after World War II (0.5-1.88 cases per 100,000 school age children per year). In contrast, in India and Sri Lanka, the prevalence of ARF has remained 140/100,000 for children between 5 and 19 years of age. Socioeconomic factors seem to be important because the highest rates in all countries have been among the impoverished in large cities. Although improved living conditions and the development of penicillin have had important roles in reducing the prevalence of ARF in the United States, the decreases had begun before antibiotics were available.
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.
Post-streptococcal Glomerulonephritis
Acute glomerulonephritis (AGN) can follow either pharyngeal or skin infection and is associated with GAS strains possessing M types 12 and 49, respectively. During epidemics of skin or pharyngeal infection produced by a nephritogenic strain, attack rates of 10-15% have been documented with latent periods of 10 days after pharyngitis and 3 weeks after pyoderma. Nonspecific symptoms include lethargy, malaise, headache, anorexia, and dull back pain. The classic signs of AGN are all related to fluid overload and are manifested initially by edema, both dependent and periorbital. Hypertension develops in most patients and is usually mild. Severe cases may be characterized by ascites, pleural effusion, encephalopathy, and pulmonary edema, although evidence of heart failure per se is lacking.
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-Schonlein 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.
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.