A. Organisms

1. Pyogenic (pus-forming) gram positive organism
2. ß-hemolytic streptococci - cultures on blood agar plates completely hemolyze media
3. Common in skin infections, pharyngitis
   1. Simiple skin infections - impetigo (pyoderma), erysipelas
   2. Toxic Shock Syndrome
   3. Necrotizing Fasciitis
   4. Scarlet Fever
4. GAS Post-infectious Autoimmune Sequellae
   1. Post-Streptococcal Glomerulonephritis
   2. Acute Rheumatic Fever and Rheumatic Heart Disease (see below)
   3. Acute infantile hemorrhagic edema (AIHE; see below)
   4. Note: streptococci associated with rheumatic fever rarely cause glomerulonephritis

B. Skin Infections

1. Impetigo (Pyoderma)
   1. Superficial skin infection usually in children
   2. Macules or papules progressing rapidly to vesicles, pustules, exudative crusts
   3. Often associated with insect bites, rhinorrhea, or minor abrasions
   4. Usually caused by ß-hemolytic GAS, but increasingly by staphyloccci
   5. Risk for development of glomerulonephritis but not rheumatic fever
   6. Penicillin IM x 1 or erythromycin is given unless S. aureus is suspected
   7. Topical potent therapy with mupirocin (Bactroban®, apply tid) is very effective
   8. Retapamulin (Altabax®) 1% ointment (pleuromutilin antibiotic) is FDA approved for treatment of bullous and and non-bullous impetigo and also covers S. aureus [17]
2. Erysipelas
   1. Superficial skin infection, bright red, indurated skin, usually in young adults
   2. Warmth, erythema, pain, leukocytosis, fever, lymphadenitis are most common
   3. Usually caused by Group A ß-hemolytic streptococci
   4. Some cases in newborns caused by Groups B Strep
   5. Organism can rarely be aspirated from advancing edge
   6. Penicillin iv or po, Clindamycin, or first generation cephalosporin
   7. First generation cephalosporins, such as cefalexin or cephadroxil, may also be used
3. Cellulitis
   1. Much more common cause than staphylococci
   2. When seen, often associated with lymphangitis (inflammation of lymphatic ducts)
   3. Lymphangitis appears as red streaking without involvement of overlying skin
   4. Gangrenous or crepitant cellulitis may occur (see below)
   5. May progress to invasive streptococcal infection, necrotizing fasciitis, myonecrosis
4. Most strains of GAS prevalent on the skin do not cause post-infectious autoimmune diseases

C. Poststreptococcal GN [2]

1. Most common type of postinfectious GN
2. Incidence <20/100,000, usually in young persons, 2-12 years old
3. Pathogenesis
   1. Formation of immune complexes including antibodies and streptococcal antigens
   2. Localization (deposition) on subepithelial portion of glomerular basement membrane
   3. Initiate inflammatory response, including Complement deposition (reduced serum levels)
   4. This leads to localized mesangial and endothelial cell proliferation
   5. Identiy of nephritogenic strep antigen not currently known
4. Serology
   1. Anti-streptolysin O (ASO) Antibodies rise in ~75% of cases
   2. Titers of ASO rise within 10-14 days; declines over 1-6 months
   3. Anti-DNase B and Anti-hyaluronidase rise more quickly
   4. Elevation in any of the titers will detect ~100% of persons with recent strep infection
   5. Note that ASO titers rise in pharangitis, not in cutaneous disease
   6. Streptococcal antigen M serotypes 12,1, and 4 are especially associated with GN
   7. Anti-Streptokinase, M-protein specific tests, and anti-NADase can also be determined
5. Symptoms and Signs
   1. Usually follows pharyngitis
   2. Many patients will have impetigo
   3. Gross hematuria in ~30%
   4. Edema in ~85%, Hypertension ~70%
   5. Usually resolves within 2 weeks of onset
6. Evaluation
   1. See below for general evaluation
   2. ASO, Anti-DNase B titers should be obtained
   3. Serum complement levels usually depressed
   4. 24 hour urine collection for protein and creatinine
   5. If resolution does not occur within 2 weeks consider other causes
   6. Renal biopsy should be considered for prolonged disease only
7. Treatment
   1. Aggressive treatment of streptococcal infection
   2. Rest, Fluid and salt restriction
   3. Correction of electrolyte abnormalities and hypertension
   4. Recovery is ~90%, with ~1% mortality in past, and chronic disease in 5-10%

D. Acute Rheumatic Fever [16]

1. Diagnosis based on Jones' Criteria
   1. Carditis - pancarditis (peri-, myo-, endocarditis / vasculitis)
   2. Arthritis, migratory, polyarticular with fevers, Jaccoud's Arthropathy (swan-neck)
   3. Subcutaneous Nodules: firm, usually over bony prominences or tendons
   4. Erythema marginatum - evanescent pink rash, trunk and proximal extremities
   5. Chorea (Sydenham's) - may include confusion or delirium
2. Mnemonic of Jones' Criteria
   1. "CANES"
   2. Carditis
   3. Arthritis
   4. Nodules
   5. Erythema
   6. Sydenham's Chorea
3. Minor Symptoms
   1. Arthralgia
   2. Fever
   3. Prolonged PR intervals
   4. Laboratory abnormalities
4. Two major or one major and two minor Jones' criteria to make diagnosis of rheumatic fever
5. World Health Organization (WHO) Criteria
   1. Chorea and indolent carditis do not require evidence of antecedent GAS
   2. First episode: as per Jones' Criteria
   3. Recurrent episode: in a patient without established RHD as per first episode
   4. In a patient with estalished RHD: requires 2 minor manifestations + evidence of prior GAS
   5. Or evidence of prior GAS as per Jones' Criteria, but with addition of recent scarlet fever

E. Toxic Shock Syndrome

1. Majority of cases caused by Staphylococcus aureus
2. Group A Streptococcus is also a major cause [1,4]
   1. Severe, toxic-shock-like cases often associated with pharyngitis, not rheumatic fever
   2. Necrotizing fasciitis, with or without myonecrosis, is present in ~50% of cases
   3. Group A ß-hemolytic S. pyogenes associated with scarlet fever also described
3. Symptoms and Signs
   1. Similar for streptococcal and staphylococcal toxic shock
   2. High Fever - often >102°F
   3. Nausea, Vomiting, Myalgias
   4. Rash - Often with mucous membrane involvement; desquamation of may occur
   5. Headache, Confusion
   6. WBC > 15K/µL in ~50% of patients
   7. Hypotension - quite refractory in many cases
   8. Severe progression may occur requiring intensive care managment

F. Necrotizing Fasciitis [5,7,8]

1. Necrotizing Fasciitis Type 2 is due to Group A streptococcus [4,6,8]
2. Overall incidence is increasing due to invasive Group A streptococci [9]
   1. Patients with underlying chronic diseases at highest risk
   2. Older patients at increased risk
   3. Persons with contact >4 hours with carrier of organism at increased risk
3. Symptoms
   1. Gangrenous or crepitant cellulitis
   2. Usual focus is a local superficial wound with spreading
   3. Pain - often excruciating
   4. Alternatively, complete anesthesia (neuronal death) may be seen
   5. Erythema
   6. Edema and/or Crepitance is usually marked
   7. Muscle damage may occur with creatine kinase leak
4. Systemic symptoms out of proportion to local reaction
   1. Hypotension
   2. Rhabdomyolysis with renal failure
   3. Left Ventricular failure
   4. Toxic-Shock like syndrome (~50% of patients) [9]
5. Treatment [1,6]
   1. Prompt surgical exploration and debridgement is essential for recovery
   2. Gram positive antibiotic coverage with clindamycin ± penicillin
   3. Consider vancomycin, oxacillin, cefazolin instead of penicillin
   4. Single dose of aminoglycoside only (high risk for renal failure)
   5. Blood cultures, wound culture and Gram stain should aid antibiotic selection
   6. Intravenous Fluids (consider added bicarbonate for severe acidosis)
   7. Pulmonary artery catheter may be helpful in assessing cardiovascular status
6. Poor Prognostic Features [9]
   1. Increased age
   2. Hypotension
   3. Bacteremia
   4. No correlation with serotype or exotoxin genes
7. Overall mortality is 20-50% despite current intensive care

G. Pharyngitis

1. Most often caused by group A streptococcus (note carrier rate in adults ~20%)
2. Groups C and G may also be causative in humans
3. Clinical Factors Suggestive of Streptococcal Pharyngitis [12]
   1. Tonsillar exudate
   2. Pharyngeal exudate
   3. Exposure to strep throat infection within previous 2 weeks
   4. Clinical characteristics alone are not sufficient for definitive diagnosis [13]
4. Laboratory [14]
   1. Very rapid, office-based optical immunoassay is available (96% sens, 89% spec) [15]
   2. Throat culture should be obtained and is probably most cost effective
   3. Complete blood counts with differential should be obtained
   4. Mononucleosis should also be ruled out with monospot test
   5. Empirical treatment is not appropriate nor cost effective [14]
5. Complications
   1. Peritonsillar abscess
   2. Retropharyngeal abscess - especially if patient has a stiff neck
   3. Scarlet fever
   4. Acute Rheumatic Fever
   5. Glomerulonephritis
   6. Bronchitis / pneumonia
6. Glomerulonephritis
   1. Acute, rapidly progressive glomerulonephritis (red cell casts, proteinuria)
   2. Early antibiotic therapy may not prevent disease
7. Treatment
   1. Penicillin 250mg po qid x 10 days or 1.2MU PCN benzathine IM x 1
   2. Amoxicillin orally once daily is not as effective as penicillin 2-4 times per day [10]
   3. Penicillin V twice daily is as effective as penicillin given 3-4 times per day [10]
   4. Erythromycin 250mg qid or 1° Cephalosporin (caution) x 10d in PCN allergy
   5. Ampicillin (and possibly Amoxicillin) is avoided because if mononucleosis is (also) present there is a high incidence (~95%) of severe rash
   6. Course of therapy must be maintained for 10 days for oral agents
   7. Oral saline gargles offer symptomatic relief

H. Scarlet Fever

1. Usually caused by group A ß-hemolytic streptococcus producing an erythrogenic toxin
2. Diffuse, macular red rash usually appears 2 days after onset of sore throat
3. May have 1-2mm punctate elevations (leading to "sandpaper" rough texture of skin)
4. Rash is more intense along skin folds
5. Soft palate may also show elevations and erythema
6. Rash lasts 4-5 days and may be followed by extensive desquamation
7. Extremely high fever may occur; high fatality rates in pre-antibiotic era

I. Diagnosis of Streptococcal Infections

1. Clinical setting usually most helpful
2. For question of pharyngitis, rapid, office-based antibody tests are available
3. Serological Analysis can be helpful but usually require 2-3 weeks to become positive
   1. Anti-DNAse B Antibody (Ab) - elevated in both pharyngitis and cutaneous disease
   2. Anti-Streptolysin O (ASO) Ab - elevated in pharyngitis (~85% of cases)
   3. Anti-hyaloronidase Ab- less common; elevated in all streptococcal infections
   4. Anti-streptokinase Ab - may impact use of streptokinase for thrombolysis
   5. Anti-NADase Ab
4. Typing of M-protein can be done for patients with post-streptococcal autoimmune disease

J. Treatment [11]

1. No resistance to pencillin is observed in CLINICAL isolates
2. Other ß-lactams may be useful in penicillin allergic patients
   1. Organisms are nearly always sensitive to macrolides and clindamycin
   2. All organisms sensitive to vancomycin
3. Dosage and course are determined by type of infection and host response

K. Acute Infantile Hemorrhagic Edema (AIHE) [3]

1. Formerly Seidlmayer Cockade Purpura or Finkelstein's Disease
2. Uncommon small vessel vasculitic condition
3. Often follows infection, vaccination, or drugs
4. Most commonly seen in children
5. Symptoms and Signs
   1. Generalized symmetric rash
   2. Medallion-like ecchymotic target lesions
   3. Scalloped rosette-shaped borders
   4. Some lesions hemorrhage (under skin)
   5. Leucocytosis and elevated inflammatory markers (ESR, CRP)
   6. Check ASO titers
   7. Skin biopsy with leucocytoclastic vasculitis
6. Typically benign, self-limited course

References

1. Working Group on Severe Streptococcal Infections. 1993. JAMA. 269(3):390
2. Black RM and Meehan SM. 1995. NEJM. 332(16):1083
3. Braun-Falco M and Abeck D. 2002. Lancet. 360(9328):210 (Case Review)
4. Hoadley DJ and Mark EJ. 2002. NEJM. 347(11):831 (Case Record)
5. Yong JM. 1994. Lancet. 343:1427
6. Hoge CW, Schwartz B, Talkington DF, et al. 1993. JAMA. 269:384
7. Bisno AL and Stevens DL. 1996. NEJM. 334(4):240
8. Davies HD, McGeer A, Schwartz B, et al. 1996. NEJM. 335(8):547
9. Kaul R, McGeer A, Low DE, et al. 1997. Am J Med. 103(1):18
10. Lan AJ and Colford JM Jr. 2000. Pediatrics. 105:E19
11. Choice of Antibacterial Drugs. 2001. Med Let. 43(1111):69
12. Ebell MH, Smith MA, Barry HC, et al. 2000. JAMA. 284(22):2912
13. Bisno AL. 2003. Ann Intern Med. 139(2):150
14. Neuner JM, Hamel MB, Phillips RS, et al. 2003. Ann Intern Med. 139(2):113
15. Gerber MA, Tanz RR, Kabat W, et al. 1997. JAMA. 277(11):899
16. Carapetis JR, McDonald M, Wilson NJ. 2005. Lancet. 366(9480):155
17. Retapamulin. 2008. Med Let. 50(1280):13