Critical Care Medicine

Streptococcal infections/toxic shock syndrome

Streptococcal Toxic Shock Syndrome

Also known as: Toxic Shock Syndrome

Related conditions: Streptococcus pyogenes, Group A Streptococcus, Necrotizing Fasciitis

1. Description of the problem

Serious infections from group A Streptococcus (Streptococcus pyogenes) may occur in children and adults, often causing high morbidity and mortality. These infections should be considered in the differential diagnosis of acute shock syndromes —presenting both with fever and shock, or fever, rash, and shock. Early recognition of the type of clinical syndrome and appropriate management are critical to reduce complications.

Streptococcal toxic shock syndrome is a clinical entity that is often associated with a rapid onset shock like state and multiorgan system failure. In some cases, the findings of necrotizing fasciitis accompany or precede a diagnosis of streptococcal toxic shock and should be considered in the differential diagnosis.

Although certain risk factors may predispose to severe streptococcal infections, they can also occur among previously healthy adults and children. Toxic shock syndrome caused by Streptococcus pyogenes may initially be indistinguishable from that caused by Staphylococcus aureus, which should also be considered in the differential diagnosis.

Clinical features

The initial diagnosis of streptococcal toxic shock may be difficult, as patients frequently present with nonspecific symptoms; however, they may then suffer a precipitous collapse with hypotensive shock occurring within hours to 1 to 2 days of the onset of initial symptoms.

Certain key clinical factors may be important clues to the diagnosis of streptococcal toxic shock syndrome and include the following:

  1. Pain out of proportion to physical findings if a soft tissue focus of infection is involved.

  2. Active varicella infection in a child, with focal signs of skin infection, onset of toxic appearance, or fever persisting for longer than 4 days.

  3. Shock presenting in association with an erythrodermatous rash.

  4. Trauma, including both non-penetrating, penetrating, from minor to severe, also including hematomas.

  5. Nonsteroidal antiinflammatory drug (NSAID) use concurrently, which remains arguable based on currently available literature.

The clinical findings of streptococcal toxic shock syndrome can be divided into three phases:

Phase 1: The main presenting symptoms often appear similar to a viral syndrome, including fever, gastrointestinal upset (often including diarrhea), and severe myalgias. Mental status changes may also be present at this point, including confusion and in children, lethargy and somnolence.

If the inciting cause is related to an underlying soft tissue infection (the most common site of primary infection), pain may be severe and described as a crescendo pattern, with a notable hallmark being pain out of proportion to the physical findings present. More specific findings to the diagnosis include an erythrodermatous or scarlatiniform rash, nonpurulent conjunctival hyperemia, pharyngeal inflammation, and a strawberry tongue.

Phase 2: During this stage, the initial symptoms of phase 1 continue, with the addition of systemic derangements such as onset of tachycardia and tachypnea. If pain is present due to a focal infection, it may continue to increase in severity. At this stage occasionally patients seek medical attention and may be misdiagnosed with other causes unless a careful differential diagnosis is considered. During this stage, laboratory abnormalities may be present which may be nonspecific clues to the diagnosis.

Phase 3: Characterized by the onset of shock and organ failure. More severe mental status changes may be present, generally related to shock, such as dizziness, fainting, or frank obtundation. If a soft tissue focus is present, skin findings may occur, with an area of initial mild inflammation turning to a violaceous or dusky appearance, occasionally with bullae, and may rapidly progress over a 24-hour period. It is important to note that soft tissue crepitus is generally not present with monomicrobial streptococcal infection and its absence should not be used to rule out the possibility of necrotizing fasciitis.

Desquamation of the erythrodermatous rash (if present) is a late finding that may occur 1 to 2 weeks after the onset of the illness and can be particularly pronounced on the fingers, palms, and soles.

Key management points

The most important management point is the early recognition of the possibility of toxic shock syndrome, which requires a high index of suspicion. A missed diagnosis may lead to ineffective or inappropriate management. Key management points that should be included in the care of the patient are as follows:

Careful search for a focus if streptococcal toxic shock is suspected, especially for findings of soft tissue infection or necrotizing fasciitis. If a soft tissue focus is present surgical drainage may be necessary. If necrotizing fasciitis is considered possible, surgical exploration is indicated, as definitive therapy requires aggressive surgical debridement of involved tissue. Medical management alone is generally insufficient if fasciitis is present. Necrotizing fasciitis should be considered a true surgical emergency.

Imaging with computed tomography (CT) or magnetic resonance imaging (MRI) may suggest a focus, but neither is sufficiently sensitive to include or exclude fasciitis definitively compared with surgical exploration, or the option of biopsy with frozen sections for pathologic review.

In women a vaginal examination should be done to look for a retained tampon or foreign body (often associated with staphylococcal toxic shock, which has overlapping clinical findings).

Fluid resuscitation is critical in patients with toxic shock, and volume requirements can be tremendous.

In adults, significant amounts of IV fluids (10 to 20 L/day) may be required due to diffuse capillary leak and hypotension.

Hypoalbuminemia is commonly associated with toxic shock syndrome and may require replacement therapy. If blood pressure is refractory to volume resuscitation, serum hemoglobin should be checked and blood transfusion may be indicated as group A Streptococcus can produce hemolysins leading to hemolysis.

Broad spectrum antimicrobial therapy should be given as soon as possible.

Regimens will vary by institution and region, but generally should cover common causes of community onset septic shock, including coverage for Streptococcus pyogenes, Staphylococcus aureus (including MRSA), meningococcemia, tick-borne diseases in endemic areas (Rocky Mountain spotted fever and ehrlichiosis), and also possibly gram-negative rods, which may be acquired from a focus such as a urinary tract infection.

Therapy should ideally include a cell wall active agent against group A Streptococcus, as well as the addition of clindamycin, which has been shown to be helpful in reducing toxin production by organisms, as well as having greater activity in fulminant group A streptococcal infections with overwhelming bacterial load than beta-lactams.

If necrotizing fasciitis is considered possible, coverage for gram-negative flora and anaerobes should also be considered, as these infections may also be polymicrobial.

Close monitoring and management of clinical parameters such as perfusion, oxygenation, ventilation, and end organ dysfunction.

- Adult respiratory distress syndrome (ARDS) is a common complication of toxic shock syndrome, and occurs in over half of adult cases reported.

- Early mechanical ventilation may be necessary in patients with streptococcal shock.

- If hypovolemia does not respond to fluid resuscitation, additional support with vasopressor agents is indicated.

- Renal failure, a common complication of streptococcal toxic shock syndrome, may require dialysis.

- Additional modalities such as hemofiltration may have a therapeutic role but have not been widely studied in this specific population.

- Consider use of immune globulin intravenous (IGIV). IGIV use remains controversial in the management of streptococcal toxic shock syndrome but can be considered as an adjunctive modality.

2. Emergency Management

- A high index of suspicion is required for patients with previously mentioned clinical symptoms, especially those presenting with fever and shock, fever and rash, or soft tissue pain out of proportion to physical findings.

- Initial management should include a careful search for a potential focus of infection by physical examination.

- Hypotension may occur precipitously and this should be anticipated during the initial work-up with appropriate management options ready for use if necessary, eg, fluids, pressor agents, intubation supplies.

- Metabolic and electrolyte derangements can occur and should be evaluated for by performing tests of renal and hepatic function, coagulation, and serum chemistries (including albumin and calcium).

- If necrotizing fasciitis is suspected or possible, surgical consultation should be considered mandatory and occur as soon as possible.

- Early and appropriate empiric antimicrobial therapy has been shown to decrease overall mortality in patients with severe sepsis.

-Consideration should be given to early infectious disease consultation to guide diagnostic and therapeutic management.

Management points not to be missed

- A high index of suspicion is critical to the correct diagnosis of toxic shock syndrome, especially if necrotizing fasciitis is coinciding.

- Early surgical consultation and management is mandatory for necrotizing fasciitis.

- Hypocalcemia, hypoalbuminemia, thrombocytopenia, and disseminated intravascular coagulation can all occur precipitously with toxic shock syndrome and should be considered when evaluating the patient.

3. Diagnosis

Diagnostic criteria

Criteria for a clinical case definition of streptococcal toxic shock have been developed:

I. Isolation of group A Streptococcus:

A. From a normally sterile site (blood, cerebrospinal fluid, peritoneal fluid, or tissue biopsy specimen)

B. From a non-sterile site (throat, sputum, vagina, surgical wound, superficial skin lesion)

II. Clinical signs of severity:

A. Hypotension: systolic blood pressure 90 mm Hg or lower in adults or lower than the 5% percentile for age in children

B. Two or more of the following signs:

  • Renal impairment: creatinine 2 mg/dL or greater for adults or 2 times or more the upper limit of normal for age in child

  • Coagulopathy: platelet count 100,000/mm3 or less or disseminated intravascular coagulation

  • Hepatic involvement: serum aspartate aminotransferase, alanine aminotransferase, or total bilirubin twice or more the upper limit of normal

  • ARDS or evidence of diffuse capillary leak syndrome

  • A generalized erythematous macular rash that may desquamate

  • Soft tissue necrosis, including necrotizing fasciitis or myositis, or gangrene

Definite Case: Fulfills criteria IA and IIA and IIB

Probable Case: Fulfills criteria IB and IIA and IIB with no other cause being identified

The diagnosis of streptococcal toxic shock syndrome rests upon recognizing the compatible clinical findings noted above in the case definition. Other tests to consider that may be helpful depending upon the clinical presentation include the following:

  1. Cultures of blood and clinically involved sites of infection (soft tissue, sputum, abscess, throat, etc).

  2. Imaging if a soft tissue focus is suspected: MRI or CT scans may be helpful in the early evaluation of potential necrotizing fasciitis to pinpoint an affected area of disease but are not sensitive or specific enough to rule in or rule out the disease entirely. Prompt surgical consultation and exploration should not be delayed for imaging if necrotizing fasciitis is felt to be likely.

  3. Surgical exploration and/or frozen section biopsy are the definitive tests for the diagnosis of necrotizing fasciitis, which often accompanies toxic shock syndrome.

Useful lab studies

Although not diagnostic, supportive laboratory studies are helpful to evaluate and follow the metabolic derangements that may occur with toxic shock syndrome. These include:

Blood counts: Both leukopenia and leukocytosis have been reported with relatively equal frequencies. A marked left shift of the differential is common. Thrombocytopenia may be seen and can be an indicator of disseminated intravascular coagulopathy.

Serum chemistries:

- Renal function is impaired in a high proportion of patients presenting with toxic shock syndrome and may be present prior to the onset of fulminant shock.

- Hypoalbuminemia may occur secondary to capillary leak syndrome.

- Hypocalcemia may occur abruptly secondary to fat necrosis associated with necrotizing fasciitis.

- Creatine phosphokinase levels are often elevated in patients with necrotizing fasciitis.

- Metabolic acidosis may develop late in the course of disease.

- Acute phase reactants (erythrocyte sedimentation rate, C-reactive protein) are typically markedly elevated.

- Pulse oximitry and blood gas monitoring may be necessary to determine the need for mechanical ventilation.

How do I know this is what the patient has?

Treatment for toxic shock syndrome is most often initially empiric. Many other causes of community onset shock syndromes may have overlapping clinical scenarios.

Definitive diagnosis rests upon isolation of group A Streptococcus from a normally sterile body site along with compatible clinical symptoms. In many cases (up to 60% in some series) bacteremia is present in the setting of streptococcal toxic shock, which is helpful in confirming the diagnosis. In one large series of children presenting to pediatric intensive care units with streptococcal toxic shock syndrome, 69% had associated bacteremia, and 78% had an associated positive rapid streptococcus test.

These findings are in contrast to the major alternative diagnosis, staphylococcal toxic shock syndrome, in which bacteremia is an unusual finding.

The definitive diagnosis of necrotizing fasciitis, which is often associated with streptococcal toxic shock, rests upon direct surgical exploration and/or compatible frozen biopsy specimens.

Differential diagnosis

The differential diagnosis of streptococcal toxic shock syndrome includes

- Staphylococcal toxic shock syndrome

- Meningococcemia

- Rocky Mountain Spotted fever

- Ehrlichiosis

- Stevens-Johnson syndrome

- Kawasaki disease

- Urosepsis

- Streptococcal or staphylococcal scarlet fever

- Leptospirosis

- Legionnaire's disease

- Acute gastroenteritis

- Hemorrhagic fever viruses

- Measles virus

- Hemophagocytic lymphohistiocytosis

- Typhus

- Systemic lupus erythematosus

Confirmatory tests

Confirmation of the diagnosis typically comes from a combination of fulfilling the clinical criteria and recovery of group A streptococcus from a normally sterile site. The major common alternative differential diagnoses should also be evaluated for with appropriate diagnostic work-ups when indicated.

4. Specific Treatment

Broad spectrum antimicrobial therapy is indicated for patients presenting with septic shock. Until the etiology can be determined drugs active against multiple types of pathogens are indicated: this may include likely gram-positive agents, gram-negative agents, as well as the potential for atypical causes such as Rocky Mountain spotted fever. If methicillin resistant Staphylococcus aureus (MRSA) is endemic in the community, it may also need to be targeted in the initial coverage.

When toxic shock is strongly suspected, differentiation of that caused by Streptococcus pyogenes and S aureus can be very difficult and coverage should include agents active against both. For suspected toxic shock of unknown etiology, a regimen containing antistaphylococcal gram-positive coverage as well as the addition of clindamycin are typically indicated. In areas with a high rate of MRSA, this initial coverage should include agents active against MRSA, such as vancomycin, linezolid, daptomycin, or tigecycline. In areas with very low rates of MRSA, nafcillin, oxacillin, or cefazolin may be substituted.

Clindamycin (or an alternative protein synthesis inhibitor) should also be used at the start of therapy in suspected cases of toxic shock syndrome. This agent has been shown in vitro, in vivo, and in some human retrospective data to improve outcome in treatment of toxin-producing gram-positive infections, and toxic shock syndrome specifically. This activity is related to the ability of clindamycin to directly inhibit toxin production by the organisms.

In addition, for infections associated with a high bacterial organism load, clindamycin may have greater activity than beta-lactam drugs, given the potential suppression of penicillin-binding proteins and slower growth phases of organisms in the stationary phase of growth. Linezolid has also been shown in vitro to inhibit toxin production and may be considered an alternative for this purpose.

Once a definitive diagnosis of streptococcal infection has been made, penicillin G can be substituted for the initial more broad spectrum agent used empirically and clindamycin should be continued. There has been no documented resistance of Streptococcus pyogenes ever recorded to penicillin, and the organism remains exquisitely sensitive to beta-lactam agents.

Immune globulin intravenous (IGIV) use may be considered for suspected or proven cases of toxic shock syndrome, although a benefit on morbidity and mortality has not been definitively proven. IGIV has the theoretical activity of blocking in vitro T-cell activation by superantigens and thereby downregulating the ensuing inflammatory cascade. In addition IGIV may have direct neutralizing activity against group A Streptococcus, and to a lesser extent S aureus. Several studies have attempted to evaluate the use of IGIV for toxic shock syndrome with conflicting results.

A retrospective observational study utilizing historical controls showed 30-day survival of 67% in those receiving IGIV versus 34% in controls; however, it has been argued that the comparison groups were not equal and bias may have been introduced. In the only randomized controlled trial conducted to compare use of IGIV versus placebo for streptococcal toxic shock, a non–statistically-significant benefit in 28-day mortality of 10% in the treatment group versus 36% in the control group was achieved. This study was stopped early due to inability to achieve sufficient recruitment.

Finally, in a large retrospective, multicenter analysis of IGIV use for streptococcal toxic shock syndrome in children, no benefit to either mortality or length of stay was noted in 192 patients.

For these reasons, IGIV use may be considered for adjunctive therapy, but it is unclear if routine use is of benefit. Some experts recommend use when there has been no clinical response after the first 6 hours of supportive therapy, or in cases in which an undrainable focus or persistent oliguria with pulmonary edema are present.

Drugs and dosages

Penicillin G:

Adults: 24 million units/day in divided doses q4 hours

Children: 400,000 units/kg/day (to max of 24 million units/day) in divided doses q4 hours

Clindamycin:

Adults: 1800mg/day in divided doses q8 hours

Children: 30 to 40mg/kg/day in divided doses q 6 to 8 hours to max of 1800mg/day

Vancomycin:

Adults: 45 to 60mg/kg/day in divided doses q 8 to 12 hours

Children: 60mg/kg/day in divided doses q 6 to 8 hours

(IGIV):

No standard dosing recommendations can be made as the optimal dosing is not defined. Various regimens have been used including 150 to 400mg/kg/day for 5 days or a single dose of 1 to 2g/kg. A 3-day regimen of 1g/kg on day one followed by 0.5g/kg on days 2 and 3 was used in the only randomized controlled trial to date.

Refractory cases

For particularly refractory cases, consideration should first be given to searching for an undrained focus of infection. If necrotizing fasciitis is considered possible, surgical consultation is mandatory. If necrotizing fasciitis has been documented, wide debridement or further debridements may be necessary.

For non-responding patients, consideration should also be given to the use of IGIV as described above. Use of hemofiltration as an adjunctive measure has also been associated with a low mortality rate in one series and may be considered. Use of hyperbaric oxygen for adjunctive management of streptococcal toxic shock syndrome and necrotizing fasciitis has been described but has not been subjected to controlled trials and remains controversial.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

Early diagnosis and aggressive management are critical elements in the management of streptococcal toxic shock. Even with appropriate early management, patients may still suffer hemodynamic collapse. A high proportion (50% or more in some series) may develop ARDS and renal insufficiency. Even with therapy, mortality remains high, with many series reporting 20% to 50% mortality, even in modern era.

For these reasons, close monitoring of hemodynamic, respiratory, and metabolic status is important. Most patients should be initially managed in an intensive care setting. Frequent and close monitoring of renal function, serum chemistries, and coagulation factors is necessary, in particular carefully following for hypoalbuminemia and thrombocytopenia. Hypocalcemia should not be overlooked if a necrotizing soft tissue focus is suspected.

If bacteremia is present, blood cultures should be followed to document clearance. If a necrotizing soft tissue infection is present, repeated examinations to determine the need for debridement are necessary and may require intraoperative evaluations. Continued involvement of surgical consultants is critical in this setting.

Incorrect diagnosis

In the setting of a patient with suspected toxic shock being adequately treated continuing to worsen, alternative etiologies that are not currently being treated should be considered. However, it is difficult to use clinical worsening while on therapy as a single marker of lack of response due to a possible wrong diagnosis, as most patients with streptococcal toxic shock have hypotension and multiorgan system dysfunction at the time of presentation, and mortality rates remain high even with appropriate therapy.

However, new clinical findings that support a different syndrome or disease, or identification of an organism other than Streptococcus pyogenes from a diagnostic specimen should prompt consideration of a different diagnosis. In areas with endemic Rocky Mountain Spotted fever, consideration should also be given to that diagnosis at the time of presentation, and empiric therapy with doxycycline may be indicated.

Follow-up

For patients who recover fully, specific follow-up is not required. For those who develop persistent sequelae of their infection such as renal dysfunction, orthopedic disability from extensive soft tissue involvement, or other significant complications, follow-up with their primary medical doctor or appropriate specialists may be indicated.

Pathophysiology

Streptococcus pyogenes is a gram-positive, catalase-negative organism with chains found on typical colony morphology.

Streptococcal toxic shock is caused by strains of Streptococcus pyogenes harboring toxin-producing genes whose products are capable of acting as superantigens. Most cases of streptococcal toxic shock have been related to infection with Streptococcus pyogenes M types 1 or 3. Superantigens are protein toxins that are capable of triggering excessive and nonconventional T-cell activation. This effect leads to activation of other cell types, as well as significant cytokine/chemokine release.

The resultant cascade may ultimately cause a systemic inflammatory response syndrome along with a pro-coagulant state, leading to capillary leakage and shock. Individual susceptibility to toxic shock syndrome may be related to the presence or absence of pre-existing antibodies against streptococcal superantigen toxins at the time of infection. These antibody levels may be lower in those with invasive disease and toxic shock than in healthy controls.

Epidemiology

Streptococcal toxic shock syndrome may occur in healthy children and adults but has a higher incidence at the extremes of age, those with underlying chronic illness, after varicella infection, and possibly after use of NSAIDs.

The incidence of invasive group A streptococcal infection has been estimated to be between 1.5 to 5.2 cases/100,000 people per year in various series. The incidence of toxic shock syndrome associated with streptococcal infections overall has been estimated to occur in 5% to 14% of infections from various sources. The incidence of secondary cases of invasive disease in households with a known primary case is increased, but currently there are no consensus recommendations for prophylaxis of contacts.

Prognosis

Streptococcal toxic shock syndrome is a serious disease with significant mortality and carries a much higher mortality rate than that seen with staphylococcal toxic shock. Despite advances in supportive care and medications, mortality rates have not fallen significantly from early reports. Mortality has generally been reported in the 20% to 50% range. One recent report in Europe showed a 44% mortality rate in those with streptococcal toxic shock.

Mortality rates in children have varied, with some reports showing rates below 5%, and others showing rates equal to adults of 20% to 30%. One study of outcomes in children with streptococcal toxic shock syndrome reported that 100% developed shock and organ dysfunction, 78% developed coagulopathy, 71% developed neurologic dysfunction, and 68% developed respiratory failure. In this series, 34.2% of children died, and 26.8% of survivors had residual sequelae.

Special considerations for nursing and allied health professionals.

In general isolation for group A streptococcal infections associated with pharyngitis or pneumonia should include droplet precautions until at least 24 hours of effective antibiotic therapy has been given. For those with extensive soft tissue disease or draining wounds, contact precautions are also indicated for a minimum of 24 hours after start of effective antibiotics.

What's the evidence?

Pickering, LK, Baker, CJ, Kimberlin, DW, Long, SS. "Group A streptococcal infections". Red Book: 2009 Report of the Committee on Infectious Diseases. American Academy of Pediatrics. 2009. pp. 616-628.

(Standard reference for pediatric infectious disease management with up-to-date consensus treatment recommendations)

Lappin, E, Ferguson, AJ. "Gram-positive toxic shock syndromes". Lancet Infect Dis. vol. 9. 2009. pp. 281-90.

(Excellent and recent review on both streptococcal and staphylococcal toxic shock syndromes)

Bisno, AL, Stevens, DL, Mandell, GL, Bennett, JE, Dolin, R. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. Churchill Livingston, Elsevier Inc. 2010. pp. 2593-2610.

(Authoritative and comprehensive text on streptococcal infections including toxic shock syndrome)

"Defining the group A streptococcal toxic shock syndrome. Rationale and consensus definition. The Working Group on Severe Streptococcal Infections". JAMA. vol. 269. 1993. pp. 390-1.

(Consensus case definition of streptococcal toxic shock that remains the standard)

Stevens, DL, Tanner, MH, Winship, J, Swarts, R, Ries, KM, Schlievert, PM, Kaplan, E. "Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A". N Engl J Med. vol. 321. 1989. pp. 1-7.

(Landmark early study describing the clinical characteristics of severe streptococcal infections including toxic shock syndrome)

Stegmayr, B, Björck, S, Holm, S, Nisell, J, Rydvall, A, Settergren, B. "Septic shock induced by group A streptococcal infection: clinical and therapeutic aspects". Scand J Infect Dis. vol. 24. 1992. pp. 589-97.

(Study describing management aspects of severe group A streptococcal infections, including the potential utility of plasma exchange)

Rodríguez-Nuñez, A, Dosil-Gallardo, S, Jordan, I. "Clinical characteristics of children with group A streptococcal toxic shock syndrome admitted to pediatric intensive care units". Eur J Pediatr. vol. 170. 2011. pp. 639-44.

(Recent article describing the clinical characteristics of children with severe toxic shock syndrome)

O'Loughlin, RE, Roberson, A, Cieslak, PR, Lynfield, R, Gershman, K, Craig, A. "The epidemiology of invasive group A streptococcal infection and potential vaccine implications: United States, 2000-2004". Clin Infect Dis. vol. 45. 2007. pp. 853-62.

(Major epidemiologic study of severe group A streptococcal infections in the United States)

Lamagni, TL, Darenberg, J, Luca-Harari, B, Siljander, T, Efstratiou, A, Henriques-Normark, B, Jasir, A. "Epidemiology of severe Streptococcus pyogenes disease in Europe". J Clin Microbiol. vol. 46. 2008. pp. 2359-67.

(Recent article highlighting the epidemiology and mortality of severe group A streptococcal infections)

Laupland, KB, Davies, HD, Low, DE, Schwartz, B, Green, K, McGeer, A. "Invasive group A streptococcal disease in children and association with varicella-zoster virus infection. Ontario Group A Streptococcal Study Group". Pediatrics. vol. 105. 2000. pp. E60.

(Study describing the epidemiologic and clinical differences between children and adults with streptococcal toxic shock syndrome, in particular the significant association of varicella infection with development of toxic shock in children)

Stevens, DL, 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. vol. 158. 1988. pp. 23-8.

(In vivo model showing the superior efficacy of clindamycin versus beta-lactam drugs for severe group A streptococcal infections)

Coyle, EA, Cha, R, Rybak, MJ. "Influences of linezolid, penicillin, and clindamycin, alone and in combination, on streptococcal pyrogenic exotoxin a release". Antimicrob Agents Chemother. vol. 47. 2003. pp. 1752-5.

(Important article describing the in vitro ability of clindamycin and linezolid to decrease superantigen toxin levels)

Kaul, R, McGeer, A, Norrby-Teglund, A, Kotb, M, Schwartz, B, O'Rourke, K. "Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome—a comparative observational study. The Canadian Streptococcal Study Group". Clin Infect Dis. vol. 28. 1999. pp. 800-7.

(The first major article describing the potential benefit of IGIV use for toxic shock syndrome)

Darenberg, J, Ihendyane, N, Sjölin, J, Aufwerber, E, Haidl, S, Follin, P. "Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial". Clin Infect Dis. vol. 37. 2003. pp. 333-40.

(The only randomized controlled trial evaluating the use of IGIV for streptococcal toxic shock syndrome to date. Results were not statistically significant, and the study was closed early, but trends towards benefit were noted.)

Shah, SS, Hall, M, Srivastava, R, Subramony, A, Levin, JE. "Intravenous immunoglobulin in children with streptococcal toxic shock syndrome". Clin Infect Dis. vol. 49. 2009. pp. 1369-76.

(Large, multicenter, retrospective review of use of IGIV in children with streptococcal toxic shock syndrome showing no benefit to mortality or length of hospital stay)
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