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A Recurrence of Group A A Recurrence of Group A Streptococcal Toxic Shock Streptococcal Toxic Shock Syndrome at GUH: Syndrome at GUH: Is there ever a Is there ever a good outcome? good outcome? Jennifer Vittorio, MD Jennifer Vittorio, MD Internal Medicine-Pediatrics Internal Medicine-Pediatrics Georgetown University Hospital Georgetown University Hospital

A Recurrence of Group A Streptococcal Toxic Shock Syndrome at

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Page 1: A Recurrence of Group A Streptococcal Toxic Shock Syndrome at

A Recurrence of Group A A Recurrence of Group A Streptococcal Toxic Shock Streptococcal Toxic Shock Syndrome at GUH: Syndrome at GUH: Is there Is there

ever a good outcome?ever a good outcome?

Jennifer Vittorio, MDJennifer Vittorio, MD

Internal Medicine-PediatricsInternal Medicine-Pediatrics

Georgetown University HospitalGeorgetown University Hospital

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HistoryHistory CC:CC: Transfer from OSH with Septic Shock Transfer from OSH with Septic Shock

HPI:HPI: TC is 47 yo Caucasian female who was in her usual state TC is 47 yo Caucasian female who was in her usual state

of health until 1 week prior to admission at which time of health until 1 week prior to admission at which time she reportedly had a brief 24-hour “viral-illness”she reportedly had a brief 24-hour “viral-illness”

Subsequently developed 2-3 days of watery diarrhea and Subsequently developed 2-3 days of watery diarrhea and abdominal painabdominal pain

She presented to OSH on 4/8/09 at 5PM with evidence of She presented to OSH on 4/8/09 at 5PM with evidence of respiratory and circulatory failure, was intubated and respiratory and circulatory failure, was intubated and admitted to MICU for further monitoring admitted to MICU for further monitoring

She was started on vasopressors and broad-spectrum She was started on vasopressors and broad-spectrum abx including vancomycin, clindamycin and zosynabx including vancomycin, clindamycin and zosyn

Her LUE was noted to be mottled and cyanotic with Her LUE was noted to be mottled and cyanotic with delayed CRT. Venous dopplers were negative for DVT delayed CRT. Venous dopplers were negative for DVT

Clinical condition continued to decline over the course of Clinical condition continued to decline over the course of the evening. She developed rhabdomyolysis, renal the evening. She developed rhabdomyolysis, renal failure and refractory hypotensionfailure and refractory hypotension

She was transferred to GUH MICU on 4/9/09 at 3PM for She was transferred to GUH MICU on 4/9/09 at 3PM for further evaluation and treatmentfurther evaluation and treatment

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History cont.History cont. PMH:PMH: Breast Cancer dx 2005 s/p CTX, XRT Breast Cancer dx 2005 s/p CTX, XRT

– in remission– in remission PSH:PSH: Breast lumpectomy Breast lumpectomy MEDS:MEDS: No home meds No home meds MEDS on Transfer:MEDS on Transfer: Levophed gtt, Levophed gtt,

Neosynephrine gtt, Vancomycin, Zosyn, Neosynephrine gtt, Vancomycin, Zosyn, Clindamycin, Heparin 5000 units subq tid, Clindamycin, Heparin 5000 units subq tid, Dilaudid, Fentanyl, ProtonixDilaudid, Fentanyl, Protonix

ALL:ALL: NKDA NKDA Fam Hx:Fam Hx: DM, CAD DM, CAD Soc Hx:Soc Hx: Works for EPA. No tobacco, Works for EPA. No tobacco,

alcohol or illicit drug use. No recent travel. alcohol or illicit drug use. No recent travel. 8 year old healthy son. Brother is next of 8 year old healthy son. Brother is next of kin & provides much of the historykin & provides much of the history

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Physical ExamPhysical Exam Vitals:Vitals: T – 37.0 BP – 110/86 P – 84 RR – T – 37.0 BP – 110/86 P – 84 RR –

14 PaO2 – 100% AC 500/24/10 FiO2 100%14 PaO2 – 100% AC 500/24/10 FiO2 100% GEN:GEN: Intubated, sedated on vent Intubated, sedated on vent HEENT:HEENT: NCAT; PERRL; anicteric sclera; NCAT; PERRL; anicteric sclera;

mottled/cyanotic MMmottled/cyanotic MM NECK:NECK: Supple, no thyromegaly, no LAD Supple, no thyromegaly, no LAD CV:CV: S1, S2, distant heart sounds, no m/r/g S1, S2, distant heart sounds, no m/r/g PULM:PULM: CTAB ant CTAB ant ABD:ABD: NABS, soft, NT/ND, no hsm NABS, soft, NT/ND, no hsm EXT: EXT: Mottled, cool, ecchymosis noted. Mottled, cool, ecchymosis noted.

Dopplerable pulses LUEDopplerable pulses LUE SKIN: SKIN: Bullous lesion noted LUEBullous lesion noted LUE VAGINAL:VAGINAL: No foreign objects in vaginal No foreign objects in vaginal

vaultvault

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Bullous LesionBullous Lesion

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Necrosis of FingertipsNecrosis of Fingertips

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Laboratory StudiesLaboratory Studies CBC:CBC:

BMP:BMP:

LFTS:LFTS: 2.7 2.7 1.21.2

1.01.0

433433 121121

12.7 35.

8

52

N45 B21 L4 M27 E1

1383.7

1179

463.1

94

58

12.112.1

5.31.56.5

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Laboratory Studies cont.Laboratory Studies cont.

Lactic Acid: Lactic Acid: 13.013.0 Lipase: 16Lipase: 16 Troponin I: 0.470Troponin I: 0.470 CPK: CPK: 24,68324,683 PT/INR: 30.7/PT/INR: 30.7/2.902.90 D dimer: >200D dimer: >200 Fibrinogen: 179Fibrinogen: 179 Blood Cx: Blood Cx: Gram + Cocci Gram + Cocci

chainschains

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Hospital CourseHospital Course Admitted to MICU and continued on early Admitted to MICU and continued on early

goal directed therapy for septic shockgoal directed therapy for septic shock Infectious disease, orthopedic, limb service Infectious disease, orthopedic, limb service

consultation were obtained at the time of consultation were obtained at the time of admissionadmission

Diagnosed with Group A strep toxic shock Diagnosed with Group A strep toxic shock syndrome & LUE necrotizing fasciitissyndrome & LUE necrotizing fasciitis

Pt was started on abx therapy with Pt was started on abx therapy with meropenem, clindamycin, vancomycinmeropenem, clindamycin, vancomycin

Received a course of IVIGReceived a course of IVIG Taken to OR around 8 PM evening of Taken to OR around 8 PM evening of

admission and underwent LUE amputation. admission and underwent LUE amputation. Diagnosis of necrotizing fasciitis confirmedDiagnosis of necrotizing fasciitis confirmed

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Hospital Course cont.Hospital Course cont. Myonecrosis disseminated to remaining Myonecrosis disseminated to remaining

3 limbs & thoracic cavity3 limbs & thoracic cavity 4/15/09: Patient underwent bilateral 4/15/09: Patient underwent bilateral

knee disarticulation & right lateral thigh knee disarticulation & right lateral thigh fasciotomyfasciotomy

4/17/09: Patient again hypotensive 4/17/09: Patient again hypotensive requiring vasopressor supportrequiring vasopressor support

Develops further necrosis of RUE, LE Develops further necrosis of RUE, LE stumps, & perineum stumps, & perineum

Pt continued to deteriorate. Code status Pt continued to deteriorate. Code status changed to DNR. Patient died on changed to DNR. Patient died on 4/19/094/19/09

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GAS Toxic Shock GAS Toxic Shock SyndromeSyndrome GAS is a common pathogen of the throat and GAS is a common pathogen of the throat and

skin that causes pharyngitis and a spectrum ofskin that causes pharyngitis and a spectrum ofskin and soft tissue infectionsskin and soft tissue infections

The incidence of invasive GAS infection in The incidence of invasive GAS infection in North America and Europe is an estimated 3.5 North America and Europe is an estimated 3.5 cases per cases per 100,000 persons annually100,000 persons annually11

8-14% of patients who develop invasive GAS 8-14% of patients who develop invasive GAS infection will also develop GAS TSSinfection will also develop GAS TSS11

It is important to recognize GAS infections It is important to recognize GAS infections early and to treat appropriately in order to early and to treat appropriately in order to limit toxin production and decrease morbidity limit toxin production and decrease morbidity and mortalityand mortality

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Streptococcus pyogenesStreptococcus pyogenes

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PathogenesisPathogenesis GAS TSS is mediated by toxins that act as GAS TSS is mediated by toxins that act as

superantigens which bypass the usual antigen-superantigens which bypass the usual antigen-mediated immune response resulting in release mediated immune response resulting in release of large quantities of inflammatory cytokinesof large quantities of inflammatory cytokines

The major virulence factor of GAS is The major virulence factor of GAS is M proteinM protein M1 and M3 are the most virulentM1 and M3 are the most virulent M protein makes the organism resistant to M protein makes the organism resistant to

phagocytosis by inhibiting activation of alternate phagocytosis by inhibiting activation of alternate complement pathways on the cell surfacecomplement pathways on the cell surface

Streptococcal exotoxinsStreptococcal exotoxins are also elaborated by are also elaborated by GASGAS Pyrogenic exotoxin A (SPEA) and B (SPEB) are found Pyrogenic exotoxin A (SPEA) and B (SPEB) are found

in majority of casesin majority of cases Trigger massive T cell proliferation and cytokine Trigger massive T cell proliferation and cytokine

release resulting in capillary leak and tissue damagerelease resulting in capillary leak and tissue damage

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Why are certain individuals more Why are certain individuals more susceptible to severe GAS susceptible to severe GAS

infections?infections? Studies have suggested that the presence of Studies have suggested that the presence of

specific anti-M Ab confers some degree of host specific anti-M Ab confers some degree of host protection from that strain of GAS. Once infected protection from that strain of GAS. Once infected however, these Ab do not appear to offer however, these Ab do not appear to offer protection from STSS. protection from STSS.

It has been proposed that It has been proposed that HLA Class IIHLA Class II allelic allelic variation contributes to differences in severity of variation contributes to differences in severity of invasive GAS infections through their ability to invasive GAS infections through their ability to regulate cytokine response triggered by regulate cytokine response triggered by streptococcal superantigensstreptococcal superantigens22

The complex immune cascade is initiated by the The complex immune cascade is initiated by the GAS superantigen and the interplay with one’s GAS superantigen and the interplay with one’s immune system determines the severity of illnessimmune system determines the severity of illness

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Risk FactorsRisk Factors Age <9 yr or Age <9 yr or

>60 yr>60 yr VaricellaVaricella HIV/AIDSHIV/AIDS CancerCancer DiabetesDiabetes Heart DiseaseHeart Disease Lung DiseaseLung Disease ?NSAIDS?NSAIDS

Alcohol Abuse Alcohol Abuse Nursing Home Nursing Home

ResidentResident Minor TraumaMinor Trauma Injury resulting Injury resulting

in hematoma, in hematoma, bruising, muscle bruising, muscle strainstrain

Surgical Surgical ProceduresProcedures

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DiagnosisDiagnosisThe Working Group on Severe Streptoccocal The Working Group on Severe Streptoccocal

Infections estInfections estthe following clinical guideline for diagnosis of the following clinical guideline for diagnosis of

GAS TSS:GAS TSS:33

1. Isolation of GAS from sterile site1. Isolation of GAS from sterile site 2. Hypotension2. Hypotension

Adult SBP < 90 mmHgAdult SBP < 90 mmHg Child SBP < 5Child SBP < 5thth % for age % for age

ANDAND two or more of the following: two or more of the following: Renal impairmentRenal impairment CoagulopathyCoagulopathy Liver involvementLiver involvement ARDSARDS Erythematous macular rash, may desquamateErythematous macular rash, may desquamate Soft tissue necrosisSoft tissue necrosis

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TreatmentTreatment AntibioticsAntibiotics

Beta-lactam antibiotics such as penicillin GBeta-lactam antibiotics such as penicillin G Reduction in efficacy of PCN has been demonstrated Reduction in efficacy of PCN has been demonstrated

when a high density of organisms is present (“Eagle when a high density of organisms is present (“Eagle Effect”)Effect”)

Clindamycin (inhibits protein synthesis)Clindamycin (inhibits protein synthesis)

IVIGIVIG Contains neutralizing antibody to streptococcal Contains neutralizing antibody to streptococcal

exotoxinexotoxin Efficacy has yet to be proved in RCTEfficacy has yet to be proved in RCT

SurgerySurgery Should be considered in pt who initially have fever, Should be considered in pt who initially have fever,

excruciating pain followed by progression to soft excruciating pain followed by progression to soft tissue swelling and formation of violaceous vesicles tissue swelling and formation of violaceous vesicles and bullaeand bullae

Debridement of all infected tissue should be carried Debridement of all infected tissue should be carried out at first operative procedureout at first operative procedure

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Eagle EffectEagle Effect First described by Eagle in 1952First described by Eagle in 195244

High inoculum of organisms encounteredHigh inoculum of organisms encounteredin overwhelming infections leads to rapidin overwhelming infections leads to rapidattainment of the stationary growth phase attainment of the stationary growth phase

Subsequent decrease in expression of cell Subsequent decrease in expression of cell wall penicillin binding proteins (PBPs), the wall penicillin binding proteins (PBPs), the molecular targets of penicillin, renders molecular targets of penicillin, renders penicillin less effectivepenicillin less effective

Clindamycin retains efficacy by inhibiting Clindamycin retains efficacy by inhibiting protein synthesisprotein synthesis

Clindamycin is also a potent suppressor of Clindamycin is also a potent suppressor of toxin formation and facilitates phagocytosis toxin formation and facilitates phagocytosis by inhibition of M-protein synthesisby inhibition of M-protein synthesis

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Evidence for IVIGEvidence for IVIG Several case reports have described the use of Several case reports have described the use of

IVIG in pt with STSS IVIG in pt with STSS

Case control study of IVIG therapy in STSS Case control study of IVIG therapy in STSS demonstrated survival benefit in pt who demonstrated survival benefit in pt who received IVIGreceived IVIG

A double blind, randomized, placebo-controlled A double blind, randomized, placebo-controlled European trial compared IVIG to placebo as European trial compared IVIG to placebo as adjunctive therapy in adults with GAS TSS with adjunctive therapy in adults with GAS TSS with or without necrotizing fasciitis. Trial was or without necrotizing fasciitis. Trial was terminated because of slow pt recruitment. terminated because of slow pt recruitment. Results were obtained from 21 pt. The mortality Results were obtained from 21 pt. The mortality rate was 36% in placebo group compared to rate was 36% in placebo group compared to 10% in IVIG but statistical significance was not 10% in IVIG but statistical significance was not reached (presumably because of small sample reached (presumably because of small sample size)size)55

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A Recurrence of Group A A Recurrence of Group A Streptococcal Toxic Shock Streptococcal Toxic Shock Syndrome at GUH: Syndrome at GUH: Is there Is there

ever a good outcome?ever a good outcome?

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Patient 2Patient 2

Pt is 62 year old previously healthy Pt is 62 year old previously healthy Caucasian female who presented to Caucasian female who presented to an OSH with 2 day hx of abdominal an OSH with 2 day hx of abdominal pain, nausea, non-bloody emesis, pain, nausea, non-bloody emesis, and worsening mental statusand worsening mental status

At OSH the pt was noted to be At OSH the pt was noted to be thrombocytopenic and was thrombocytopenic and was presumptively diagnosed with TTP presumptively diagnosed with TTP and transferred to GUH for further and transferred to GUH for further managementmanagement

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Patient 2 cont.Patient 2 cont. Upon transfer to GUH the pt was

diagnosed with meningitis, septic shock and respiratory failure and was subsequently intubated

Skin examination was significant for petechial rash, purpura fulminans, and right thigh eschar

Her admission labs were notable for leukopenia, thrombocytopenia, acute renal failure

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Purpura FulminansPurpura Fulminans

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Patient 2 cont.Patient 2 cont. Streptococcus pyogenesStreptococcus pyogenes grew from 4/4 grew from 4/4

blood culture bottles within 8 hoursblood culture bottles within 8 hours The patient was treated with penicillin The patient was treated with penicillin

G, clindamycin, and IVIG x 3 dosesG, clindamycin, and IVIG x 3 doses Microthrombosis of limbs became life Microthrombosis of limbs became life

threatening and threatening and all 4 extremities all 4 extremities were amputatedwere amputated

The patient had a prolonged, The patient had a prolonged, complicated ICU course but was complicated ICU course but was ultimately discharged 2 months later to ultimately discharged 2 months later to acute rehabacute rehab with plans for prosthesis with plans for prosthesis fittingsfittings

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PrognosisPrognosis Mortality associated with GAS TSS Mortality associated with GAS TSS

ranged from 33 to 81% in several ranged from 33 to 81% in several population based studiespopulation based studies66

A retrospective study of 66 pt with GAS A retrospective study of 66 pt with GAS TSS in Japan, noted the following TSS in Japan, noted the following statistically significant finding amongst statistically significant finding amongst survivors and those who died:survivors and those who died:77

Lower WBCLower WBC Lower platelet countsLower platelet counts Higher serum creatinineHigher serum creatinine Lower body temperatureLower body temperature Lower systolic blood pressureLower systolic blood pressure

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Prognosis cont.Prognosis cont. Prospective, population-based surveillance study Prospective, population-based surveillance study

conducted in Ontario, Canada from 1991 to 1995 conducted in Ontario, Canada from 1991 to 1995 uncovered the following findings:uncovered the following findings:88

77 clinical cases of Group A Strep NF uncovered during 77 clinical cases of Group A Strep NF uncovered during this time period; 47 % of cases associated with GAS TSSthis time period; 47 % of cases associated with GAS TSS

Overall case fatality rate was 34%Overall case fatality rate was 34% Mortality was correlated with increasing Mortality was correlated with increasing ageage, presence of , presence of

hypotensionhypotension, and , and bacteremiabacteremia Outcome was not correlated with M-type or the presence of Outcome was not correlated with M-type or the presence of

spe genespe gene Surgical Role:Surgical Role:

16 pt did not have surgery (100% Mortality) – all of 16 pt did not have surgery (100% Mortality) – all of these pt diedthese pt died

10/61 pt died despite surgery (16% Mortality): 6 had 10/61 pt died despite surgery (16% Mortality): 6 had amputations, 4 had debridement aloneamputations, 4 had debridement alone

51 survivors had a median of 2 surgical procedures51 survivors had a median of 2 surgical procedures 12/51 (24%) of those who survived required amputation12/51 (24%) of those who survived required amputation There was no difference in time to first surgical There was no difference in time to first surgical

procedure in those who died compared with those who procedure in those who died compared with those who survived survived

Pt who died were more likely to have had amputation as Pt who died were more likely to have had amputation as their initial proceduretheir initial procedure

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Prognosis cont.Prognosis cont. Mehta S, McGeer A, Low D, et al. Morbidity Mehta S, McGeer A, Low D, et al. Morbidity

and mortality of patients with invasive Group A and mortality of patients with invasive Group A Streptococcal infections admitted to the ICU. Streptococcal infections admitted to the ICU. CHESTCHEST 2006; 130:1679-1686. 2006; 130:1679-1686.

Prospective, population-based surveillance Prospective, population-based surveillance study conducted in Ontario, Canadastudy conducted in Ontario, Canada

Overall mortality rate was 40%. Mortality Overall mortality rate was 40%. Mortality rates in patients with and without GAS TSS rates in patients with and without GAS TSS were 68% and 8% respectivelywere 68% and 8% respectively

CoagulopathyCoagulopathy and and liver failureliver failure were were associated with increased mortalityassociated with increased mortality

Use of IVIG, surgical intervention and Use of IVIG, surgical intervention and clindamycin use were not significantly clindamycin use were not significantly associated with survivalassociated with survival

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SummarySummary Group A Streptococcal TSS associated Group A Streptococcal TSS associated

with necrotizing fasciitis continues to with necrotizing fasciitis continues to carry a high mortality ratecarry a high mortality rate

In the ICU setting the mortality rate is In the ICU setting the mortality rate is as high as 68%as high as 68%

Survivors of GAS TSS can anticipate Survivors of GAS TSS can anticipate limb-threatening morbidity with limb-threatening morbidity with amputation rates as high as 24%amputation rates as high as 24%

Without surgical intervention mortality Without surgical intervention mortality rates have approached 100%rates have approached 100%

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Summary cont.Summary cont.

Although optimal management Although optimal management includes surgical intervention, the includes surgical intervention, the addition of clindamycin and the addition of clindamycin and the administration of IVIG, data from the administration of IVIG, data from the literature using these modalities has literature using these modalities has not always resulted in a favorable not always resulted in a favorable outcomeoutcome

The literature fails to address quality The literature fails to address quality of life issues associated with this of life issues associated with this devastating illnessdevastating illness

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ReferencesReferences1.1. Baxter F, McChesney J. Severe group A streptococcal infection and Baxter F, McChesney J. Severe group A streptococcal infection and

streptococcal toxic shock syndrome. streptococcal toxic shock syndrome. Can J AnesthCan J Anesth 2000;47:1129- 2000;47:1129-1140.1140.

2.2. Kotb M, Norrby-Teglund A, McGeer A, et al. An immunogenetic and Kotb M, Norrby-Teglund A, McGeer A, et al. An immunogenetic and molecular basis for differences in outcomes of invasive group A molecular basis for differences in outcomes of invasive group A streptococcal infections. streptococcal infections. Nat MedNat Med Published 2002; 8:1398-1404. Published 2002; 8:1398-1404.

3.3. Defining the group A streptococcal toxic shock syndrome: rationale Defining the group A streptococcal toxic shock syndrome: rationale and consensus definition. The working group on severe streptococcal and consensus definition. The working group on severe streptococcal infections. infections. JAMAJAMA 1993; 269:390. 1993; 269:390.

4.4. Eagle H. Experimental approach to the problem of treatment failure Eagle H. Experimental approach to the problem of treatment failure with penicillin. I. Group A streptococcal infection in mice. with penicillin. I. Group A streptococcal infection in mice. Am J MedAm J Med 1952: 13;389.1952: 13;389.

5.5. Darenberg J, Ihendyane N, Sjolin J, et al. Intravenous Darenberg J, Ihendyane N, Sjolin J, et al. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: A immunoglobulin G therapy in streptococcal toxic shock syndrome: A European randomized, double-blind, placebo-controlled trial. European randomized, double-blind, placebo-controlled trial. Clin Clin Infect DisInfect Dis 2003; 37:333. 2003; 37:333.

6.6. Mehta S, McGeer A, Low D, et al. Morbidity and mortality of patients Mehta S, McGeer A, Low D, et al. Morbidity and mortality of patients with invasive Group A Streptococcal infections admitted to the ICU. with invasive Group A Streptococcal infections admitted to the ICU. CHESTCHEST 2006; 130:1679-1686. 2006; 130:1679-1686.

7. Hasegawa T, Hashikawa SN, Nakamura T, et al. Factors determining prognosis in streptococcal toxic shock-like syndrome: results of a nationwide investigation in Japan. Microbes Infect 2004; 6:1073.

8.8. Kaul R, McGeer A, Low D, et al. Population-based surveillance for Kaul R, McGeer A, Low D, et al. Population-based surveillance for Group A Streptococcal necrotizing fasciitis: clinical features, Group A Streptococcal necrotizing fasciitis: clinical features, prognostic indicators, and microbiologic analysis of seventy-seven prognostic indicators, and microbiologic analysis of seventy-seven Cases. Cases. Am J MedAm J Med 1997; 103:18-24. 1997; 103:18-24.