A Recurrence of Group A Streptococcal Toxic Shock Syndrome at GUH: Is there ever a good outcome

1
A Recurrence of Group A Streptococcal Toxic Shock
Syndrome at GUH Is there ever a good outcome?

• Jennifer Vittorio, MD
• Internal Medicine-Pediatrics
• Georgetown University Hospital

2
History

• CC Transfer from OSH with Septic Shock
• HPI
• TC is 47 yo Caucasian female who was in her usual
  state of health until 1 week prior to admission
  at which time she reportedly had a brief 24-hour
  viral-illness
• Subsequently developed 2-3 days of watery
  diarrhea and abdominal pain
• She presented to OSH on 4/8/09 at 5PM with
  evidence of respiratory and circulatory failure,
  was intubated and admitted to MICU for further
  monitoring
• She was started on vasopressors and
  broad-spectrum abx including vancomycin,
  clindamycin and zosyn
• Her LUE was noted to be mottled and cyanotic with
  delayed CRT. Venous dopplers were negative for
  DVT
• Clinical condition continued to decline over the
  course of the evening. She developed
  rhabdomyolysis, renal failure and refractory
  hypotension
• She was transferred to GUH MICU on 4/9/09 at 3PM
  for further evaluation and treatment

3
History cont.

• PMH Breast Cancer dx 2005 s/p CTX, XRT in
  remission
• PSH Breast lumpectomy
• MEDS No home meds
• MEDS on Transfer Levophed gtt, Neosynephrine
  gtt, Vancomycin, Zosyn, Clindamycin, Heparin 5000
  units subq tid, Dilaudid, Fentanyl, Protonix
• ALL NKDA
• Fam Hx DM, CAD
• Soc Hx Works for EPA. No tobacco, alcohol or
  illicit drug use. No recent travel. 8 year old
  healthy son. Brother is next of kin provides
  much of the history

4
Physical Exam

• Vitals T 37.0 BP 110/86 P 84 RR 14
  PaO2 100 AC 500/24/10 FiO2 100
• GEN Intubated, sedated on vent
• HEENT NCAT PERRL anicteric sclera
  mottled/cyanotic MM
• NECK Supple, no thyromegaly, no LAD
• CV S1, S2, distant heart sounds, no m/r/g
• PULM CTAB ant
• ABD NABS, soft, NT/ND, no hsm
• EXT Mottled, cool, ecchymosis noted. Dopplerable
  pulses LUE
• SKIN Bullous lesion noted LUE
• VAGINAL No foreign objects in vaginal vault

5
Bullous Lesion
6
Necrosis of Fingertips
7
Laboratory Studies
12.1

• CBC
• BMP
• LFTS 2.7 1.2
• 1.0
• 433 121

12.7
52
35.8
N45 B21 L4 M27 E1
5.3
138
117
46
94
1.5
3.7
9
3.1
6.5
58
8
Laboratory Studies cont.

• Lactic Acid 13.0
• Lipase 16
• Troponin I 0.470
• CPK 24,683
• PT/INR 30.7/2.90
• D dimer gt200
• Fibrinogen 179
• Blood Cx Gram Cocci chains

9
Hospital Course

• Admitted to MICU and continued on early goal
  directed therapy for septic shock
• Infectious disease, orthopedic, limb service
  consultation were obtained at the time of
  admission
• Diagnosed with Group A strep toxic shock syndrome
  LUE necrotizing fasciitis
• Pt was started on abx therapy with meropenem,
  clindamycin, vancomycin
• Received a course of IVIG
• Taken to OR around 8 PM evening of admission and
  underwent LUE amputation. Diagnosis of
  necrotizing fasciitis confirmed

10
Hospital Course cont.

• Myonecrosis disseminated to remaining 3 limbs
  thoracic cavity
• 4/15/09 Patient underwent bilateral knee
  disarticulation right lateral thigh fasciotomy
• 4/17/09 Patient again hypotensive requiring
  vasopressor support
• Develops further necrosis of RUE, LE stumps,
  perineum
• Pt continued to deteriorate. Code status changed
  to DNR. Patient died on 4/19/09

11
GAS Toxic Shock Syndrome

• GAS is a common pathogen of the throat and
• skin that causes pharyngitis and a spectrum of
• skin and soft tissue infections
• The incidence of invasive GAS infection in North
  America and Europe is an estimated 3.5 cases per
• 100,000 persons annually1
• 8-14 of patients who develop invasive GAS
• infection will also develop GAS TSS1
• It is important to recognize GAS infections early
  and to treat appropriately in order to limit
  toxin production and decrease morbidity and
  mortality

12
Streptococcus pyogenes
13
Pathogenesis

• GAS TSS is mediated by toxins that act as
  superantigens which bypass the usual
  antigen-mediated immune response resulting in
  release of large quantities of inflammatory
  cytokines
• The major virulence factor of GAS is M protein
• M1 and M3 are the most virulent
• M protein makes the organism resistant to
  phagocytosis by inhibiting activation of
  alternate complement pathways on the cell surface
• Streptococcal exotoxins are also elaborated by
  GAS
• Pyrogenic exotoxin A (SPEA) and B (SPEB) are
  found in majority of cases
• Trigger massive T cell proliferation and cytokine
  release resulting in capillary leak and tissue
  damage

14
Why are certain individuals more susceptible to
severe GAS infections?

• Studies have suggested that the presence of
  specific anti-M Ab confers some degree of host
  protection from that strain of GAS. Once infected
  however, these Ab do not appear to offer
  protection from STSS.
• It has been proposed that HLA Class II allelic
  variation contributes to differences in severity
  of invasive GAS infections through their ability
  to regulate cytokine response triggered by
  streptococcal superantigens2
• The complex immune cascade is initiated by the
  GAS superantigen and the interplay with ones
  immune system determines the severity of illness

15
Risk Factors

• Age lt9 yr or gt60 yr
• Varicella
• HIV/AIDS
• Cancer
• Diabetes
• Heart Disease
• Lung Disease
• ?NSAIDS

• Alcohol Abuse
• Nursing Home Resident
• Minor Trauma
• Injury resulting in hematoma, bruising, muscle
  strain
• Surgical Procedures

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Diagnosis

• The Working Group on Severe Streptoccocal
  Infections est
• the following clinical guideline for diagnosis of
  GAS TSS3
• 1. Isolation of GAS from sterile site
• 2. Hypotension
• Adult SBP lt 90 mmHg
• Child SBP lt 5th for age
• AND two or more of the following
• Renal impairment
• Coagulopathy
• Liver involvement
• ARDS
• Erythematous macular rash, may desquamate
• Soft tissue necrosis

17
Treatment

• Antibiotics
• Beta-lactam antibiotics such as penicillin G
• Reduction in efficacy of PCN has been
  demonstrated when a high density of organisms is
  present (Eagle Effect)
• Clindamycin (inhibits protein synthesis)
• IVIG
• Contains neutralizing antibody to streptococcal
  exotoxin
• Efficacy has yet to be proved in RCT
• Surgery
• Should be considered in pt who initially have
  fever, excruciating pain followed by progression
  to soft tissue swelling and formation of
  violaceous vesicles and bullae
• Debridement of all infected tissue should be
  carried out at first operative procedure

18
Eagle Effect

• First described by Eagle in 19524
• High inoculum of organisms encountered
• in overwhelming infections leads to rapid
• attainment of the stationary growth phase
• Subsequent decrease in expression of cell wall
  penicillin binding proteins (PBPs), the molecular
  targets of penicillin, renders penicillin less
  effective
• Clindamycin retains efficacy by inhibiting
  protein synthesis
• Clindamycin is also a potent suppressor of toxin
  formation and facilitates phagocytosis by
  inhibition of M-protein synthesis

19
Evidence for IVIG

• Several case reports have described the use of
  IVIG in pt with STSS
• Case control study of IVIG therapy in STSS
  demonstrated survival benefit in pt who received
  IVIG
• A double blind, randomized, placebo-controlled
  European trial compared IVIG to placebo as
  adjunctive therapy in adults with GAS TSS with or
  without necrotizing fasciitis. Trial was
  terminated because of slow pt recruitment.
  Results were obtained from 21 pt. The mortality
  rate was 36 in placebo group compared to 10 in
  IVIG but statistical significance was not reached
  (presumably because of small sample size)5

20
A Recurrence of Group A Streptococcal Toxic Shock
Syndrome at GUH Is there ever a good outcome?
21
Patient 2

• Pt is 62 year old previously healthy Caucasian
  female who presented to an OSH with 2 day hx of
  abdominal pain, nausea, non-bloody emesis, and
  worsening mental status
• At OSH the pt was noted to be thrombocytopenic
  and was presumptively diagnosed with TTP and
  transferred to GUH for further management

22
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

23
Purpura Fulminans
24
Patient 2 cont.

• Streptococcus pyogenes grew from 4/4 blood
  culture bottles within 8 hours
• The patient was treated with penicillin G,
  clindamycin, and IVIG x 3 doses
• Microthrombosis of limbs became life threatening
  and all 4 extremities were amputated
• The patient had a prolonged, complicated ICU
  course but was ultimately discharged 2 months
  later to acute rehab with plans for prosthesis
  fittings

25
Prognosis

• Mortality associated with GAS TSS ranged from 33
  to 81 in several population based studies6
• A retrospective study of 66 pt with GAS TSS in
  Japan, noted the following statistically
  significant finding amongst survivors and those
  who died7
• Lower WBC
• Lower platelet counts
• Higher serum creatinine
• Lower body temperature
• Lower systolic blood pressure

26
Prognosis cont.

• Prospective, population-based surveillance study
  conducted in Ontario, Canada from 1991 to 1995
  uncovered the following findings8
• 77 clinical cases of Group A Strep NF uncovered
  during this time period 47 of cases associated
  with GAS TSS
• Overall case fatality rate was 34
• Mortality was correlated with increasing age,
  presence of hypotension, and bacteremia
• Outcome was not correlated with M-type or the
  presence of spe gene
• Surgical Role
• 16 pt did not have surgery (100 Mortality) all
  of these pt died
• 10/61 pt died despite surgery (16 Mortality) 6
  had amputations, 4 had debridement alone
• 51 survivors had a median of 2 surgical
  procedures
• 12/51 (24) of those who survived required
  amputation
• There was no difference in time to first surgical
  procedure in those who died compared with those
  who survived
• Pt who died were more likely to have had
  amputation as their initial procedure

27
Prognosis cont.

• Mehta S, McGeer A, Low D, et al. Morbidity and
  mortality of patients with invasive Group A
  Streptococcal infections admitted to the ICU.
  CHEST 2006 1301679-1686.
• Prospective, population-based surveillance study
  conducted in Ontario, Canada
• Overall mortality rate was 40. Mortality rates
  in patients with and without GAS TSS were 68 and
  8 respectively
• Coagulopathy and liver failure were associated
  with increased mortality
• Use of IVIG, surgical intervention and
  clindamycin use were not significantly associated
  with survival

28
Summary

• Group A Streptococcal TSS associated with
  necrotizing fasciitis continues to carry a high
  mortality rate
• In the ICU setting the mortality rate is as high
  as 68
• Survivors of GAS TSS can anticipate
  limb-threatening morbidity with amputation rates
  as high as 24
• Without surgical intervention mortality rates
  have approached 100

29
Summary cont.

• Although optimal management includes surgical
  intervention, the addition of clindamycin and the
  administration of IVIG, data from the literature
  using these modalities has not always resulted in
  a favorable outcome
• The literature fails to address quality of life
  issues associated with this devastating illness

30
References

• Baxter F, McChesney J. Severe group A
  streptococcal infection and streptococcal toxic
  shock syndrome. Can J Anesth 2000471129-1140.
• Kotb M, Norrby-Teglund A, McGeer A, et al. An
  immunogenetic and molecular basis for differences
  in outcomes of invasive group A streptococcal
  infections. Nat Med Published 2002 81398-1404.
• Defining the group A streptococcal toxic shock
  syndrome rationale and consensus definition. The
  working group on severe streptococcal infections.
  JAMA 1993 269390.
• Eagle H. Experimental approach to the problem of
  treatment failure with penicillin. I. Group A
  streptococcal infection in mice. Am J Med 1952
  13389.
• Darenberg J, Ihendyane N, Sjolin J, et al.
  Intravenous immunoglobulin G therapy in
  streptococcal toxic shock syndrome A European
  randomized, double-blind, placebo-controlled
  trial. Clin Infect Dis 2003 37333.
• Mehta S, McGeer A, Low D, et al. Morbidity and
  mortality of patients with invasive Group A
  Streptococcal infections admitted to the ICU.
  CHEST 2006 1301679-1686.
• 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 61073.
• Kaul R, McGeer A, Low D, et al. Population-based
  surveillance for Group A Streptococcal
  necrotizing fasciitis clinical features,
  prognostic indicators, and microbiologic analysis
  of seventy-seven Cases. Am J Med 1997 10318-24.