Resurgence of Severe Group A Streptococcus Infections

1
Resurgence of Severe Group A Streptococcus
Infections

• Kathryn J. Sowerwine, MD Ram Srinivasan, MD
  Princy N. Kumar, MD
• Internal Medicine
• Georgetown University Hospital

2
Introduction

• Group A streptococcus (GAS) infections can cause
  serious life threatening illnesses
• These devastating infections are known to the
  public as the flesh eating bacteria
• In the mid 1990s increased numbers of healthy
  adults were falling ill to GAS

3
Introduction

• In April 1995, invasive GAS infections and strep
  toxic shock syndrome (TSS) were added to the
  National Public Health Surveillance System
• In 2006
• 4,587 cases of severe GAS disease were reported
  to the Centers for Disease Control and Prevention
  (CDC)

4
Nationwide Recognition of strep TSS

• The New York Times
• THE DOCTOR'S WORLD Henson Death Shows Danger of
  Pneumonia
• By LAWRENCE K. ALTMAN, M.D.
• Published May 29, 1990
• LEAD The untimely death of Jim Henson, the
  creator of the Muppets, from pneumonia this month
  at the age of 53 may have shocked many Americans
  who believed that bacterial infections no longer
  could kill with such swiftness.

5
Case Presentation

• CC abdominal pain
• HPI 62 year old previously healthy WF who
  presented to an outside hospital (OSH) with 2
  days of abdominal pain, nausea, non-bloody
  emesis, and worsening mental status

6
History of Present Illness

• Per familys report, patient was in good health
  until the day prior to admission, and had even
  played tennis with friends 2 days before
  admission
• Patient was complaining of vague abdominal pain,
  nausea and non-bloody emesis
• Patients family noticed that patient had been
  confused, wandering around the house, and seemed
  to be disoriented when talking

7
Further History

• PMHx None
• PSgHx None
• Social
• Active, no smoking, rare ETOH, married with
  children
• Family Hx - Noncontributory

• Meds
• Ambien 5 mg prn
• Motrin prn
• All - NKDA

8
ROS

• confusion, fevers
• abdominal discomfort, nausea, non-bloody
  emesis
• rash on buttock area, bugbite on thigh
• vaginal discharge for two weeks, no history of
  tampon use or IUD

9
Physical Exam at OSH

• BP - 95/72(91-95/48-72) HR 92 (92-186) RR
  20 95RA
• Gen confused
• HEENT dry mucus membranes
• Skin rash on buttock area
• Neuro confused, hallucinating

10
Initial Labs

• 2.4 50
• 44.4
• N 68 B 20 L 2
• 137 98 67
• 122
• 3.9 18 3.5

• 6.9 3.5
• 2.2
• 134 62
• 110

11
Initial Treatment

• 2.5 liters of normal saline
• 1 mg Ativan per hour x 5 hours
• Transferred to GUH for presumed TTP

12
Physical Exam at GUH

• Vitals
• T 36C BP 100/56 HR 125 RR 40 Pox
  undetectable
• Gen oriented to person, in respiratory distress
• HEENT - nuchal rigidity, photophobia, dry
  mucus membranes
• CV Tachycardic
• Pulm Tachypneic
• Abd benign other than petechial rash
• GU erythema of labia, yellowish-green
  discharge
• Ext cyanotic, mottled appearing extremities
  bilaterally
• Skin non-blanching petechial rash on buttocks,
  abdomen, and upper chest R thigh 2x2 cm eschar,
  healing

13
Right Thigh Eschar and Petechial Rash
14
Purpuric coalescing rash consistent with
purpura fulminans
15
Necrosis of Fingertips
16
Labs (on arrival to GUH)

• 14.3 134 108 67
• 2.3 28 94
• 41.5 3.8 14 3.5
• 16 39 Ca 6.5
• 1.3 Mg 1.9
• P 5.4
• FSP - 40
• D-dim -10000 5.0 2.4
• Fib - 390 2.7 1.6
• 100 51
• 77

• Man diff 40 Bands, 44 Neut, 3 lymph, 10 mono,
  NO schistocytes
• UA pH 6.0, SG 1.010, 2bact, 4blood, 3prot,
  5RBC, 10 WBC
• ABG 7.21/22/79 prior to intubation

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Labs

• CSF HSV - neg
• Cryptococcal Ag neg
• Legionella Ur Ag neg
• MRSA nasal swab neg

• CSF
• Glc 20
• WBC 21
• RBC 178
• Neut 80
• Lymph 5
• Mono- 15
• Prot 152
• WNV IgG 5.9
• WNV IgM -
• Ehrlichia PCR - negative

Blood Cx-Streptococcus pyogenes grew within 8
hours in 4/4 bottles Urine Cx- Streptococcus
pyogenes
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Hospital Course

• On arrival to Georgetown ICU, patient was given
  vancomycin, ceftriaxone, doxycycline, ampicillin,
  acyclovir and prednisone for possible
  meningitis/encephalitis
• Once blood culture results were available
  antibiotics were changed to penicillin G,
  clindamycin, and IVIG daily x 3 doses

19
Hospital Course

• Microthrombosis of limbs became life threatening
  and all 4 extremities were amputated
• Prolonged hospital course requiring tacheostomy,
  complicated by HIT and atrial fibrillation

20
Hospital Course

• Discharged 2 months later to acute rehab

21
Streptococcal TSS Criteria from CDC

• A. Isolation of GAS
• 1. From a sterile site
• 2. From a nonsterile body site
• B. Clinical signs of severity
• 1. Hypotension
• 2. Clinical and laboratory abnormalities
  (requires two or more of the following)
• a)Renal impairment
• b)Coagulopathy
• c)Liver abnormalities
• d)Acute respiratory distress syndrome
• e)Extensive tissue necrosis
• f)Erythematous rash
• Definite Case A1 B(12)
• Probable Case A2 B(12)

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Epidemiology
Non-necrotizing
Necrotizing
CID 200234454 Ontario, Canada
23
Epidemiology / Risk Factors

• Case Presented
• Skin breakdown as seen by R thigh eschar
• NSAID use
• population-based, case-control study by Factor
  et al. demonstrated that new NSAID use
  prior increased risk of severe infection by
  decreasing neutrophil chemotaxis

• Skin breakdown (varicella is well known in
  children)
• Immunosuppression
• Chronic illnesses
• Age 65
• Male

Ontario study 1992-96 CID 200234454
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Pathophysiology

• GAS produce 2 major classes of protein antigens
  M antigens and T antigens
• The major virulence factor of GAS is M protein
• - M1 and M3 are the most virulent
• The M protein makes the organism resistant to
  phagocytosis by inhibiting activation of
  alternate complement pathways on the cell surface

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Superantigen
Adapted from IMMUNOLOGY - CHAPTER 11  Illustration
s by Dr Richard Hunt
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Pathophysiology

• Why are certain individuals more susceptible to
  severe GAS infections?
• Recent murine studies suggest it may be HLA class
  II polymorphisms
• Due to the overwhelming immune response,
  mortality for strep TSS, remains 3050 even with
  appropriate therapy

27
Immune Response Th1/Th2
American Society for Microbiology. 65, 5209-5215.
28
Treatment

• B-lactam antibiotics such as penicillin G is
  effective in combination with clindamycin as
  shown in multiple studies
• Clindamycin works by inhibiting protein synthesis
  and therefore decreases superantigen production
  and should be initiated when there is any
  suspicion of GAS

29
Evidence for IVIG

• Kaul et al. showed better outcomes with IVIG
• IVIG patients were sicker, had more surgical
  interventions and more likely to have been on
  clindamycin than historical subjects
• Darenberg et al. studied IVIG in a double-blind,
  placebo-controlled trial from northern Europe
• Significant increase in plasma neutralizing
  activity against superantigens with IVIG
• Mortality rate was 3.6 times higher in group who
  did not receive IVIG but this did not reach
  statistical significance
• There is editorial support for IVIG as an
  efficacious adjunctive therapy in step TSS

CID 1999 288007.
CID 2003 3733340.
30
It seems to be in the air

• Three more cases of severe GAS in a three week
  period?
• Never before has GUH ever had such a cluster
• CDC was contacted and concluded no investigation
  is warranted

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Coincidence or Resurgence?
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Case 1
33
Case 2
34
Case 3
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Conclusion

• Awareness of severe GAS infections will help with
  early recognition and specific treatment (i.e.
  b-lactam antibiotic, clindamycin and /- IVIG)
• There are vaccines currently under investigation
  that would potentially eliminate the spectrum of
  disease from GAS
• More research is needed to understand why certain
  individuals are more susceptible than others

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References

• Demers, B. et al. Severe invasive group A
  streptococcal infections in Ontario, Canada
  1987-1991. Clin Infect Dis 16, 792-800 (1993).
• Kotb, M. et al. An immunogenetic and molecular
  basis for differences in outcomes of invasive
  group A streptococcal infections. Nat Med
  Published online November 18, 2002.
• Vlaminckx, B. et al. Site-specific manifestations
  of invasive group a streptococcal disease type
  distribution and corresponding patterns of
  virulence determinants. Journal of Clinical
  Microbiology, 2003 (Vol. 41) (No. 11) 4941-4949.
• Baxter, F, McChesney, J Severe group A
  streptococcal infection and streptococcal toxic
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• S. Mehta et al. Stewart Morbidity and Mortality
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• Norrby-Teglund, A and Stevens, DL. Novel
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• Basma, H, Norrby-Teglund, A, McGeer, A, et al
  Opsonic antibodies to the surface M protein of
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  Immun 199866,2279-2283.
• Journal Of The American Medical Association
  (2004, August 11). Early Results Show Promise For
  Strep Vaccine. ScienceDaily.
• Norrby-Teglund et al. (1997). Differential
  Induction of Th1 versus Th2 Cytokines by Group A
  Streptococcal Toxic Shock Syndrome Isolates.
  American Society for Microbiology. 65, 5209-5215.
• Kaul R, McGeer A, Norrby-Teglund A, et al.
  Intravenous immunoglobulin therapy for
  streptococcal toxic shock syndrome a comparative
  observational study. Clin Infect Dis
  1999 288007.
• Darenberg J, Ihendyane N, Sjolin J, et al.
  Intravenous immunoglobulin G therapy in
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  trial. Clin Infect Dis 2003 3733340.

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Thank You