TIBDN: Retrospective review of group A streptococcal toxic shock cases

Retrospective review of group A streptococcal toxic shock cases

» Background

Toxic shock syndrome (TSS) is the most severe complication associated with group A streptococcal (GAS) infection and is characterized by the sudden onset of shock and a high case fatality rate. GAS TSS is triggered by the release of streptococcal superantigens that bind non-specifically to host T-cells and MHC class II molecules on antigen presenting cells, resulting in widespread T-cell activation, cytokine release and shock. Intravenous immunoglobulin (IVIG) neutralizes streptococcal superantigens, reducing cytokine release. Until recently, all of the evidence for the clinical efficacy of IVIG in GAS TSS came from case-reports and a retrospective, observational trial that demonstrated a 50% reduction in mortality. In 2003, a randomized controlled trial conducted in Europe was published. This trial showed a trend towards a clinically significant improvement in outcome, but the trial was terminated early due to poor enrollment, with a total sample of only 21 cases and was therefore underpowered. As a result, clinicians still do not have adequate information upon which to base treatment decisions. This RCT clearly demonstrates the challenges inherent in conducting such a trial. It is therefore critical to obtain as much information as possible from other study designs. A retrospective cohort study designed to minimize selection bias is feasible and could serve as the impetus to conduct a North American randomized controlled trial of IVIG in GAS TSS. On the other hand, a second trial showing a large mortality benefit from IVIG could serve as interim evidence to guide clinicians. Currently, only 50% of patients with GAS TSS in Ontario receive IVIG and its use in other regions is even lower.

We hypothesize that there is a relationship between early IVIG administration in GAS TSS and mortality. We propose to conduct a retrospective, cohort study to evaluate this association. All cases of GAS TSS occurring in Ontario have been identified since 1992. Given that a prior analysis has been conducted on cases occurring between 1992 and 1995, this analysis will include episodes of GAS TSS identified between July 1, 1995 and Dec. 31, 2003. Cases will include patients admitted to hospital, diagnosed with GAS TSS and treated with antibiotics and IVIG. Control patients will include patients admitted to hospital, diagnosed with GAS TSS and treated with antibiotics but not with IVIG. The primary outcome is all-cause mortality at 30 days. This study will require re-review of charts of patients enrolled in the surveillance study between 1995 and 2003. Additional data to be collected includes more detailed data on initial symptoms, signs and management, including details of the doses and timing of antibiotic and IVIG administration. Multivariate analyses will be used to adjust for known risk factors including age, comorbidity and APACHE II score.

» Methods

Case and Control Group Selection: Patients will be selected from the Ontario GAS Study database if they have been hospitalized between Jul. 1, 1995 and Dec 31, 2003 and met the consensus definitions for GAS TSS. A definite GAS TSS case is defined as a positive group A streptococcus culture from a normally sterile site and hypotension (systolic blood pressure ?90mmHg) in combination with two or more of the following: acute renal failure, coagulation abnormalities, liver abnormalities, acute respiratory distress syndrome, generalized rash and necrotizing fasciitis. Cases will include all patients that meet the inclusion/exclusion criteria (below) and were ordered appropriate antibiotics and IVIG. Controls will include patients that meet the inclusion/exclusion criteria (see below) and were ordered appropriate antibiotics but not IVIG.

Inclusion Criteria:
- Patients must be an adult (=18 year-old)
- Meets consensus criteria for definite GAS TSS
- Survived until clinical diagnosis of GAS TSS made and therapy ordered OR
- Survived until microbiologic confirmation of invasive GAS documented and appropriate therapy ordered

Exclusion Criteria
- Death prior to clinical/microbiological diagnosis
- Death within 12 hours of admission
- Failure to order appropriate antibiotics***
- Patients at hospitals <50 beds or without critical care capacity
- Patient/family or physician deem aggressive care (any of ICU admission, intubation, IVIG, surgery when indicated) inappropriate or patient likely to die within 30 days due to causes unrelated to GAS

***Appropriate antibiotics are defined as high doses of IV anti-streptococcal B-lactam (penicillin G, ceftriaxone, cefotaxime, cefazolin etc.) AND IV clindamycin.
Data not available in the GAS database will be collected by chart review. For each patient, the required clinical, laboratory and radiographic information will be collected to determine if inclusion/exclusion criteria are met, to determine treatment group (IVIG, control), to assess key prognostic factors (age, comorbidities, APACHE II (78) and SOFA (79) scores at admission), to evaluate the presence of IVIG side-effects and to determine outcome. Chart review will be performed by a trained observer using standardized data collection forms. A subset of charts (20%) will be reviewed by two observers to confirm inter-observer reliability. The primary outcome measure is all-cause 30 day mortality. Patients discharged alive from hospital prior to 30 days will be assumed to be survivors. All-cause 7 day mortality, time to shock resolution, duration of ICU stay, duration of hospitalization, need for surgery, number of surgical procedures, time to no further progression of the tissue infection, serious adverse events and IVIG adverse effects will be secondary outcomes.