group a streptococcus ( strep . pyogenes or gas ) is a -hemolytic bacterium often found in the throat and the skin .
the two most severe manifestations of gas are streptococcal toxic shock syndrome ( stss ) and necrotizing fasciitis ( nf ) . annually in the united states there are between 9,000 - 11,500 cases of invasive disease ( 3.2 to 3.9/100,000 population ) ; stss and nf each account for approximately 6 - 7% of invasive cases .
the isolation of gas , in a patient with severe sepsis , from a normally sterile site defines severe invasive gas disease .
gas produces exotoxins and these superantigens are thought to circumvent traditional immune mechanisms , producing vast discharge of inflammatory cytokines .
there is an identifiable need for adjunctive therapy in these cases , as attributable mortality may be as high as 80% , despite prompt antimicrobial therapy .
a 40-year - old ex - smoker presented after 2 days of vomiting and severe right - sided chest pain .
relevant blood tests were a reduced wcc at 2  10/l , raised crp 361 mg / l , and acute renal failure with urea 14.8 mmol / l and creatinine 358 mmol / l . there were no factors predisposing to the patient being immunocompromised , and a human immunodeficiency virus ( hiv ) test was negative .
blood gases showed ph 7.12 , base excess 10 , lactate 4.2 , po2 17.5 kpa , and pco2 3.1 on 80% inspired oxygen .
following intubation he was commenced on renal replacement therapy , at 80 ml / kg for severe sepsis .
vasopressin and dobutamine were added , and cardiac output monitoring with pulse contour analysis ( lidco ) commenced : scvo2 was 80% .
hydrocortisone and drotrecogin alfa ( activated protein c ) ( apc ) ( see footnote ) were also instituted . in relation to indications for the use of apc , all four systemic inflammatory response syndrome ( sirs ) criteria were met ; the patient had more than one sepsis - induced organ failure and there were no specific contraindications .
in particular the platelet count was > 30  10/l ( at 90 10/l ) and the inr < 3.0 ( 1.5 ) .
the patient remained in a refractory septic shock and in multiorgan failure , and an adrenaline infusion was commenced .
however muscle layer biopsies and blood cultures soon grew extensive gas and an initial diagnosis of nf was made .
the patient was felt to be too unstable to take to theatre for debridement , and a plan was made to observe the chest wall and attempt operative intervention only if there was spreading fasciitis .
utilizing the recent centers for disease control ( cdc ) position statement for the clinical case definition of stss , classifies this patient as a confirmed case of stss .
in addition to identifying gas from a normally sterile site ( blood ) , the patient also satisfied the clinical manifestations within the definition .
namely these were hypotension ( systolic blood pressure  90 mmhg ) and multiorgan involvement characterized by the presence of two or more of renal impairment , coagulopathy , liver involvement , acute respiratory distress syndrome , a generalized erythematous macular rash , and soft tissue necrosis , including nf .
a decision was made to commence intravenous immunoglobulin ( ivig ) at 1 g / kg on day 1 , followed by 0.5 g / kg on days 2 and 3 , as the patient was continuing to deteriorate despite the above maximal medical therapy .
the relevant public health authorities were informed , noting that scarlet fever ( also caused by gas ) remains a notifiable disease in the united kingdom . over the next 24 hours the patient improved , was extubated 3 days later and was subsequently discharged from hospital after 2 weeks .
the exact role played by ivig within the improvement of this patient is difficult to quantify within the context of a case report ; however we will discuss the mechanisms and evidence base , which we feel justified its use in this case .
ivig is a gamma globulin made from purified pooled plasma of thousands of donors , consisting mainly of igg , and sourced from outside the united kingdom due to the risk of creutzfeldt - jakob disease .
ivig is thought to work by a variety of mechanisms including antibody protection against lipopolysaccharides , neutralizing superantigens , modulation of fc - receptor blockade and expression , inhibition of membrane attack complexes ( c5b-9 ) , and complement activation and also by facilitating the opsonization of gas bacteria .
this concept of immunomodulation of the inflammatory cascade may apply during sepsis , with use of ivig in gas . a multicenter ,
double - blind rct examining the use of high dose ivig as adjunctive therapy in stss , in addition to clindamycin and penicillin , was published in 2003 .
placebo control was with 1% albumin , with the primary end point being effect on 28-day mortality with use of ivig ( 1 g / kg on day 1 , then 0.5 g / kg on days 2 and 3 ) .
power calculation was for 120 patients , and only 21 were randomized due to recruitment difficulties .
an insignificant trend toward lower mortality ( 10% vs. 36% ) , as well as a significant decrease in sepsis - related sofa scores at days 2 ( p=0.02 ) and 3 ( p=0.04 ) , was observed in the ivig group .
further evidence is provided from a canadian observational study comparing 21 consecutive patients who were given ivig for stss .
although there was no difference in duration of ventilation or hospital stay ( los ) , survival to 30 days was improved in the ivig group ( 67% vs. 34% , p=0.02 ) .
in contrast a recent paper examining the use of ivig in 84/192 pediatric stss patients found no significant mortality reduction and longer los and higher hospital costs .
current uk department of health guidelines for use of ivig in infectious diseases [ table 1 ] recommends that  ivig may be added to adequate toxin - neutralising antimicrobials , source control and sepsis management when these approaches have failed to elicit a response .  united kingdom department of health guidelines for immunoglobulin use in infectious diseases this patient had severe septic shock where use of ivig has also been reported .
turgeon et al . looked at rcts comparing ivig with placebo ( or no intervention ) in critically ill adult patients with sepsis , and found a 26% survival benefit associated with use of polyclonal ivig ( rr 0.74 [ 95% ci , 0.62 - -0.89 ] : p=0.001 with a number of patients needed to treat to save one life ( nnt ) of 9 .
a meta - analysis by laupland et al . found overall significant reduction in mortality with ivig treatment ( or 0.66 ( 95% ci , 0.53 - -0.83 ; p<0.0005 ) , although this result was not confirmed when only high - quality studies were analyzed .
looked at 27 rcts , 15 of which involved 1492 adults and children with trials of polyclonal ivig in septic patients .
again reduced mortality was demonstrated , with adult data showing rr 0.79 ( 95% ci , 0.69 - -0.90 ) . among the authors conclusions in these trials was that ,  an adequately powered rct was needed to confirm the effects of ivig in septic shock ,  on the background of previous trials having methodological flaws and heterogeneous data . in 2007 the placebo - controlled rct sbits was published , which examined the use of ivig in patients with sepsis .
twenty - eight - day mortality was not reduced significantly , 37.3% versus 39.3% in the ivig group ( p=0.6695 ) , and there was also no improvement in 7-day mortality or pulmonary function .
one point of note was that this trial used a smaller total dose of ivig ( 0.9 mg / kg ) , than the multicenter trial using ivig in stss . a cochrane review update , which found 17 trials in adults ( n=1958 ) , concluded that polyclonal ivig had a mortality benefit in adults ( rr 0.77 , 95% ci 0.68 - -0.87 ) ; however this was not reproduced when examining trials with low risk of bias .
current doh guidance , and recent drugs and therapeutics bulletin advice , do not recommend the use of ivig in general sepsis .
( $ 10,000 for a 100 kg ( 220 lbs ) person at 2 g / kg ) , this will necessitate careful appraisal of its cost benefit by each treating institution .
neilson et al . showed , on the basis of a meta - analysis of studies undertaken in adult septic patients , that the addition of igm - enriched ivig to standard therapy has a positive association with reduced mortality .
the increased cost equated to  5715-28443/life saved which compares favorably with other recommendations for adjuvant therapies in sepsis .
for example , the addition of apc had a cost implication of  100728-120176/life saved .
a further meta - analysis demonstrated favorable comparisons with other current recommendations in sepsis , in relation to nnt and on an economic basis , e.g. , ivig in adults ; nnt 9 , rr ( 95% ci ) : 0.74 ( 0.62 - -0.89 ) compared to apc ; nnt 16 , rr ( 95% ci ) : 0.80 ( 0.69 - -0.94 )
. there are no recommendations for the use of ivig in the current surviving sepsis guidelines for adults , though it may be considered it pediatric septic shock .
the omission of ivig from these adult guidelines was recently reviewed , with the conclusion being that small trials of low quality formed the basis of positive results .
in addition the largest rct ( sbits trial described above ) failed to demonstrate benefit , with standard igg ivig in adult septic patients .
however the potential benefit of igm - enriched ivig preparations has been shown in experimental sepsis models and meta - analyses , with kreyman et al . raising the possibility of  significant benefit of igm - enriched ivig in adult and neonatal sepsis .
 it is likely that further larger controlled rct 's concerning igm - enriched ivig in adult sepsis will be needed prior to concrete recommendations in international sepsis guidelines .
a uk perspective , we feel the limited worldwide supply and high cost implications , together with an inconclusive evidence base , warrant restricting its use to cases in which conventional therapy has failed .
pharmaceutical company eli lilly 's recent decision to withdraw xigris ( drotrecogin alfa ( activated ) ) from the market worldwide further to the 28-day mortality results from the prowess - shock study .
pharmaceutical company eli lilly 's recent decision to withdraw xigris ( drotrecogin alfa ( activated ) ) from the market worldwide further to the 28-day mortality results from the prowess - shock study .
 group a streptococcus ( gas ) is a -hemolytic bacterium often found in the throat and skin . 
 the two most severe clinical manifestations of gas are streptococcal toxic shock syndrome and necrotizing fasciitis . 
 intravenous immunoglobulin ( ivig ) is a gamma globulin made from purified pooled plasma of thousands of donors , consisting mainly of igg . 
 we report the case of a 40-year - old man admitted after 2 days of vomiting and severe right - sided chest pain . 
 he was hypotensive with a sinus tachycardia , pyrexial , and vasodilated . 
 the only other positive finding was a swollen and erythematous chest wall . 
 muscle layer biopsies and blood cultures soon grew extensive gas , and an initial diagnosis of necrotizing fasciitis was made . 
 the clinical syndrome was of severe septic shock secondary to invasive gas . 
 the patient quickly deteriorated with a worsening metabolic acidosis . despite maximal intensive care therapy including fluids , vasoactive agents , and also activated protein c , the patient continued to remain profoundly hypotensive . 
 a decision was made to commence ivig , with the aim of immunomodulation of the inflammatory cascade seen in sepsis . over the next 24 hours the patient improved , 
 was extubated 3 days later , and subsequently discharged from hospital after 2 weeks . 
 although the evidence for the use of ivig in severe invasive gas disease is limited , we feel that on reviewing the available literature its use in this case was justified . 
 the limited worldwide supply and high costs , together with a limited evidence base , warrant restricting its use to cases in which conventional therapy has failed . 
 the literature for use of intravenous immunoglobulin in invasive gas infection will be reviewed in this article . 
Introduction
Case Report
Discussion
Conclusion
The authors note