During the study period, 192 patients were diagnosed with streptococcal TSS. There was a median of 4 patients (IQR, 3-8 patients) per hospital; one hospital contributed 16 patients. Forty-three (22.4%) patients were transferred to the participating hospital after initial evaluation elsewhere. The characteristics of study patients are shown in . The mean age was 8.8 years (median, 8.2 years; IQR, 5.0-13.4 years). Most patients (n=182; 94.8%) received adjunctive therapy with intravenous clindamycin in combination with either penicillin or vancomycin. Three patients (1.6%) had varicella zoster virus infection.
Characteristics of patients with streptococcal toxic shock syndrome.
Intravenous Immune Globulin Use
IVIG was administered to 84 (44%) children either as a single dose (n=51, 61%) or once daily on 3 consecutive days (n=33, 39%). There was no significant change in the proportion of patients receiving IVIG over time: 2003, 44.1%; 2004, 29.7%; 2005, 50.0%; 2006, 50.0%; and 2007, 44.7% (chi-square test for trend, P=0.353). However, IVIG use varied by hospital; shrunken estimates of IVIG use ranged from 29% to 60% of patients with streptococcal TSS at any hospital. IVIG was administered to 12 (30%) of the 40 patients not requiring admission to the intensive care unit and 72 (47%) of 152 patients admitted to the intensive care unit; 5 (63%) of the 8 patients who died received IVIG.
The overall mortality was 4.2% (95% CI: 1.8% to 8.0%). The unadjusted difference in mortality between IVIG (n=5, 6.0%) and non-IVIG (n=3, 2.8%) recipients was not statistically significant (Fisher exact, P=0.300). The mean LOS was 14 days; approximately 25% of patients had a LOS >14 days while 17% of patients had a LOS >21 days. In unadjusted analysis, the total hospital LOS and intensive care unit LOS were significantly longer for IVIG recipients than non-IVIG recipients ().
Unadjusted outcomes of patients with streptococcal toxic shock syndrome.
The total cost for all patients was $9,392,968; drug costs accounted for $2,165,784 or 23.1% of the total hospital cost. The cost of hospitalization exceeded $115,000 for 10% of patients and $164,000 for 5% of patients. Drug costs were significantly higher for patients receiving the 3 day IVIG regimen (median, $18,472; IQR: 10,910-33,044) compared with the 1 day IVIG regimen (median, $9,447; IQR: 5,453-16,698; P=0.002). Patient outcomes are summarized in . In unadjusted analysis, the total hospital cost, drug cost, and all other cost subcategories were greater in IVIG recipients than non-recipients. There was no significant difference in the proportion of IVIG recipients (22%) or non-recipients (25%) admitted to the participating hospitals as transfers from other acute care institutions (chi-square, P=0.832).
When stratifying the unadjusted (i.e., unmatched) analysis by age, there was no difference in LOS (median, 13 days; IQR: 7-18 days) or total hospital costs (median, $35,886; IQR: $18,606-$76,893) between IVIG recipients and non-recipients <5 years of age. Among children ≥5 years of age, the LOS was significantly longer for IVIG recipients (median, 14 days) than non-recipients (median, 7 days; P<0.001). In this older age group, IVIG recipients also had higher total hospital costs (median, $43,488) than non-recipients (median, $13,705; P<0.001).
Analysis of Patients Matched by Propensity Scores
In the propensity score analysis, 67 (80%) of 84 patients receiving IVIG were matched to appropriate controls (i.e., IVIG non-recipients). Differences in demographic characteristics, comorbid conditions, and specific diagnostic and therapeutic interventions between patients matched by propensity scores were not statistically significant with one exception; IVIG recipients had more arterial blood gas measurements than non-recipients (). In propensity-matched analysis, the differences in mortality between IVIG recipients (n=3, 4.5%) and non-recipients (n=3, 4.5%) were not statistically significant (McNemar's test, P=1.000). The other outcomes of the propensity-matched analysis are summarized in . Patients receiving IVIG had higher total hospital and drug costs than non-recipients. While patients receiving IVIG had a longer LOS and higher supply, clinical and laboratory costs compared with non-recipients, these differences were not statistically significant when accounting for multiple comparisons (). The difference in the cost of hospitalization between IVIG recipients and non-recipients was not significant once drug costs were subtracted from total hospital costs (median difference between matched patients, $6,139; IQR: -$8,316, to $25,993; P=0.060), suggesting that the differences in drug costs accounted for the differences in total costs.
Characteristics of patients with streptococcal toxic shock syndrome who were matched by propensity score.*
Results of the propensity-matched analysis comparing differences in outcomes between intravenous immune globulin recipients and non-recipients with streptococcal toxic shock syndrome.
In a secondary analysis, the characteristics and outcomes of unmatched and matched IVIG recipients were compared. There were no differences in age or sex between unmatched and matched patients. Unmatched patients had a greater number of arterial blood gas measurements and were more like to receive blood product transfusions and corticosteroids compared with matched patients. Unmatched IVIG recipients also had a significantly longer LOS (25 days vs. 12 days; P=0.003) and higher total ($115,500 vs. $38,120; P=0.001) and drug costs ($30,507 vs. $11,433; P=0.002) compared with matched IVIG recipients.
This multicenter study is the largest to describe the epidemiology and outcomes of children with streptococcal TSS and the first to explore the association between IVIG use and clinical outcomes. There was variability in the use of IVIG among participating hospitals. While overall mortality was low, the costs of caring for children with streptococcal TSS were substantial. Importantly, IVIG use was not associated with reduction mortality or hospital LOS. The total hospital costs were higher for children receiving IVIG, a difference that was attributable to higher drug costs for IVIG recipients compared with non-recipients. The results of our study suggest that IVIG use increases the costs of caring for children with streptococcal TSS but does not improve their outcome.
There was significant variation in the use of IVIG for TSS between hospitals. Increased illness severity incompletely accounted for this variation. It is likely that the variability between hospitals indicates poor consensus on best practices for treatment, due in part to the lack of evidence supporting IVIG use. Institutional cultural differences also may drive variability; certain champions of therapies may define therapy at a particular institution, which may be more likely in the setting of a rare and potentially fatal disease entity.
The mortality rate of 4.2% in this study is similar to the 7.7% mortality rate in a previous United States study by O'Loughlin et al.[38
] which included 26 children <10 years of age from 2000-2004, and dramatically lower than the 38-44% case fatality rate for those >
10 years of age in the same study, or two recent European studies that included all patient ages from 2002-2004.[39
] The difference in pediatric outcomes could be due to differences in the study populations, recognition of disease, case definitions or care provided. In particular, virtually all patients in our study received adjunctive treatment with clindamycin, which has greater efficacy than penicillin alone in experimental infections with group A beta-hemolytic streptococci.[41
IVIG has been suggested as a potential adjunctive therapy for streptococcal TSS because of its ability to neutralize a wide variety of superantigens and to facilitate opsonization of streptococci.[42
] In an observational study of adults, the unadjusted 30-day mortality was significantly lower among 21 IVIG recipients (33%) compared with 32 non-recipients (66%, P=0.02).[11
] The odds of survival was 8-fold higher among IVIG recipients (adjusted odds ratio, 8.1; 95% confidence interval: 1.6-45.0) after adjusting for illness severity at presentation.[11
] However, a disproportionate number of IVIG non-recipients studied by Kaul et al. did not receive clindamycin.[11
] Darenberg et al.[12
] conducted a randomized trial involving 21 adults from 17 European hospitals. The trial was terminated early because of low enrollment. Although mortality was lower in IVIG recipients (10%) compared with placebo recipients (36%), this difference was not statistically significant.[12
Our large multicenter study of children with streptococcal TSS did not find an association between IVIG use and mortality or LOS. While there was substantial variability in IVIG use for children with streptococcal TSS, clindamycin was administered almost routinely. When given to mice at the time of experimental group A beta-hemolytic streptococcal infection (and in the absence of antibiotic therapy), IVIG neutralized circulating superantigens and reduced systemic inflammatory response.[10
] However, when used in combination with penicillin and clindamycin in a delayed treatment setting (to more closely mimic what occurs in the clinical setting), IVIG did not confer additional therapeutic benefit.[10
] These experimental results raise two important points that lend credence to our findings that IVIG use was not associated with improved outcomes in children with streptococcal TSS. First, the benefit of IVIG may depend predominantly and perhaps exclusively on the timing of administration. IVIG may not have any clinical benefit if it is not administered sufficiently early in the course of infection, a goal that may be difficult to accomplish in clinical practice. Second, the concurrent use of clindamycin therapy may improve outcomes to such an extent that detection of any additional benefit conferred by IVIG would require prohibitively large numbers of study subjects.
This study has several limitations. First, the use of administrative data precluded the use of the formal case definition of streptococcal TSS[44
] to identify the study cohort. We attempted to minimize such misclassification bias by using a rigorous definition of streptococcal TSS that incorporated ICD-9 discharge diagnosis codes and billing data for receipt of intravenous penicillin. However, discharge diagnosis coding may be unreliable for specific diseases or pathogens. Furthermore, it is possible that IVIG recipients were more likely to have streptococcal TSS than non-recipients. If the outcomes of these groups of patients differed, then our approach would underestimate the actual benefit of IVIG.
Second, it is likely that we were underpowered to detect small benefits of IVIG use on mortality in streptococcal TSS. However, since the overall mortality rate in children with streptococcal TSS is considerably lower than mortality in adults, any absolute reduction in mortality attributable to IVIG in children with streptococcal TSS is likely to be minimal. Furthermore, given the relative rarity of streptococcal TSS in children, it is unlikely that a randomized controlled trial of IVIG use in children with streptococcal TSS will ever be conducted. Despite the fact that streptococcal TSS occurs more commonly in adults, the only randomized trial of streptococcal TSS and IVIG use in adults was terminated early due to low enrollment; the numbers of patients in our study was 6-fold greater than the number enrolled in the adult randomized trial.
Third, the effectiveness of IVIG may be underestimated in our study because neutralizing activity against various streptococcal superantigens could not be determined for any of the IVIG doses administered. Titers against streptococcal superantigens vary in different IVIG preparations[45
] and such differences, at least in theory, could influence IVIG effectiveness. Fourth, there may be confounding by indication for IVIG use in streptococcal TSS. We attempted to account for this possibility by including variables associated with increased illness severity (e.g., vasoactive infusions, blood product administration) in our propensity score. The matched patients had a similar distribution of these factors. However, as in any observational study, there may still be residual confounding from unmeasured confounders. Finally, while matching patients on propensity score balances covariates between two groups (in this case, IVIG recipients and non-recipients) better than other matching methods, the exclusion of unmatched patients may bias the study. This form of spectrum bias (i.e., the most ill patients are excluded) would cause us to overestimate the benefit of IVIG.
In conclusion, the role of IVIG in children with streptococcal TSS has been controversial. Until now, pediatricians have had to decide the extent to which findings from experimental animal models and adult studies are applicable to the treatment of children with streptococcal TSS. In our large multicenter observational study of children with streptococcal TSS, mortality was substantially lower than reported in studies of adults. IVIG use increased the costs of hospitalization but was not associated with improved clinical outcomes. While it may be reasonable to recommend IVIG as adjunctive therapy for adults with streptococcal TSS, our data do not support its use in children with streptococcal TSS.