The Nationwide Children’s Hospital Institutional Review Board approved the study. We queried electronic medical records during January 2010–December 2017 for diagnosis codes from the International Classification of Diseases, 10th Revision, for toxic shock syndrome, severe sepsis with septic shock, GAS bacteremia, and necrotizing fasciitis. The addition of diagnoses other than TSS helped us identify 7 STSS patients who were discharged with diagnoses of sepsis and septic shock. In addition to discharge and admission diagnoses, we considered any diagnosis during the hospitalization period associated with these billing codes. We also reviewed preadmission records related to the admission diagnoses. We included patients in the study if their illness met criteria for definite or probable TSS. Where all CDC criteria for either STSS or NSTSS were fulfilled, we defined cases as definite (4,5). Where a single criterion was missing because of incomplete data or because GAS was isolated from a nonsterile site, we classified the case as probable (4). Data collected were age, sex, height, weight, body mass index, date of presentation, and clinical signs and symptoms (Table 1). We also collected duration of hospitalization; use and type of antimicrobial agents; use and timing of clindamycin, intravenous immunoglobulin (IVIg), or both after initial evaluation; and clinical outcomes, including mechanical intubation, amputation, and death. We reviewed several admission laboratory and radiologic parameters: complete blood count, urinalysis, blood urea nitrogen, creatinine, estimated glomerular filtration rate, alanine transaminase, aspartate transaminase, total bilirubin, creatinine kinase, coagulation studies, and chest radiographs. We also reviewed additional studies and any imaging study done during the hospitalization period that identified possible sites and sources of infection.

During the study period, 456 patients had diagnosis codes of TSS, severe sepsis with septic shock, GAS bacteremia, and necrotizing fasciitis at admission, discharge, or both. Our review of electronic medical records indicated that illnesses of 58 patients met the CDC diagnostic criteria for TSS. None of the patients had a prolonged preadmission course that would affect their treatment start time. Twenty-seven (47%) patients had STSS and 31 (53%) had NSTSS. Of the STSS patients, 16 had confirmed and 11 had probable STSS. Of the NSTSS patients, 11 had confirmed and 20 had probable NSTSS.

Data are limited on the incidence and management of children with TSS (3,8). Our large, single-institution retrospective analysis of 58 cases showed similarities and unexpected findings among children with TSS. In comparison with patients with NSTSS, children with STSS were younger, experienced more severe illness with higher rates of capillary leak and pulmonary symptoms, and had longer hospital stays. Similar to our findings, STSS has been associated with more severe disease and worse outcomes than NSTSS in the literature (2,3,7,8,15,17). Unlike our findings, those studies do not indicate whether late recognition and treatment of STSS in patients without rash played any role in the reported disease outcomes and hospitalization duration.

Case definitions for streptococcal and NSTSS are generally designed to optimize specificity rather than sensitivity. Our data suggest that unified criteria for TSS, rather than separate criteria for STSS and NSTSS, might improve sensitivity. We found that certain clinical and laboratory findings were common in both STSS and NSTSS but only included in the case definition of one or the other. First, although pyuria is a criterion for NSTSS but not for STSS (4,5), half the urinalyses performed in both groups demonstrated pyuria. Second, acute respiratory distress syndrome is a criterion for STSS but not for NSTSS. However, 61% of the patients in our study with NSTSS had diffuse pulmonary infiltrates and decreased PaO2:FiO2 ratio <200. Finally, coagulation abnormalities are included in the case definition of STSS but not NSTSS, yet most patients in both groups had abnormalities. The pulmonary involvement, pyuria, and coagulation abnormalities were common and were observed at admission. Case definitions are generally designed to have high specificity, sometimes at the expense of sensitivity. If the relatively inexpensive evaluation methods, such as urinalysis, chest radiograph, PaO2:FiO2 ratio of <200 and coagulation panels were incorporated into TSS evaluations, our data suggest that they might have aided accurate and timely diagnosis. Consideration of these additional organ dysfunctions, and considering TSS as a unifying diagnosis rather than as STSS and NSTSS, could potentially strengthen the conclusive diagnosis rather than discrediting it.

Data from published literature illustrate the importance of prompt recognition of TSS and early treatment (7,18–24). Complementary treatment with clindamycin improves the survival of patients with STSS by reducing toxin release (7,18–24). Although IVIg is suggested as a possible adjunctive agent, published patient outcomes have varied (24–28). IVIg functions by inhibiting T-cell activation that would result in decreased cytokine release, down-regulation of adhesion molecules, chemokine and chemokine-receptor expression, and neutralization of superantigens (25–28). In some studies, IVIg did not show significant benefit in treatment of patients with STSS (20,24,29). One report that pooled 5 studies of clindamycin and IVIg treatment for STSS showed the death rates decreased from 33.7% to 15.7% (30). We did not identify significant differences in hospitalization rates and duration of mechanical ventilation among patients treated with or without IVIg. Fewer than half the patients in our study received clindamycin and IVIg. Similarly, only 50%–67% of patients with severe GAS infection have received clindamycin (2,18,20,24). Our results suggest that the lack of appropriate treatment may be associated with absence of rash at the time of presentation. In our study, in STSS patients without rash, sepsis alone was often diagnosed, and the patients were not treated with clindamycin or IVIg. These patients also experienced delays in diagnosis and had longer hospital stays than those with a rash.

Our study had several limitations. Although Nationwide Children’s Hospital serves almost all of central Ohio’s children, our data were not population based and were from 1 pediatric center. We might not have identified all patients with NSTSS because we were unable to review individual charts for patients with staphylococcal bacteremia if they did not have additional diagnoses of sepsis or septic shock. Despite our efforts to capture the clinical and laboratory changes at the time of initial evaluation, the duration of illness, as well as rapidly changing signs such as rash, might not have been accurately recorded in the patient charts, which would affect the overall diagnosis and possibly lead to misclassification of patients. In addition, because of the retrospective nature of our study, none of the bacterial isolates were archived for further typing or microbiological analysis.

Our findings indicate organ system involvement in TSS beyond that predicted by existing CDC criteria. Because clinicians appear to rely on archetypal presentations of TSS (e.g., fever, hypotension, and rash) to diagnose TSS, updated clinical and diagnostic criteria would facilitate early accurate diagnosis and treatment. Physicians should be aware of TSS presentations without rash. Furthermore, the updated criteria may benefit from a unifying definition.