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Severe Group A Streptococcal Soft-Tissue Infections in Ontario: 1992–1996

  1. Abdu Sharkawy1,
  2. Donald E. Low1,
  3. Raphael Saginur2,
  4. Daniel Gregson3,
  5. Benjamin Schwartz4,
  6. Peter Jessamine2,
  7. Karen Green1,
  8. Allison McGeer1, and
  9. Ontario Group A Streptococcal Study Groupa
  1. 1Departments of Microbiology and Medicine, Mount Sinai Hospital, University of Toronto, London, Ontario, Canada
  2. 2Department of Medicine, Ottawa Hospital, University of Ottawa, London, Ontario, Canada
  3. 3Department of Medicine, St. Joseph's Health Centre, London, Ontario, Canada
  4. 4Centers for Disease Control and Prevention, Atlanta, Georgia
  1. Reprints or correspondence: Dr. Allison McGeer, Room 1460, Dept. of Microbiology, Mount Sinai Hospital, 600 University Ave., Toronto, Ontario, Canada M5G 1X5 (amcgeer{at}mtsinai.on.ca).

  • ↵a Study group members are listed at the end of the text.

 
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Abstract

A prospective, population-based, surveillance study of invasive soft-tissue infections due to group A streptococci was conducted in Ontario, Canada, from 1992 through 1996. Demographic and clinical information was obtained by patient interview and chart review. Isolates were characterized by M protein and T agglutination typing. The incidence of necrotizing fasciitis (NF) increased from 0.08 cases per 100,000 population in 1992 to 0.49 cases per 100,000 population in 1995. The case-fatality rate was 13% (68 of 520 patients died). Hypotension and multiorgan dysfunction complicated 64 cases (12%), and NF complicated 119 cases (23%). Underlying diabetes, alcohol abuse, cancer, and cardiac and pulmonary disease increased the risk of disease. Prior use of nonsteroidal anti-inflammatory agents did not influence disease severity. All 197 patients without NF, underlying illness, and hypotension at presentation survived, as did 95 (99%) of 96 normotensive patients who were <65 years old but who had underlying chronic illness. Previously healthy patients without hypotension or NF may be considered for outpatient treatment.

After 50 years of decreasing rates of morbidity and mortality related to group A streptococcal (GAS) infections, the past decade has witnessed a resurgence of severe disease that has not yet been explained [1–10]. The failure to explain this phenomenon is in part because much of what has been reported is derived from case reports and hospital-based case series that have been limited by sample size and referral biases [1, 3, 5, 8]. The objectives of this study were to prospectively obtain population-based data on risk factors for invasive GAS infection with a soft-tissue focus, to describe its epidemiology, to characterize disease presentations, and to assess prognostic indicators.

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Methods

Population-based surveillance. From 1 January 1992 through 31 December 1996, a prospective, population-based, surveillance study of all invasive GAS infections in Ontario, Canada (population in 1996, 11.2 million persons) was performed [10]. All microbiology laboratories serving Ontario hospitals telephoned the study office when Streptococcus pyogenes was isolated from specimens recovered from sterile sites. Attending physicians and hospital infection-control practitioners were contacted to confirm that the patient was an Ontario resident and to obtain clinical and demographic data (age, sex, comorbid conditions, site of infection, clinical manifestations, treatments, and outcome). Annual audits were done in all laboratories to ensure reporting accuracy.

“Invasive GAS disease” was defined as the isolation of GAS from a normally sterile body site. “Soft-tissue infection” was defined as infection associated with inflammation of skin or soft tissue but that excluded cervical adenitis, pharyngeal infections, and cutaneous inflammation overlying septic arthritis. For soft-tissue foci, normally sterile sites included blood, intraoperative or postmortem tissue specimens, intraoperative swabs, or aspirates of soft tissue or abscesses. “Severe systemic disease” was defined as the presence of hypotension (systolic blood pressure, <90 mm Hg, or <5th percentile for age) plus ⩾2 of the following characteristics: acute renal failure (creatinine level, >176 µmol/L, or >2 times the baseline value in the patients with chronic renal failure); coagulation abnormalities (platelet count, <100,000 × 109 platelets/L, or evidence of disseminated intravascular coagulation); hepatic dysfunction (aspartate aminotransferase or alanine aminotransferase level of 2 times the upper limit of normal or, in patients with chronic liver disease, of 2 times the baseline value); and adult respiratory distress syndrome [11, 12]. Infections occurring at sites of lymphatic drainage were identified as those that occurred in the upper arm, axilla, thigh, or groin, that involved no antecedent skin lesion or trauma at these sites. “Nosocomial cases” were defined as those in which disease was neither present nor incubating at the time of admission [13]. “Necrotizing fasciitis” (NF) was defined as described elsewhere [9]. To estimate the incidence and relative incidence of disease in persons with chronic illness, we classified cases into the same chronic disease categories used by the Ontario Health Survey and combined prevalence data on chronic underlying illness from the Ontario Health Survey with category-specific numbers of cases from surveillance [9, 14].

The study was approved by the Human Subjects Review Committee of the University of Toronto.

Laboratory methods. Clinical isolates were confirmed as S. pyogenes by use of standard methods. M protein and T agglutination typing [15] and PCR detection of streptococcal pyrogenic exotoxin genes A and C (speA, speC) were done at the Canadian National Centre for Streptococcus in Edmonton [16].

Statistical analysis. Differences in group proportions were assessed by use of the χ2, likelihood ratio χ2, and Fisher's exact tests. Differences in mean and median values were assessed by Student's t test or the Wilcoxon rank-sum test, respectively. Differences in the incidence of disease among groups of patients were assessed with a normal approximation for the comparison of Poisson counts [17]. Logistic regression modeling (with SAS, version 6.12 for PC; SAS Institute) was used for multivariate analysis of factors available at diagnosis that were useful in predicting NF, severe systemic disease, and mortality. The variables considered in univariate analysis were age, sex, presence of underlying illness, location of soft-tissue infection, use of nonsteroidal anti-inflammatory drugs (NSAIDs), blood pressure at presentation, and initial laboratory values. Variables considered for inclusion into multivariable models were those potentially associated with these outcomes (P < .10) in univariate analysis. We first evaluated colinearity of variables and attempted to select variables representing independent risks of disease severity. We then used stepwise backward elimination of variables to arrive at a final model. Secondary analyses were also done, taking into account only infections in which cultures of blood samples yielded positive results. Because there were no differences in identified risk factors or the magnitude of ORs between these analyses and the primary analyses, only data from the primary analyses are presented.

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Results

Patient characteristics and disease presentation. From January 1992 through December 1996, 524 cases of soft-tissue infection due to invasive GAS were identified. Complete clinical data were available for 474 cases (90%). Data on use of NSAIDs were collected in 1992, 1993, and 1995 and were available for 316 (76%) of 415 cases during this time period.

The annual incidence of invasive disease with a soft-tissue focus ranged from 0.62 cases per 100,000 population in 1992 to 1.29 cases per 100,000 population in 1995 (P < .001). Most of this variability was in the annual rate of NF, which ranged from 0.08 cases per 100,000 population in 1992 to 0.49 cases per 100,000 population in 1995 (figure 1). There were no differences in the age or sex distribution of patients, the case-fatality rate, or the proportion of patients with severe systemic disease during the 5-year period.

Figure 1
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Figure 1

Occurrence of invasive group A streptococcal soft-tissue infections in Ontario, Canada, by month, 1992–1996. Left to right, months are January, April, July, and October. Solid bars, cases of necrotizing fasciitis; hatched bars, nonnecrotizing infections.

The median age of patients was 47 years (range, 0–102 years). The incidence of all invasive soft-tissue infection, including NF, was highest among elderly patients (figure 2). Cases were more likely to occur in male patients (overall average annual rate, 1.1 cases per 100,000 male patients vs. 0.80 cases per 100,000 female patients; P < .001). Sixty-six cases (13%) were nosocomial, and 27 (5%) occurred in residents of nursing homes.

Figure 2
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Figure 2

Age-specific rates of invasive group A streptococcal soft-tissue infections occurring in Ontario, 1992–1996. Solid bars, cases of necrotizing fasciitis; open bars, nonnecrotizing infections.

A total of 237 (50%) of 474 cases occurred in patients with ⩾1 chronic underlying illness, of which diabetes mellitus and alcoholism were the most common (table 1). The incidence of infection was significantly increased in patients with chronic illness (table 2).

Table 1
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Table 1

Underlying chronic illness and other characteristics of patients with invasive soft-tissue infection due to group A streptococci, Ontario, 1992–1996.

Table 2
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Table 2

Risk of invasive group A streptococcal soft-tissue infection associated with selected underlying conditions.

In univariate analyses of patient and disease characteristics available at presentation, the factors that were significantly associated with NF were hypotension, the absence of cancer, and infection at sites other than the head and neck (table 3). In multivariate analysis, all 3 factors were retained in the model. WBC count at presentation was not different between patients with NF (median, 13.8 × 109 cells/L) and those without NF (median, 14.7 × 109 cells/L; P = .36). Patients with NF had statistically significantly lower platelet counts and higher serum creatinine and creatine phosphokinase values than did patients without NF, but the overlap was substantial, and the addition of laboratory test results did not significantly improve the model's ability to predict the presence of NF (data not shown). In univariate and multivariate analysis of patient and disease characteristics available at presentation, only the presence of NF (OR, 5.6; 95% confidence limits, 2.9, 11) and the presence of infection at a lymphatic drainage site (OR, 3.0; 95% confidence limits, 1.2, 7.5) were significantly associated with severe systemic disease.

Table 3
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Table 3

Risk factors for death in 524 patients with invasive group A streptococcal soft-tissue infections.

Microbiology. The majority of patients (316 [60%] of 523 patients) had bacteremia. Among the 208 patients without bacteremia, S. pyogenes was isolated from postmortem or intraoperative tissue or swab samples obtained from 153 patients and from abscess or tissue aspirate samples obtained from 55 patients. Of the 443 isolates available (85%), the 6 most common M serotypes were M1 (24%), M12 (10%), M3 (9%), M28 (7%), M6 (6%), and M4 (5%). Sixty-one percent of all cases of invasive disease, 78% of all cases of NF, and 71% of fatal cases of infection were caused by isolates of 1 of these 6 serotypes.

Mortality. The overall case-fatality rate was 13%. In multivariate analysis of factors identifiable at presentation, hypotension, increased age, and underlying chronic illness were significantly associated with an increased case-fatality rate (table 4). None of the 198 patients (including 92 who had bacteremia) who did not have hypotension or chronic underlying illness died (upper 95% confidence limit, binomial distribution, 1.5%), versus 10 (6%) of 162 patients who had chronic underlying illness but no hypotension, 5 (15%) of 34 who had hypotension but no chronic illness, and 38 (54%) of 70 who had both (P < .0001; determined by analysis of variance). Of the 158 patients who had chronic underlying illness but no hypotension for whom age was known, 1 of 96 patients aged <65 years died, compared with 9 of 62 patients aged ⩾65 years (P = .001).

Table 4
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Table 4

Risk factors for death in 524 patients with invasive group A streptococcal soft-tissue infections.

Patients with positive blood culture results were more likely to die (61 [19%] of 315 vs. 7 [3.4%] of 205; P < .001) and to have severe systemic disease (37 [12%] of 301 vs. 10 [4.9%] of 203; P = .008). Patients who were infected with M1 and M3 strains were more likely to have NF than were other patients: 22 (55%) of 40 patients infected with M3 strains had NF compared with 34 (32%) of 105 infected with M1 strains and 46 (16%) of 295 infected with other M serotypes. Patients infected with M3 strains were also more likely to die: 11 (28%) of 40 patients who were infected with M3 strains died, compared with 11 (10%) of 105 patients who were infected with M1 strains and 36 (12%) of 293 who were infected with strains of other serotypes.

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Discussion

Although rates of invasive GAS disease appear to be stable in some populations, the majority of recent evidence supports the contention that this disease is increasing in both incidence and severity [1, 4, 7, 8]. During the 5 years of surveillance in Ontario, the incidence of invasive GAS disease with a soft-tissue focus increased nearly 2-fold and that of NF increased >5-fold. Changes were not attributable to M serotype of GAS or an increase in disease in any particular age group or geographic area. Bacteremic patients did not differ from nonbacteremic patients with regard to the rates of infection, and the proportion of cases detected in an audit did not differ from year to year, suggesting that reporting biases do not explain the differences in rates. Although culture may have been performed with increasing frequency for persons with soft-tissue infection during this period, it seems unlikely that changes in rates of blood and tissue culture alone could be enough to explain why the incidence of infection increased from 1992 to 1995. Year-to-year variability in rates of invasive GAS infection has not been well studied, and the rates of increase in overall invasive disease during the 5 years of the study may not represent a longer-term trend. However, the increased incidence of NF is striking, and we believe this represents a significant change in the epidemiology of GAS disease in our population.

Initial case series describing the resurgence of severe GAS disease identified an apparent association between severe systemic disease and NF in young, previously healthy adults [1, 5]. Subsequently, a population-based analysis of GAS bacteremia from Pima County, Arizona, from 1985 through 1990, failed to find an association between NF and shock or organ-system dysfunction [7]. Data regarding infections with M3 strains in Ontario documented that organism characteristics associated with NF and severe systemic disease were different [18]. In multivariate analysis of this cohort of patients with invasive soft-tissue infection, NF is strongly associated with severe systemic disease. One reasonable hypothesis to explain these conflicting results is that the multiple virulence factors associated with GAS provide >1 mechanism for the development of sepsis syndrome and/or NF.

In attempting to understand risk factors for NF, it is important to distinguish between risk factors for soft-tissue infections and risk factors for NF. For example, diabetic patients are at increased risk for invasive GAS infection at any site. However, the relative risk of invasive soft-tissue infection in diabetic patients is 4 times greater than that of other invasive infections, such as pneumonia or arthritis [10]. There are several possible explanations for this finding, including vascular insufficiency and peripheral neuropathy. When all infections due to GAS are considered, diabetic patients are at increased risk of NF. However, our data demonstrate that this risk is entirely the result of the increase in risk of soft-tissue infection. In the setting of established soft-tissue infection, the presence of diabetes per se does not predispose persons to either NF or severe systemic illness.

There are several possible reasons why patients with cancer and soft-tissue infections may be less likely to develop NF. It is possible that the natural progression of NF depends on a certain level of immune integrity that is altered by neoplastic disease. Such factors as distinctive portals of entry (e.g., via central venous access) may also be important. In addition, because 40% of the infections in patients with cancer were nosocomial in origin, and because hospitalized patients with cancer may have infections diagnosed and treated early, it is possible that early aggressive treatment may reduce the risk of NF.

At least 3 other recent studies have attempted to define risk factors for NF [19–22]. Our findings are in agreement with those of Hsieh et al. [23] and Simonart et al. [24], in that indicators of severity of illness (such as hypotension at presentation) are associated with the presence of NF, but no single result or combination of results yielded useful sensitivity or specificity. In the study by Wall et al. [25], a WBC count of >15.4 × 109 cells/L and/or a serum sodium level of <135 µM had a sensitivity of 90% and a specificity of 76% for NF [25]. Although we did not assess serum sodium levels at presentation, patients with NF in our cohort had, on average, a lower WBC count than did others, which makes it unlikely that the score would perform well for our patients. This may in part be because 68% of the patients in the study by Wall et al. [25] were injection drug users, whose infections may have a different pathogenesis than do other soft-tissue infections.

Several case reports and a case-control study have implicated the use of NSAIDs with severe presentations of invasive GAS disease [19–22, 26–30]. NSAIDs are known to impair granulocyte adherence, phagocytosis, and bactericidal activity; to augment inflammatory cytokine release; and to inhibit renal prostaglandin synthesis. These activities potentiate renal failure. However, experimental data establishing the effect of these functions in the setting of sepsis are lacking, and in 1 animal model, administration of diclofenac after infection protected rabbits from NF instead of potentiating tissue damage [31]. In this cohort analysis, the majority of patients who were receiving NSAIDs were receiving long-term treatment for other illnesses. In this setting, our data suggest that there is no association between NSAID use and NF, severe systemic disease, or mortality. Few patients started taking NSAIDs after the onset of illness due to GAS; within this group, those who received NSAIDs were more likely to have NF than were those who did not receive NSAIDs. However, systemic disease was not more severe, and, because the NSAIDs were taken for management of pain and fever associated with the illness, it is not possible to determine whether NSAIDs cause more-severe soft-tissue infection or are taken for more severe symptoms.

Our data support evidence reported elsewhere [1, 5–8] that serotypes M1 and M3 are associated with more severe disease. However, our data also emphasize the need for group A streptococcal vaccines, like pneumococcal vaccines, to include antigens from multiple M serotypes; nearly half of all cases of NF and 62% of all deaths resulted from infections with serotypes other than M1 and M3.

Cellulitis is a common disease that is seldom life threatening and can usually be managed in an outpatient setting. Several recent studies have emphasized the generally good outcomes associated with cellulitis and have suggested that the great majority of cases may be managed without hospitalization [32–35]. Our data, although limited to disease caused by group A streptococci, support this contention. All patients in this series were admitted to hospitals, all had positive results of cultures of samples of sterile sites, and 60% had bacteremia. Despite this, no patients without chronic underlying illness or hypotension died, and the case-fatality rate among patients aged <65 years who had underlying illness was 1%. Because the only active interventions for patients without hypotension or other complicating chronic illnesses are antibiotic therapy and local wound care, these data suggest that the majority of such patients who have GAS bacteremia with a soft-tissue source may safely be treated in an outpatient setting. However, it is important to remember that NF can be missed early in its course and may progress despite administration of intravenous antibiotic therapy; thus, adequate follow-up is needed to assess disease progression and response to therapy [36].

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Ontario Group A Streptococcal Study Group

Other study group members are H. D. Davies (Alberta Children's Hospital, Calgary, Alberta), W. Gold (University Health Network, Toronto), M. Loeb (Hamilton Health Sciences Corporation, Hamilton, Ontario), J. Talbot and M. Lovgren (National Centre for Streptococcus, Edmonton, Alberta), B. Mederski (North York General Hospital, North York, Ontario); L. Trpeski (Mount Sinai Hospital, Toronto); A. Sarabia (Peel Memorial Hospital, Brampton, Ontario); A. Simor (Sunnybrook and Women's College Health Sciences Centre, Toronto); and B. Willey (Mount Sinai Hospital, Toronto).

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Acknowledgements

We are indebted to the microbiology laboratories, infection control practitioners, and physicians across Ontario; without their time, effort, and enthusiasm, this surveillance would not be possible. We also thank the many staff members of the Ontario Ministry of Health and public health departments across Ontario, who have supported this study

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Footnotes

  • Financial support: Centers for Disease Control and Prevention (Atlanta, Georgia) and MDS Health Group (Toronto, Ontario, Canada).

  • Received May 2, 2001.
  • Revision received September 10, 2001.
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  1. Clin Infect Dis. (2002) 34 (4): 454-460. doi: 10.1086/338466
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