ORIGINAL ARTICLE

http://dx.doi.org/10.5546/aap.2016.eng.199

Multicenter study on invasive Streptococcus pyogenes infections in children in Argentina

 

Aldo D. Cancellara M.D.^a, Pablo Melonari M.D.^b, María V. Firpo M.D.^c, Andrea Mónaco M.D.^d, Gustavo C. Ezcurra M.D.^e, Lía Ruiz M.D.^f, Alicia M. Aletti M.D.^g, Gabriela Gregorio M.D.^h, Alejandra Gaiano M.D.ⁱ, Alberto Aird M.D.^j, Luciana Bellone M.D.^k, Miriam Calvari M.D.^l, Carolina Torregrosa M.D.^ll, Sandra Morinigo M.D.^m, María L. Vozza M.D.n, Ivana Tonetto M.D^ñ, Luis P. Flynn M.D.^o, Nancy M. Bidone M.D.^p, Carlota Russ M.^q and Alejandro Ellis M.D.^r

a. Hospital de Niños Pedro de Elizalde, Autonomous City of Buenos Aires.
b. Hospital Pediátrico Dr. Notti, Villa Nueva de Guaymallén, Mendoza.
c. Hospital del Niño Jesús, San Miguel de Tucumán, Tucumán.
d. Hospital de Niños Pedro de Elizalde, Autonomous City of Buenos Aires, Argentina.
e. Hospital de Niños Dr. Orlando Alassia, Santa Fe, Santa Fe.
f. Hospital de Niños de la Santísima Trinidad, Córdoba.
g. Hospital de Niños Víctor J. Vilela, Rosario.
h. Hospital A. Posadas, El Palomar, Buenos Aires.
i. Hospital Materno Infantil de San Isidro, San Isidro.
j. Hospital Infantil Municipal, Córdoba.
k. Hospital Regional Ushuaia, Ushuaia, and Hospital Regional de Río Grande, Río Grande.
l. Hospital Pediátrico del Niño Jesús, Córdoba.
ll. Sanatorio Mater Dei, Autonomous City of Buenos Aires.
m. Hospital Pediátrico Dr. Avelino Castelán, Resistencia.
n. Hospital Misericordia Nuevo Siglo, Güemes Capital neighborhood, Córdoba.
ñ. Hospital Interzonal Penna, Bahía Blanca, Buenos Aires.
o. Sanatorio de Niños, Rosario, Santa Fe, and Hospital Italiano, Rosario, Santa Fe.
p. CEMIC, Autonomous City of Buenos Aires
q. Fundación Hospitalaria, Autonomous City of Buenos Aires
r. CEMIC and Sanatorio Mater Dei, Autonomous City of Buenos Aires.

E-mail address: Aldo D. Cancellara, M.D. : adcancel@intramed.net

Funding: None.

Conflict of interest: None.

Received: 08-27-2015
Accepted: 11-23-2015

 

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ABSTRACT

Introduction. Invasive Streptococcus pyogenes infections (ISpIs) cause a high morbidity and mortality, even at present; however, at a regional level there are few publications on this subject in the field of pediatrics.
Objective. To describe the prevalence, predisposing factors and clinical characteristics of children hospitalized for ISpI, and analyze risk factors associated with bacteremia and lethality. Material and methods. Retrospective, descriptive study on ISpIs in children <18 years old hospitalized in the Pediatric Ward of 20 healthcare facilities across Argentina between 2010 and 2012. Assessed outcome measures: age, gender, early and late clinical sources of infection, prior chronic condition, predisposing factors, treatment and evolution.
Results. One hundred and forty-three patients were analyzed. The incidence of ISpI was 4.97 cases/10 000 hospital discharges. Patients' median age was 54 months old, and 11.2% had a prior chronic condition. Also, 67.1% had predisposing factors. The most common clinical manifestations were in the skin and soft tissue in 77 patients, sepsis in 30, bone and joint involvement in 19, necrotizing fasciitis in 13, and toxic shock syndrome in 11. Streptococcus pyogenes was isolated in the blood cultures of 56.6%. More than one clinical source of infection and no surgery were associated with bacteremia (odds ratio [OR]: 4.8, p= 0.003 and OR: 3.1, p= 0.0012, respectively). The average length of stay in the hospital was 13.4 days. Fatality rate was 7.6% in association with toxic shock syndrome (OR: 10, p= 0.005), necrotizing fasciitis (OR: 104, p < 0.0001) and admission to the Pediatric Intensive Care Unit (OR: 26, p < 0.001).
Conclusions. Most ISpIs were observed in patients without a prior chronic condition. The most common manifestation was, frequently with bacteremia, in the skin and soft tissue. A statistically significant association was observed between bacteremia and ≥2 early sources of infection and no surgery. Fatality rate, in association with streptococcal toxic shock syndrome and necrotizing fasciitis, was similar to that observed in other publications.

Key words: Streptococcus pyogenes; Necrotizing fasciitis; Toxic shock syndrome.

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INTRODUCTION

Beta-hemolytic Streptococcus or Streptococcus pyogenes has been recognized as an important bacterial agent since the beginnings of modern microbiology and is one of the top ten leading causes of mortality due to infections.¹

A wide range of clinical manifestations are the result of Streptococcus pyogenes, including pharyngitis, impetigo, scarlet fever and severe invasive infections.² Invasive Streptococcus pyogenes infections (ISpIs) are defined as those whose pathogen is isolated in normally sterile sites (blood, cerebrospinal fluid, joint fluid, etc. ), that cause bacteremia, osteomyelitis, cellulitis, meningitis, necrotizing fasciitis and streptococcal toxic shock syndrome (STSS), and have a high morbidity and mortality.³

Over the past three decades, the occurrence of ISpIs has increased worldwide.^3-8 ISpI's epidemiological features are complex. A greater aggressiveness has been associated with the emergence of more virulent strains related to M1 and M3 serotypes, capable of altering phagocyte function, and with the production of pyrogenic exotoxins, especially SpeA, which may act as superantigens.^6,9,10 In adults, overall fatality rate caused by invasive infections has been observed to range from 10% to 80%, in spite of an adequate management.^3,11 STSS accounts for more than 50% of fatality rate, while necrotizing fasciitis, for 10-20%. Studies conducted in the pediatric population have evidenced that severe invasive infections are less common and less lethal, accounting for 5-10% of deaths.¹²

In our setting, there are very few publications available in which the clinical characteristics and the course of this type of pediatric infections are analyzed.^13,14

The objective of this study is to describe the prevalence and clinical characteristics of ISpI in hospitalized children, identify its clinical signs and symptoms and risk factors, and analyze outcome measures associated with blood culture results and fatality rate.

MATERIAL AND METHODS

Design

Cross-sectional, descriptive, observational study conducted between January 1st, 2010 and December 31st, 2012. All patients with ISpI and hospitalized in 20 healthcare facilities located across Argentina were included. Participating facilities were those that accepted the invitation made by the National Committee on Infectious Diseases of the Argentine Society of Pediatrics.

Eligibility criteria

Patients were initially screened by reviewing the records of the Department of Microbiology of participating facilities: isolation of Streptococcus pyogenes in blood samples or puncture fluid tests (cerebrospinal, pleural, abscess or osteoarticular fluids). Medical records of identified patients were then reviewed to assess outcome measures: age, site of infection, early and late clinical sources of infection (>72 h), prior chronic condition, predisposing factors, lab test alterations and evolution.

Inclusion criteria

• Patients younger than 18 years old hospitalized in the Pediatric ward (patients hospitalized in the Department of Neonatology were excluded).
• Hospitalized in any of the participating facilities, and with documented invasive Streptococcus pyogenes infection.
• Living in Argentina.

Definitions

Invasive Streptococcus pyogenes infection was considered based on the criteria established by the working Group on Severe Streptococcal Infections, and defined as the isolation of Streptococcus pyogenes in the blood culture of a normally sterile site (cerebrospinal, synovial, peritoneal or pleural fluid) or a tissue biopsy.³

Infections were considered nosocomial if acquired more than 72 hours after the patient hospitalization.

Sample size

Assuming an invasive infection incidence of 4/10 000 hospitalizations, with a 2 in 10 000 precision, it was proposed a sample including at least 38 401 medical records (denominator) to assess cases with a 95% confidence level.

Assessment record

A separate record was specially designed to collect data. Assessed outcome measures included prior chronic condition, predisposing factors, clinical manifestation, microbiological characteristics, treatment and evolution (Annex).

Microbiological samples were processed and microorganisms were identified and typified using standard microbiological procedures.¹⁵

Necrotizing fasciitis was defined as a rapidly destructive and progressive infection of subcutaneous tissue involving the muscle fascia.¹⁶ STSS was considered based on publications.¹⁷

Treatment

The following options were considered, either in combination or monotherapy.

• Initial empiric antibiotic treatment with subsequent antibiotic cycling. Treatment was considered adequate if the empiric antibiotic had coverage against Streptococcus pyogenes, and if it was associated with clindamycin during antibiotic cycling.
• Surgery, drainage and/or debridement requirement.
• Use of intravenous gamma globulin at a recommended dose of 2 g/kg at the time of diagnosis of STSS or necrotizing fasciitis.¹
• Requirement for admission to the Pediatric Intensive Care Unit (PICU).

Course

Discharge was recorded according to one of the following criteria:

• Discharge without sequelae, discharge with sequelae, or deceased.

Statistical analysis

The incidence of ISpI was estimated based on each hospital's data.

Antibiotic susceptibility was summarized as an absolute value and a relative value of the total studied samples.

The STATA 11 software was used for data analysis. Studied cases were described using, for continuous outcome measures, mean, standard deviation, median and minimum-maximum and, for categorical outcome measures, rate and odds ratio (OR) with the corresponding 95% confidence interval. Comparisons were made based on blood culture result (positive-negative) and death (yes-no) using the χ² test or Fisher's test. Results were considered statistically significant if their significance level was 0.05 or lower (p ≤ 0.05).

RESULTS

Data from 143 patients were analyzed. Ninety-two patients were male (64.3%). Patients' median age was 54 months old (range: 1-168 months old); 23.8% were younger than 24 months old. Sixty-four percent of cases occurred in the spring or summer.

The overall incidence in the study period was 4.97 cases/10 000 hospital discharges (143/287 760), with a discharge rate of 3.69 (35 cases), 6.15 (60 cases) and 5.76 (48 cases) per 10 000 hospital discharges between 2010 and 2012, with variations among the different facilities (Table 1). Most patients (130) had acquired the infection outside the hospital setting, while 13 (9%) had a nosocomial infection.

Table 1. Rate of invasive Streptococcus pyogenes infections

No prior chronic condition was observed in 88.8% of children (127/143). Among the 11.2% (16/143) of patients who had a prior chronic condition, recurrent wheezing and/or bronchial asthma was observed in 8, heart disease in 5, diabetes in 2, and epilepsy, dysautonomia, obesity, malnutrition, rheumatic disease and hematological disease each in 1 patient. Some patients had more than one condition.

Predisposing factors were present in 67.1% of patients (93/143): chickenpox in 31, prior trauma in 31, impetigo in 24, surgery in 10, eczema in 6, burn wound in 3. Other skin lesions not included in the above categories were more common (abrasions, lacerations, puncture wounds, etc. ), which were observed in 38 patients. Some patients had more than one predisposing factor. No predisposing factor was detected in 32.9% (47/143) of patients.

Figure 1 shows the early and late clinical manifestations. Some patients had more than one clinical source of infection. Two or more early sources of infection were observed in 26.6% (38/143) of patients. Children with more than one early source of infection were more likely to have a positive blood culture, compared to those who had a single early source of infection (OR: 4.8, p= 0.0003).

Figure 1. Early or late clinical manifestations (N: 143 patients)

Leukocytosis above 15 000/mm³ was seen in 73.2% of patients, while 21.6% had more than 20 000/mm³. Erythrocyte sedimentation rate >30 mm in the first hour was detected in 68.0% (66/97) of studied patients. Abnormalities in liver function tests were observed in 25.5% (13/51). Lactate dehydrogenase was high in 86.7% (13/15) of studied patients, creatine phosphokinase was high in 77.8% (7/9), and creatinine, in 30.3% (17/56) of those who had this test requested.

Streptococcus pyogenes was isolated from blood cultures in 81 patients (56.6%); the pathogen was isolated from the skin and soft tissue in 45, from joint fluid in 10, from cerebrospinal fluid in 7, and from pleural fluid in 6. The agent was isolated from more than one site in some patients.

An adequate initial empiric antibiotic treatment was administered to 142 patients (only 1 received azithromycin empirically). The antibiotic schedule was changed once culture results were available from 88 patients; in these cases, the most common schedule included beta-lactam antibiotics and clindamycin.

Surgical drainage was performed in 63 patients (44.0%). Children who had no surgery were more likely to have a positive blood culture compared to those who had undergone surgery (OR: 3.1, p= 0.0012) (Table 2). Intravenous gamma globulin was administered to 9 patients (6.3%). Four patients had sequelae (2.8%).

Table 2. Outcome measures related to blood culture results. Univariate analysis

The average hospital length of stay was 13.4 days (range: 1-80 days). Admission to the ICU was required in 20.3% (29/143). As per the univariate analysis, children admitted to the PICU had a much higher chance of dying than those who were not admitted to the PICU (OR: 26, p < 0.0001) (Table 3).

Table 3. Outcome measures associated with lethality. Univariate analysis.

The overall fatality rate was 7.69% (11 patients). Among children with STSS, death was more probable (4/11) compared to those who did not have STSS (OR: 10, p= 0.005). Among children with necrotizing fasciitis death was much more probable (5/11) compared to those who did not have it (OR: 104, p < 0.0001).

DISCUSSION

Over the past decades, several studies have indicated that ISpI cases have increased, both in adults and children.^2-5,10,18 In our setting, our series accounts for the largest number of cases reported in children, whose median age was 54.0 months old, similar to the median age reported by Davies et al. of 48 months old,¹² and to that reported by Zachariadou et al. of 5.4 years old, but younger than the mean age referred by Burnett of 7.8 years old.²⁰

Although in our study the hospitalization rate was greater in 2012 than at the study initiation, the limited period allows to show an actual increasing trend in invasive infections, as pointed out by other publications.^5,7,8,21

A history of chronic conditions was detected in 11.2% of children, similar to what was reported by Stockmann in a review of 1514 ISpI cases in Utah, where 11% of children and 51% of adults had a history of comorbidities (p < 0.001).⁷ In our series, the most common chronic conditions were recurrent wheezing and/or asthma, followed by heart disease, which was the prevailing condition in Stockmann's study.⁷ A review of the literature regarding adult patients evidences that a prior disease is more common in this population than among pediatric patients.^6,16,22

Predisposing factors were observed in 67.1% of our patients. Chickenpox as a predisposing factor was well described by Laupland et al.²³ In our study, chickenpox was detected in 21.6% of patients, similar to what was reported by Zachariadou et al. ,¹⁹ and higher than in other recent studies conducted in other countries of the same region where chickenpox immunization is part of the national immunization schedule.¹⁸ According to the predisposing factors observed in our series, skin was the prevailing source of infection.²⁴

Skin and soft tissue infection was the most common early source of disease, similar to other publications.^{7,14,22,24-26} The rate of necrotizing fasciitis and STSS is lower than what has been published regarding adults^10,12 and similar to or lower than what was reported in other pediatric series.9,14,19,25-29

Bacteremia was present in 56.6% of our patients, which is higher than what was referred in our setting by Paganini et al. (39%),¹⁴ similar to the reports of Cancellara et al. (64%),²⁶ and somewhat lower than the 72%²⁸ and 74%¹⁹ reported in the international literature.

In our review, leukocytosis above 20 000/mm³ was not associated with a higher rate of bacteremia and fatality. Given the retrospective design of this study, there might be a bias in requested lab tests, which may have been ordered in those patients who had a more severe condition.

Purulent material was drained in 44.4% of patients as part of treatment, which is related to the prevailing skin and soft tissue sources of infection. Not having undergone a surgery was associated with a higher rate of bacteremia.

Although Shah et al.³⁰ did not find a statistically significant difference in mortality among patients with STSS who received intravenous gamma globulin and placebo, there is consensus regarding the use of intravenous gamma globulin in the more severe forms of ISpI.³¹ Given the retrospective nature of our study, not all facilities had recorded the gamma globulin schedule used and, although we believe use was scarce, the rate of overall fatality rate was similar to that published by other authors.

All, except one patient, received an adequate initial antibiotic treatment, which was then adapted to the recommended schedule with beta-lactams and clindamycin once culture results were available.^31-34

Only a small number of our patients (9%) acquired the infection in the hospital setting, which was in general associated with prior surgeries.

The fatality rate in our study was 7.69%, similar to that reported in other publications in the pediatric field.^14,28,35 The fatality rate associated with STSS and necrotizing fasciitis was 36% (4/11) and 38% (5/13), respectively. This underscores the highly-specific fatality rate caused by these two conditions, similar to what has been observed by Johansson, who described a 67% STSS fatality rate, compared to 4.9% among those who did not have STSS.²⁴

One of the limitations of this study is that the sample size was not enough to perform a multivariate analysis; in addition, and for the same reason, other significant associations may have gone undetected.

Another limitation is that, given the study's retrospective nature, it was not possible to establish whether the fatality rate observed in our study was related to other Streptococcus pyogenes virulence factors (based on antibiotic susceptibility, serotypes or emm genotypes, as mentioned in other publications).^4,6,11,13,35 Also, in this study the time elapsed between the onset of symptoms and the introduction of treatment with adequate antibiotics was not assessed.

ISpI is an ongoing health problem with a high rate of morbidity and mortality. It is important to suspect ISpI during an early diagnosis so as to start an adequate management.

CONCLUSIONS

Most ISpIs were observed in patients without a prior chronic condition. The most common manifestation was, frequently with bacteremia, in the skin and soft tissue. A statistically significant association was observed between bacteremia and more than two early sources of infection and no surgery. Fatality rate, in association with STSS and necrotizing fasciitis, was similar to that observed in other publications.

Acknowledgments

We would like to thank Laura Gutiérrez, B.S. in Statistics, Adriana Isola, Systems Analyst, the Work Group, and the Department of Bacteriology.

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