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# Necrotizing soft-tissue infections in pediatric intensive care: a prospective multicenter case-series study

Stéphane Dauger, Renaud Blondé, Olivier Brissaud, Marie-Odile Marcoux,

François Angoulvant, Michael Levy

► To cite this version:

Stéphane Dauger, Renaud Blondé, Olivier Brissaud, Marie-Odile Marcoux, François Angoulvant, et al.. Necrotizing soft-tissue infections in pediatric intensive care: a prospective multicenter case-series study. Critical Care, 2021, 25 (1), pp.139. 10.1186/s13054-021-03562-0. hal-03941829

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RESEARCH LETTER

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# Necrotizing soft-tissue infections in pediatric intensive care: a prospective multicenter case-series study

Stéphane Dauger<sup>1,2*</sup>①, Renaud Blondé<sup>3</sup>, Olivier Brissaud<sup>4</sup>, Marie-Odile Marcoux<sup>5</sup>, François Angoulvant<sup>6</sup>, Michael Levy<sup>1,7</sup>, Groupe Francophone de Réanimation et Urgences Pédiatriques (GFRUP) and Réseau Mères-Enfants de la Francophonie (RMEF)

To the Editor,

Necrotizing soft-tissue infections (NSTIs) are severe diseases with documented high morbidity and mortality rates in adults [1]. In pediatric patients, data are scant and prospective studies extremely scarce [2]. Eneli et al. [3] reported 36 cases collected prospectively in Ontario from 2001 to 2003. The largest studies used North-American databases and exhibited the biases inherent in this methodology [4, 5]. We designed a prospective international observational study of all severe NSTI cases seen in pediatric intensive care units (PICUs), to evaluate the outcomes and treatments.

From February 2011 to July 2016, we included consecutive patients with NSTI aged 1 month to 18 years and admitted to 33 PICUs located in high-resource countries (continental France and French overseas territories, Switzerland, Canada, and The Netherlands). Institutional review board approval (IRB-0006477) and parental consent to data recording were obtained. NSTIs are infections of any of the soft tissue layers during which tissue necrosis occurs. For this study, we defined NSTI as painful, rapidly progressive, superficial, spreading erythema

or skin necrosis, with laboratory evidence of inflammation and a fever (> 38.5 °C) or hypothermia (< 36 °C). We collected demographics; clinical, laboratory, and bacteriological data; radiological findings; and medical and surgical treatments. Descriptive data, collected without a statistical analysis plan, are reported as median [25th; 75th centiles], mean ± SD, or *n* (%).

In the 50 patients included during the 4.5-year period (Table 1), time from symptom onset to PICU admission was 2 [1; 2] days. Triggers were postoperative care (n=12; 24%) and trauma or animal bite (n=11; 22%). Severe comorbidities included cancer (n=10; 20%), varicella (n=9; 18%), and preexisting chronic skin disease (n=3; 6%). No predisposing factors were identified in 8 (16%) patients. At diagnosis, 10 (20%) patients had received non-steroidal antiinflammatory drugs, 5 (10%) immunosuppressive agents, and 3 (6%) glucocorticoids. Most patients had severe critical illness at admission, often with respiratory and circulatory failure, translating into high mortality prediction scores. Bacteria were recovered from 43 (86%) patients in blood cultures (n=16; 32%), skin swabs (n=16; 32%), and skin biopsies (n=4; 8%) (Table 2). Treatment combined respiratory support (58%), hemodynamic support (70%), antitoxin antibiotic (84%), and surgery (68%) (Table 2). Three (6%) patients died; all had severe comorbidities (mitochondrial cytopathy, solid tumor, and leukemia). Most patients had long hospital stays. Our sample was too small to identify factors associated with surgery or mortality.

<footnote>*Correspondence: stephane.dauger@aphp.fr</footnote>

<footnote n="1">¹ Pediatric Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Service de Médecine Intensive - Réanimation Pédiatriques, Hôpital Universitaire Robert Debré, Université de Paris, 48 boulevard Sérurier, 75019 Paris, France</footnote>

<footnote>Full list of author information is available at the end of the article</footnote>
<table><caption>**Table 1** Characteristics of the study patients during the first 24 h after admission</caption><thead><tr><th>Parameters</th><th>Values</th></tr></thead><tbody><tr><td>Age (months)</td><td>60 (17.8; 128.5)</td></tr><tr><td>Weight (kg)</td><td>17.5 (11; 42)</td></tr><tr><td>Males/females</td><td>21 (42%)/29 (58%)</td></tr><tr><td>In-hospital patients</td><td>25 (50%)</td></tr><tr><td>Scores on admission</td><td></td></tr><tr><td>PRISM-3 (first day in PICU)</td><td>9.5 ± 15.9</td></tr><tr><td>PIM-2 (first hour in PICU)</td><td>12.6 ± 23.3</td></tr><tr><td>PELOD (first day in PICU)</td><td>11.6 ± 25.1</td></tr><tr><td>POPC</td><td>1.6 ± 1.1</td></tr><tr><td>Clinical presentation</td><td></td></tr><tr><td>Body temperature (°C)</td><td>38.2 (37; 38.8)</td></tr><tr><td>Respiratory distress</td><td>33 (66%)</td></tr><tr><td>Hypotension for age</td><td>28 (56%)</td></tr><tr><td>Oliguria (&lt; 1 mL/kg/h)</td><td>14 (28%)</td></tr><tr><td>Main primary skin lesion</td><td></td></tr><tr><td>Erythrosis</td><td>27 (54%)</td></tr><tr><td>Necrosis</td><td>13 (26%)</td></tr><tr><td>Bullae</td><td>10 (20%)</td></tr><tr><td>Surface (% of total body surface)<sup>a</sup></td><td>6 (3; 10)</td></tr><tr><td>Location</td><td></td></tr><tr><td>Legs</td><td>13 (26%)</td></tr><tr><td>Arms</td><td>12 (24%)</td></tr><tr><td>Head/neck</td><td>12 (24%)</td></tr><tr><td>Chest/abdomen</td><td>13 (26%)</td></tr><tr><td>Laboratory tests</td><td></td></tr><tr><td>White blood cells (/mm³)</td><td>9 610 (5 445; 18 820)</td></tr><tr><td>Hemoglobin (g/dL)</td><td>9.7 (8.9; 11.2)</td></tr><tr><td>Platelets (/mm³)</td><td>187 500 (70 000; 305 250)</td></tr><tr><td>CRP (mg/L)</td><td>176 (85; 289)</td></tr><tr><td>Fibrinogen (g/L)</td><td>5 (3.7; 6.5)</td></tr><tr><td>Lactatemia (mmol/L)</td><td>2 (1.4; 3.8)</td></tr><tr><td>Total proteins (g/L)</td><td>52.5 (43.8; 63)</td></tr><tr><td>Urea (mmol/L)</td><td>4 (2.6; 5.9)</td></tr><tr><td>Creatinine (µmol/L)</td><td>28 (21; 57.5)</td></tr></tbody></table>

PRISM-3: Paediatric Risk of Mortality measured during the first 24 h after PICU admission; PIM-2: Paediatric Index of Mortality measured during the first hour after PICU admission; PELOD: Paediatric Logistic Organ Dysfunction, measured during the first 24 h after PICU admission; POPC: Paediatric Overall Performance Category

A few data were missing: CRP: 3, Fibrinogen: 7, Lactatemia: 1, Total proteins: 2, Urea: 1, and Creatinine: 1

The results of this largest prospective study of pediatric NSTIs to date confirm that this disease is rare in PICUs [2–6]. Predisposing conditions have shifted from varicella to healthcare and trauma [2, 3]. The percentage of body surface area involved on PICU admission was consistent with studies in adults [1], whereas a major difference in absolute value was noted (about 5 cm² in children vs. 12 cm² in adults), which may contribute to diagnostic delays in children. MRI was rarely used to assess lesion depth. As reported by others [2, 6], surgery was performed in two-thirds of patients, usually within 24 h, and aggressive medical treatments were used. This may explain the low mortality rate, in agreement with recent data [6], despite the high predicted mortality on admission. Most NSTIs were monobacterial and many were due to Gram-positive organisms, including methicillin-resistant *S. aureus* in a few patients, as previously reported [3]. Polyvalent immunoglobulin therapy was often used, perhaps due to frequent circulatory failure suggesting toxic shock, and might also have influenced mortality rates, as suggested in a recent adult study [1]. Strong collaboration between surgeons, anesthesiologists, and pediatric intensivists should be the cornerstone of NSTI management.

<footnote>a Lund and Browder chart. Data are reported as median [25th; 75th centiles], mean ± SD, or n (%)</footnote>
<table><caption>**Table 2** Assessments, treatments, and course of the disease during the PICU stay</caption><thead><tr><th>Parameters</th><th>Values</th></tr></thead><tbody><tr><td>Radiological assessment</td><td></td></tr><tr><td>Ultrasound</td><td>21 (42%)</td></tr><tr><td>CT scan</td><td>22 (44%)</td></tr><tr><td>MRI</td><td>7 (14%)</td></tr><tr><td>Identified bacteria</td><td>43 (86%)</td></tr><tr><td>Only one micro-organism/two or more micro-organisms</td><td>36 (72%)/7 (14%)</td></tr><tr><td>Gram positive</td><td>40 (91%)</td></tr><tr><td><i>Staphylococcus aureus</i></td><td>17 (39%)</td></tr><tr><td>Methicillin-sensitive</td><td>15 (88%)</td></tr><tr><td>Panton valentine Leukocidin</td><td>15 (88%)</td></tr><tr><td>Toxic shock syndrome toxin</td><td>10 (59%)</td></tr><tr><td>Group A β-hemolytic <i>Streptococcus</i></td><td>14 (32%)</td></tr><tr><td>Gram negative</td><td>12 (25%)</td></tr><tr><td><i>Escherichia coli</i></td><td>5 (11%)</td></tr><tr><td><i>Pseudomonas aeruginosa</i></td><td>4 (9%)</td></tr><tr><td>General treatments in the PICU</td><td></td></tr><tr><td>Mechanical ventilation/duration (days)</td><td>29 (58%)/3 (2; 3)</td></tr><tr><td>Fluid expansion/volume (mL/kg)</td><td>35 (70%)/37.5 (22.8; 65)</td></tr><tr><td>Vasopressors/duration (days)</td><td>27 (54%)/3 (2; 3)</td></tr><tr><td>Morphine/duration (days)</td><td>43 (86%)/5 (4; 10.5)</td></tr><tr><td>Benzodiazepine/duration (days)</td><td>33 (66%)/5 (2; 9)</td></tr><tr><td>Transfusion of blood products</td><td>25 (50%)</td></tr><tr><td>Transfusion of albumin</td><td>25 (50%)</td></tr><tr><td>Specific treatments</td><td></td></tr><tr><td>Surgery/time since admission (days)</td><td>34 (68%)/1 (1; 5)</td></tr><tr><td>One surgical procedure</td><td>15 (44%)</td></tr><tr><td>Multiple surgical procedures/median per patient</td><td>19 (56%)/3.5 (2; 5)</td></tr><tr><td>Amputation</td><td>0</td></tr><tr><td>Antitoxin antibiotics</td><td>42 (84%)</td></tr><tr><td>Immunoglobulins/doses (g/kg)<sup>a</sup></td><td>18 (36%)/2 (2; 2)</td></tr><tr><td>Hyperbaric oxygen</td><td>5 (10%)</td></tr><tr><td>On PICU discharge</td><td></td></tr><tr><td>Deep thrombosis</td><td>6 (12%)</td></tr><tr><td>Nosocomial infections</td><td>12 (24%) during 4 stays</td></tr><tr><td>In-hospital death/day of death</td><td>3 (6%)—D7, D9, and D13</td></tr><tr><td>POPC (without the 3 deaths)</td><td>1.7 ± 0.9</td></tr><tr><td>In-PICU length of stay (days)</td><td>12.5 ± 14.5; 8 (5; 14)</td></tr><tr><td>In-hospital length of stay (days)</td><td>35.6 ± 42; 21 (12.5; 41.8)</td></tr></tbody></table>

POPC: Pediatric Overall Performance Category; PICU: pediatric intensive care unit; Data are reported as median [25th; 75th centiles], mean ± SD, or n (%)

**Abbreviations**

NSTI: Necrotizing soft-tissue infections; PICU: Pediatric intensive care unit; PRISM-3: Paediatric risk of mortality, measured during the first 24 h after PICU admission; PIM-2: Paediatric index of mortality, measured during the first hour after PICU admission; PELOD: Paediatric logistic organ dysfunction, measured during the first 24 h after PICU admission; POPC: Pediatric overall performance category.

**Acknowledgements**

We thank Jérôme Grasset, IRISEO, Saint-Victurnien, France, for his invaluable help in designing, building, and monitoring the SCIPIC database.

**Collaborators who included patients:**

Laurent Balu, MD, CHU Félix Guyon, Saint-Denis de la Réunion, France (GFRUP). Marc-André Dugas, MD, CHU de Québec, Canada (RMEF). Hélène Gatti, MD,

<footnote>a Immunoglobulins (1 g/kg twice in 15 patients and 1 g/kg once in 3 patients) were started before surgery in patients with suspected toxic shock</footnote>
Centre Hospitalier de Polynésie Française, Papeete, Tahiti, France (GFRUP). Etienne Javouhey, MD, PhD, Hôpital Femmes-Mères-Enfants, HCL, Lyon-Bron, France (GFRUP, RMEF). Nicolas Joram, MD, Hôpital mères-enfants, CHU Nantes, France (GFRUP, RMEF). Joris Lemson, MD, Radboud University Medical Centre, Nijmegen, The Netherlands. Fabrice Lesage, MD, Hôpital Universitaire Necker Enfants malades, Paris, France (GFRUP, RMEF). Christophe Milesi, MD, CHU Arnaud de Villeneuve, Montpellier, France (GFRUP). Marie-Hélène Perez, MD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (GFRUP). Isabelle Wroblewski, MD, Hôpital Nord La Tronche, CHU Grenoble, France (GFRUP).

**List of the 33 participating centers:**

France: Dupuytren University Hospital, Limoges; Jean Minjoz University Hospital, Besançon; Pellegrin University Hospital, Bordeaux; Côte de Nacre University Hospital, Caen; Estaing University Hospital, Clermont-Ferrand; Raymond Poincaré University Hospital, Garches; Grenoble-Alpes University Hospital Grenoble; Jeanne de Flandres University Hospital, Lille; Femme-Mère-Enfant University Hospital, Lyon-Bron; La Timone University Hospital, Marseille; Marseille Nord University Hospital, Marseille; Nancy-Brabois University Hospital, Vandoeuvre-les-Nancy; Mère-Enfants University Hospital, Nantes; Lenval University Hospital, Nice; Robert Debré University Hospital, Paris; Necker-Enfants malades University Hospital, AP-HP, Paris; Armand-Trousseau University Hospital, AP-HP, Paris; American Memorial University Hospital, Reims; Charles-Nicolles University Hospital, Rouen; University Hospital, Saint-Etienne; University Hospitals, Strasbourg; Mères-Enfants University Hospital, Toulouse; Gatien de Clocheville University Hospital, Tours; Arnaud de Villeneuve University Hospital, Montpellier; Mamoudzou Hospital, Mayotte; Felix Guyon University Hospital, Saint-Denis, La Réunion; Mamao Hospital, Papeete, Tahiti. Switzerland: Lausanne University Hospital, Lausanne. Québec (Canada): Laval University Hospital, Québec; Sainte-Justine University Hospital, Montréal; Fleurimont University Hospital, Sherbrooke. The Netherlands: Wilhelmina Children's University Hospital, Utrecht; Rabdoud University Hospital, Nijmegen.

**Authors' contributions**

SD and RB had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. RB served as co-investigator for this study. Concept and design: SD, RB. Acquisition: all authors. Analysis and interpretation of data: SD, RB, FA, ML. Drafting of the manuscript: SD, FA, ML. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: FA. Obtained funding: SD, RB. Administrative, technical, or material support: SD, RB. Supervision: SD, RB, FA, ML. All authors read and approved the final manuscript.

**Funding**

This work was supported by the Réseau Mère Enfants de la Francophonie (RMEF) with a Grant of 7 000 $CA. The funder had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication.

**Availability of data and materials**

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

**Declarations**

**Ethics approval and consent to participate**

The study was approved by Robert-Debré Hospital International Review Board (IRB-0006477) and parental or legal guardian consent was obtained.

**Consent for publication**

Not applicable.

**Competing interests**

The authors declare that they have no competing interests.

**Author details**

¹ Pediatric Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Service de Médecine Intensive - Réanimation Pédiatriques, Hôpital Universitaire Robert Debré, Université de Paris, 48 boulevard Sérurier, 75019 Paris, France.

² Université de Paris, NeuroDiderot, INSERM UMR 1141, 75019 Paris, France.

³ Adult and Pediatric Intensive Care Unit, Centre Hospitalier de Mayotte, 97600 Mamoudzou, France. ⁴ Pediatric Intensive Care Unit, Hôpital Universitaire Pellegrin, Université de Bordeaux, 33000 Bordeaux, France. ⁵ Pediatric Intensive Care Unit, Hôpital Universitaire Purpan, Université de Toulouse, 31000 Toulouse, France. ⁶ Pediatric Emergency Department, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, 75005 Paris, France. ⁷ Institut Pasteur, Invasive Bacterial Infection Unit, 75724 Paris, France.

Received: 22 February 2021 Accepted: 31 March 2021

Published online: 12 April 2021

**References**

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2. Schröder A, Gerin A, Firth GB, Hoffmann KS, Grieve A, Oetzmann von Sochaczewski C. A systematic review of necrotising fasciitis in children from its first description in 1930 to 2018. BMC Infect Dis. 2019;19:317–29.

3. Eneli I, Davies HD. Epidemiology and outcome of necrotizing fasciitis in children: an active surveillance study of the Canadian Paediatric Surveillance Program. J Pediatr. 2007;151:79–84.

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