- Research Letter
- Open access
- Published:
Factors associated with death in children with purpura fulminans: a French national prospective cohort study
Critical Care volume 25, Article number: 181 (2021)
To the editor,
As there is a high mortality rate and major risk of sequelae of purpura fulminans (PF), early identification of patients at highest risk of poor outcome is crucial to optimize the initial management. To date, only a few studies have suggested clinical or biological factors associated with an unfavorable evolution because of the rarity of PF in children. These studies were most often monocentric and retrospective [1, 2] or did not specifically study PF in children [3]. We analyzed the clinical and biological factors available at initial presentation associated with death in children with PF.
We conducted a national population-based prospective French cohort of pediatric PF over 15 years. From 2003 to 2017, we included all children < 15 years with PF with or without meningitis in one of the 227 participating centres. The methodology of this surveillance system was previously published [4]. The diagnosis of PF followed published recommendations [5] and remained unchanged over the study period. The main outcome was the case fatality rate before hospital discharge. We assessed demographic, clinical and biological factors, along with initial treatments used associated with death. For biological factors, we considered explorations performed at admission.
We included 1042 cases of PF: N. meningitidis was the most frequent bacterium isolated (910, 86.5%), including 581 with serogroup B (64.5%), 218 serogroup C (24.2%). Table 1 shows the demographic and clinical characteristics at admission and outcomes. Among 1042 patients with PF, 166 (16.1%; 95% CI [13.9; 18.5]) died during hospitalization. For the 876 survivors, 143 (16.3%; 95% CI [13.9; 18.9]) had acute complications or sequelae, including extensive skin necrosis (n = 56), neurological complications (n = 32), and limb amputation (n = 20). Table 2 summarizes the risk factors for death in children with PF. On multivariate analysis, death was significantly associated with age < 1 year and leucopenia < 5000/mm3; while leukocytosis > 10,000/mm3 was protective. Initial appropriate antibiotic treatment was not associated with death. Furthermore, death was faster with than without leucopenia (mean time to death 1.9 vs. 4.9 days, p = 0.013). Our multivariable model estimated that the probability of death could range from 3% for children without risk factors to 36% for children < 1 year old and with leucopenia < 5000/mm3.
To our knowledge, this 15-year population-based national study is the largest prospective study focusing on pediatric PF. We identified young age and leucopenia as independent risk factors for death in pediatric PF.
Younger age is a well-identified risk factor for poor outcomes in numerous pediatric invasive bacterial diseases and may be explained by the immaturity of the immune system [2, 3]. The findings regarding leukocytes may be less expected [2]. Several hypotheses should be considered. First, the lower leukocyte count in non-survivors suggests a shorter disease course and the completeness of the meningococcal infection. This suggestion may be supported by a shorter time from admission to death for children with leukopenia versus other children. Second, several immunological studies suggested that the development of neutropenia may indicate an exhaustion of bone-marrow progenitors, a maturation arrest in granulocytic lineage or an imbalance between extravasation and production [2, 6]. These mechanisms may also be associated with impaired neutrophil functions (chemotaxis, phagocytosis and production of reactive oxygen species), thus leading to poor outcomes during sepsis.
In conclusion, we identified several factors easily available at initial care independently associated with death. These findings may help physicians better appreciate the risk of short-term fatal evolution when managing PF in children. If these risk factors are not modifiable, their presence might lead clinicians to faster use aggressive therapies at initial care.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Kornelisse RF, Hazelzet JA, Hop WC, Spanjaard L, Suur MH, van der Voort E, et al. Meningococcal septic shock in children: clinical and laboratory features, outcome, and development of a prognostic score. Clin Infect Dis. 1997;25:640–6.
Maat M, Buysse CM, Emonts M, Spanjaard L, Joosten KF, de Groot R, et al. Improved survival of children with sepsis and purpura: effects of age, gender, and era. Crit Care. 2007;11:R112.
Sadarangani M, Scheifele DW, Halperin SA, Vaudry W, Le Saux N, Tsang R, et al. Outcomes of invasive meningococcal disease in adults and children in Canada between 2002 and 2011: a prospective cohort study. Clin Infect Dis. 2015;60:e27-35.
Ouldali N, Levy C, Varon E, Bonacorsi S, Béchet S, Cohen R, et al. Incidence of paediatric pneumococcal meningitis and emergence of new serotypes: a time-series analysis of a 16-year French national survey. Lancet Infect Dis. 2018;18:983–91.
Goldstein B, Giroir B, Randolph A, International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6:2–8.
Aird WC. The hematologic system as a marker of organ dysfunction in sepsis. Mayo Clin Proc. 2003;78:869–81.
Acknowledgements
We are very grateful to Elodie Nattes, Marion Lagrée, Didier Pinquier, Alexis Rybak and Stéphane Bechet for her contributions to the report. We thank all of the French Pediatric Meningitis Network: Abdelhadi, Aberrane, Abi Warde, Abou Tara, Abrudan, Adam, Adamon, Akitani, Alba-Sauviat, Al Chaar, Albertini, Aljazayri, Aljumaidi, Allali, Allia, Al Mazini, Amama, Amara, Amira, Amirault, Andriantahina, Ansoborlo, Arlet, Armengaud, Armouche, Arnault, Asensio, Aubert, Auburtin, Audry, Aujard, Autret, Azemar, Bachelier, Badran, Bajolle, Baleine, Bandin, Banegas, Banerjee, Banige, Barbier, Bardou, Baret, Barnaud, Baron-Joly, Barrans, Barraud, Barré, Barrey, Barsotti, Barthez, Bartizel, Baruteau, Basmaci, Bassil, Battaglini, Bayle, Bednarek, Belgaid, Belivier, Bellulo, Benabdelmalek, Benchekroun, Benezech, Bengrina, Benmahammed, Benmoulai, Benoist, Benoit, Bensaid, Benseddik, Benzaim, Berche, Berrahma, Beretta-Salaun, Bergounioux, Berrahma, Berterottiere, Berthier, Bertrou, Besson-Leaud, Biendo, Biessy, Billaud, Billion, Bina, Bineau, Biran, Bitar-Obeid, Blanc, Blasquez, Blondel, Blondin, Boileau, Boivin, Boize, Bolot, Bonacorsi, Boniface, Bongo Boina, Bonnin, Boquet, Bordes, Born, Bosdure, Bosi, Bost-Bru, Bouainane, Bouderlique, Boukezia, Boulard, Bour, Bourennane, Bourgeois-Nicolaos, Boussadia, Boussicault, Boutros, Boutte, Bouvet, Bouziges, Bovero, Boyer, Branca, Branger, Bresson, Breton, Breuil, Briand, Brieu, Brizard, Brocard, Brouard, Bruna, Brunel, Bruno, Bruyas, Bucher, Bucur, Buisson-Touati, Bulteau-Cowan, Cabaret, Cadot, Caillon, Callamand, Calvez, Cambonie, Campet, Canis, Canzi, Capdeville, Carbajal, Carbonnelle, Carre, Carre-Cavellier, Carrer, Carriere, Carroger, Cartier, Cartier-Riviere, Cascarigny, Castella, Castelnau, Cathenoz, Cattoen, Cattoir, Cau, Cavalier, Cecille, Chabrol, Chace, Chaix, Chale, Chalumeau, Chalvon Demersay, Chami, Chamouilli, Chamoux, Champion, Chandesris, Chantelat, Chantepie, Chaplain, Chappet, Charachon, Charbonneau, Chardon, Charras, Chenaud, Chenel, Cheron, Cheuret, Chevallier, Chevrel, Chomienne, Chrisment, Ciupek, Clair, Claris, Cloix, Coche, Coinde, Cointin, Colin Gorski, Collignon, Colombani, Combe, Constanty, Cordier, Cormier, Corniau, Cosson, Costa, Cottin, Coumenges, Coupe, Courcol, Courdavault, Courouble, Courtade, Craiu, Crepet, Croizé, Cuzzi, D'albignac, Dagorne, Dalmon, Daltroff, Danan, Danekova, Danjean-Deguin, Danjoux, Dao-Dubremptz, Daoud, Daoudi, Darai, Darras, Dassieu, Dauger, Debriel, Dechamps, Decobert, Decoster, Decousser, Deforche, Degas, Degrange, Delacour, Delamare, Delaporte, Delarbre, Delattre, Delavelle, Delbeke, Delesalle, Deligne, Delisle, Delvart, Delorme, Deluca, Demachy, Demarcq, Demarque, Demay-Legros, Demersay, Demonchy, De Barbentane, De Champs, De Decker, De Montclos, De Mongolfier, De Pontual, Denis, De Ricaud, Desbois, Desfrere, Desprez, Dessein, Dessioux, Desvigne, Deutscher, Devictor, Deville, Devouge, Dhaoui, Dieckmann, Dit Dinard, Djafari, Djaghri, Doit, Dolfi Fiette, Dolhem, Dommergues, Dorangeon, Doucet, Doucet-Populaire, Douchain, Dubois, Dubos, Dubourdieu, Dubus, Duchaine, Duchene, Ducrocq, Dufillot, Dufour, Dugain, Dumont, Dumoulard, Dupre, Duquesne, Durand, Duthilly, Dutron, Duval, Duval Arnould, Eb, Eicher, Eitenschenck, El Hamri, Elbez, Elharrif, Elias, Emond, Enchery, Enoch, Epaud, Escarguel, Estapa, Esteve, Estournet Mathiaud, Estrangin, Etienne, Evers, Evrard, Evreux, Eyer, Eyssette-Gayraud, Ezzedine, Fabbro, Faibis, Fargeot, Farges, Farhat, Farrugia, Fasquelle, Faul, Favaretto, Faye, Feldmann, Ferey, Ferroni, Fevre, Fieschi, Fiette, Fihman, Filippi, Fischbach, Flevin, Flipo, Flurin, Forget, Fortin, Fos, Foskett, Foucaud, Franc, Francois-Chervet, Francoise, Frey, Gagliardone, Gaillard, Gallet, Gallou, Ganivala, Garandeau, Garbarg-Chenon, Garcera, Garnier, Garrec, Gaschet, Gaschignard, Gaudelus, Gauduchon, Gaugler, Gavignet, Gbadamassi, Geffroy, Gendrel, Geniez, Georget, Geraudel, Gerony-Laffitte, Gilles, Gillet, Giorgi, Girard, Gire, Girier, Glastre, Glatz, Gleize, Goguelin, Goissen, Goldstein, Goudeau, Gougeon, Goumy, Gouraud, Gouriet, Goux, Graber, Graff, Grailles, Graine, Grancher, Grando, Granier, Granry, Greco, Gremeaux, Gremillet, Gressier, Grimprel, Grise, Grollmuss, Guerin, Guibert, Guichard, Guiet, Guigonis, Guilbert, Guillaume Baudet, Guillermet Fromentin, Guillois, Guillot, Guilluy, Guitton, Guyon, Haas, Hachani, Hachart, Hachem, Haegy-Doehring, Hage, Halfatuhi, Hallage, Hallalel, Halna, Halphen, Hamdad, Haouisee, Harchaoui, Hasselmann, Hautefort, Hedjem, Hees, Heidt, Hentgen, Heraud, Herve, Heurte, Heusse, Hevin Martin, Heyman, Hidri, Hochart, Hoffmann, Hombrouck-Alet, Honore, Horea, Hubert, Hudebine, Huet, Huguet, Huin, Hureaux, Huvenne, Ikounga, Issa-Brunet, Izopet, Jacob, Jalloul, Jan, Jaouen, Jarlier, Jarreau, Jaulhac, Javouhey, Jeannoel, Jeannot, Jehan, Jensen, Jeny, Jeudy, Jokic, Joly-Guillou, Joly-Sanchez, Joram, Jorion, Julienne, Jullian, Juvin, Kalach, Kalkas, Kayal, Kayemba, Khaled, Khalfi, Khazaal, Khorsi, Kitzis, Klein, Klink, Klosowski, Kone-Paut, Kouame, Kovacs, Kozisek, Kretz, Kucerova, Kuntzel, Labarthe, Labbe, Labenne, Laborie, Labrune, Lafargue, Lafendi, Lagier, Lagree, Lahrach, Laidj, Laisney, Lakhdari, Lamarcq, Lambert, Lamoureux, Landragin, Lanotte, Lapeyre, Larchet, Laugel, Launay, Lavigne, Layadi, Lazarro, Le Bail, Le Bideau, Le Coustumier, Le Galloudec, Le Luyer, Leblanc, Leboucher, Lebrun, Lecarpentier, Lecine, Leclerc, Leclercq, Lecomte, Ledru, Lefevre, Lefrand-Crepin, Legagneur, Legros, Leheup, Lehnert, Lehours, Lejri, Lelioux, Lelorier, Leluan, Lemarié, Lemble, Lemeland, Lemonnier, Lenclen, Leneveu, Leotard, Lepage, Leret, Lesage, Lescanne, Letellier, Leturdu, Levy, Lienhardt, Lorrot, Louf, Lounis, Loznewski, Lureau, M'bamba, Maakaroun-Vermesse, Macchi, Madhi, Mager, Magrhraoui, Mahisatra, Maisonneuve, Malbrunot, Malige, Mallet, Mammeri, Mammes, Mancini, Mandjee, Mangeol, Manin, Mansir, Manteau, Marani, Marchand, Marcou, Marguet, Mariette, Marin, Marmonier, Marmouset, Marret, Martha, Martin, Martinat, Martinez Ozenda, Martinot, Marty, Mathieu, Matray, Maugard, Maurage, Maurin, May, Mazataud, Mellier, Melon, Menager, Menget, Menouar, Menouni-Foray, Merlot, Mermet Jeanvoine, Meslin, Meunier, Meyer, Mezgueldi, Micaelo, Mignard, Mignot, Mikail, Milcent, Milh, Milleret-Proyart, Mitanchez, Mondaud, Monier, Monin, Montagnon, Moquet, Morales-Gineste, Moreigne, Morice, Moriette, Morin, Morisot, Morville, Motte, Mougin-Joubert, Moulene, Moulin, Mouly, Mounzer, Mselati, Muller, Muller, Murbach, Nacer, Naudion, Naudot, Navarro, Nelson, Nerl Schiavini, Nerome, Netter, Neuwirth, Nevine, Nguyen, Nicola, Nordmann, Noulard, Nsimba, Oprea, Orzechowski, Osman, Ould Hocine, Oules, Ozanne, Pages, Paget, Palette, Pancher, Pangon, Pannecouck, Paon, Parisi Duchene, Pateyron, Patoz, Paul, Paut, Pejoan, Pellerin, Pelloux, Penaud, Penel-Capelle, Peralta, Pere, Perez, Perrin, Perroud, Pesenti, Petit, Petitboulanger, Phan, Philippon, Picherot, Pierre, Pina, Pierrejean, Pietrement, Pigeon, Pina, Pinchi, Pindi, Pinquier, Pinturier, Pladys, Planchenault, Plassart, Plasse, Plouvier, Poilane, Poilly, Pollet, Pons, Popelard, Porcheret, Poulain, Poyard, Poynard, Pradeaux, Prere, Priqueler, Prudent, Py, Queinnec, Questiaux, Quinet, Raber, Rafin, Raignoux, Raoult, Rault, Raymond, Raynaud, Rebaud, Renault, Renaud Vialet, Rennes, Renolleau, Retali, Retornaz, Rey, Reynaud, Richardin, Rimet, Rimpici, Rio, Rivaux, Riviere, Roche, Rodiere, Rolland, Romain, Romeo, Rosellini, Rossignol, Roth, Rottman, Roubin, Roudaut, Roudière, Rougeoreille, Rougier, Roullaud, Rousseau, Roussellier, Roux, Roybet, Roze, Sachs, Sadik, Sadki, Saf, Said-Menthon, Sakr, Saliba, Salomon, Sanchez, Santerne, Sanyas, Sarlangue, Sarthou, Sartre, Saumureau, Saunier, Savoy, Scanvic, Scat, Schaefer, Schneider, Seaume, Sebag, Secher, See, Sevin, Sfez, Simonin, Siouala, Sirot, Sivadon-Tardy, Smati, Smets, Sommabere, Soto, Soustelle, Spicq, Stefaniuk, Stephan, Sweertvaegher, Tahiri, Tarral, Tchanga, Terki, Texier, Therond, Thevenot, Thibault, Thiriez, Thore, Thouvenin, Tiry, Tixier, Tommasi, Toubiana, Touroult-Jupin, Tourrand, Tran, Trioche, Troller, Tronc, Trouilloud, Tuypens, Tytgat, Ursulescu, Uzan, Vachee, Vaillant, Valade, Valayer, Valensi, Vallee, Vallet, Vandenesch, Van de Perre, Vanel Contamin, Varengue, Vasselon-Raina, Vaucel, Venot, Verdan, Verdet, Vergerond, Vergnaud, Vergne, Vernet-Garnier, Vervel, Viala, Vialette, Vic, Vignaud, Vigneron, Villeneuve, Violette, Vittecoq, Vodoff, Vogt, Vorlet, Vray, Vrillon, Vu Thien, Warin, Wasels, Weber, Weisse, Wemeau, Worcel, Yang ting, Ygout, Youssef, Ythier, Zaoui, Zarzour, Zehani, Zelinsky-Gurung, Zenkhri, Zimmermann, Zitvogel, Zumbo. We are grateful to M Boucherat, I Ramay, C Prieur, and A Prieur from ACTIV. We are grateful to Laura Smales for help with preparing the English manuscript.
Funding
The authors indicate that they have no financial relationships relevant to this article to disclose.
Author information
Authors and Affiliations
Consortia
Contributions
FM and NO had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. Concept and design: FM, NO, CL, RC. Acquisition: FM, NO, CL, the French Pediatric Meningitis Network. Analysis and interpretation of data: FM, NO, CL, RC, MKT. Drafting of the manuscript: FM, NO, MKT, RC. Critical revision of the manuscript for important intellectual content: FM, NO, CL, MKT, RC. Statistical analysis: FM, NO. Supervision: FM, NO. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
The data collection was approved by the French National Data Protection Commission (CNIL, no. 913006).
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Madhi, F., Ouldali, N., Levy, C. et al. Factors associated with death in children with purpura fulminans: a French national prospective cohort study. Crit Care 25, 181 (2021). https://doi.org/10.1186/s13054-021-03603-8
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s13054-021-03603-8