Factors associated with death in children with purpura fulminans: a French national prospective cohort study

© The Author(s) 2021. 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:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. 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. Open Access


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.

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*Correspondence: fouad.madhi@chicreteil.fr 1 Service de Pédiatrie Générale, Centre Hospitalier Intercommunal de Créteil, 40, avenue de Verdun, 94000 Créteil, France Full list of author information is available at the end of the article 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. Time from admission to death (days), mean ± SD* 3.9 ± 11.3 Median 1