Discussion
We report on the first multicenter cohort of adult patients admitted to the ICU for a pneumococcal purpura fulminans. The main results are as follows: (1) half of pneumococcal purpura fulminans occurred in asplenic or hyposplenic patients, (2) pneumococcal vaccination coverage was only 29% in adult asplenic/hyposplenic patients with pneumococcal purpura fulminans, (3) the time interval between asplenia/hyposplenia and pneumococcal purpura fulminans was 20 years, and (4) outcomes did not differ between patients with or without asplenia/hyposplenia. These results must be interpreted with caution due to the relatively small number of patients included, which limited our ability to show significant statistical differences between groups. Our study is, to the best of our knowledge, the first one to compare clinical features and outcomes of patients with pneumococcal purpura fulminans according to the presence/absence of a spleen, rendering comparisons with other studies difficult.
The median time interval between asplenia/hyposplenia and pneumococcal purpura fulminans observed in our study was 20 years, with only very few patients with pneumococcal purpura fulminans occurring within the 2 years following splenectomy or hyposplenia. This time interval is longer than the 5.75 years time interval observed in a recent prospective multicenter German study on overwhelming post-splenectomy infection from every cause and pathogen [
2]. It is commonly accepted that the greatest risk of overwhelming post-splenectomy infection is maximal within the first 2 years after splenectomy [
11‐
13]. However, most of these studies [
11‐
13] included immediate post-operative infections and had a limited follow-up duration, potentially underestimating the risk of late overwhelming post-splenectomy infection. The time interval observed in our cohort highlights that the risk of overwhelming post-splenectomy infection remains lifelong [
3,
4,
14,
15].
In the present study, only 35% of the patients with asplenia or hyposplenia had received a pneumococcal vaccination despite current recommendations of the Centers for Disease Control and Prevention [
16]. However, it is worth noticing that 2/34 (6%) patients were not aware of their asplenic status since asplenia was diagnosed in the ICU and revealed by the pneumococcal purpura fulminans episode. Moreover, given the wide study period (17 years), recommendations about pneumococcal vaccination may have varied over time. The vaccination rate observed in our cohort is consistent with the 31% rate reported by Waghorn et al. in a series of 77 patients with overwhelming post-splenectomy infection [
3]. In a recent multicenter German cohort study including 52 patients with overwhelming post-splenectomy infection, only 11 (21%) had received a pneumococcal vaccination within the past 5 years. In the global population of splenectomized patients without infection, the coverage of pneumococcal vaccination rates is as high as 80% [
17,
18]. Our finding of one third of the asplenic/hyposplenic patients with pneumococcal purpura fulminans having received a pneumococcal vaccination emphasizes that pneumococcal vaccination may reduce but does not abolish the risk of overwhelming post-splenectomy infection in splenectomized patients.
Our study showed similar severity levels and outcomes between patients with and without asplenia/hyposplenia. This observation is in line with a prospective multicenter German cohort study reporting a similar ICU, 7-day or 28-day mortality between patients with overwhelming post-splenectomy infection (from every cause and pathogen) and matched patients without asplenia or hyposplenia [
2]. Similarly, a large prospective Canadian cohort study including 2435 patients with invasive pneumococcal disease over a 15-year period reported on similar in-hospital mortality rates between asplenic/hyposplenic and eusplenic non-ICU patients [
19]. This observation underlines the fact that asplenia is a risk factor for severe pneumococcal sepsis but seems not to worsen the course of a declared sepsis, pointing out that our efforts must focus on preventing the disease. In this regard, a retrospective Australian before-after study recently showed that including patients in a registry of asplenic patients (with educational kit containing information sheet, alert cards regarding the history of splenectomy, educational DVD, personalized vaccine report, information regarding antibiotic prophylaxis, emergency plan in case of fever, newsletter to their general practitioners with updates regarding recommended vaccinations and booster doses) was associated with a significant reduction in the incidence of infections caused by encapsulated bacteria after splenectomy [
4].
Limitations
Our study certainly suffers from several limitations. This was a retrospective study with inherently associated bias, as well as missing data and possible associated errors in data abstraction. However, due to the extreme rarity of pneumococcal purpura fulminans, a prospective study would be hardly feasible. A previous prospective multicenter study on overwhelming post-splenectomy infection in 173 German ICUs prematurely ended due to slow recruitment [
2]. Abdominal CT scan and detection of Howell-Jolly bodies in peripheral blood smears or counting of pitted erythrocytes by phase-interference microscopy was not routinely performed. Therefore, we cannot exclude that patients included in the eusplenic group had an unknown asplenia potentially related to congenital asplenia or other diseases (severe celiac disease, inflammatory bowel disease, Whipple’s disease, amyloidosis, Sjögren’s syndrome, HIV infection, cirrhosis) associated with hyposplenism or splenic atrophy [
5,
20]. However, only 15% (
n = 5/33) of the eusplenic patients had pre-existing diseases potentially associated with hyposplenism (ulcerative colitis
n = 1, Sjögren’s syndrome
n = 1, HIV infection
n = 2, cirrhosis
n = 1). Because the patients were recruited over a 17-year period in 55 centers, ICU procedures were inevitably heterogeneous. The serotypes of the
Streptococcus pneumoniae strains involved was not available due to the retrospective nature of the study, precluding any comparison to be made between both groups of patients. Last, the absence of significant outcome differences observed between asplenic/hyposplenic and eusplenic patients may be due to a lack of power related to a relatively small number of included patients.
Our study also has some strengths, including the large number of centers and patients included for a very rare infectious disease [
6], the comparison between asplenic and non-asplenic patients, with a paucity of previously published data due to the rarity of overwhelming post-splenectomy infection [
2], the collection of pneumococcal vaccination status which is poorly reported, and the fact that the definitions used for inclusion of the patients were well-standardized, rendering the comparison of the two groups relevant.
Clinical implications
Asplenic or hyposplenic patients admitted to the ICU for a purpura fulminans seem to have a high risk of pneumococcal purpura fulminans. In patients surviving pneumococcal purpura fulminans, unknown congenital asplenia should be searched with abdominal CT-scan. Detecting Howell-Jolly bodies in peripheral blood smear and counting pitted erythrocytes by phase-interference microscopy may also help diagnosing hyposplenia [
5]. In such patients, pneumococcal vaccination seems welcomed in order to avoid recurrences of overwhelming post-splenectomy infection. As recommended by the Centers for Disease Control and Prevention 2019 guidelines [
16], patients with asplenia or hyposplenia should receive one dose of the 13-valent pneumococcal conjugate vaccine together with one (for persons aged ≥ 64 years) or two doses (for persons aged 19–64 years) of the 23-valent pneumococcal polysaccharide vaccine. Furthermore, continuing education is required to advise patients with a risk of severe infection inherent to asplenia and the need for immediate antibiotic therapy in case of fever, especially since it has been reported that 40 to 84% of splenectomized individuals were not aware of the infectious risks associated with their condition [
18,
21]. In adult asplenic/hyposplenic patients, long-term antibiotic prophylaxis [
5] is still debated, except in those who survived overwhelming post-splenectomy infection [
20], a targeted subgroup of patients in whom such a strategy seems appropriate, although supported by a low evidence.
Acknowledgements
On behalf of the Hopeful Study Group:
1. Laurent Argaud (Lyon)
2. François Barbier (Orléans)
3. Amélie Bazire (Brest)
4. Gaëtan Béduneau (Rouen)
5. Frédéric Bellec (Montauban)
6. Pascal Beuret (Roanne)
7. Pascal Blanc (Pontoise)
8. Cédric Bruel (Saint-Joseph)
9. Christian Brun-Buisson (Mondor, AP-HP)
10. Gwenhaël Colin (La Roche-sur-Yon)
11. Delphine Colling (Roubaix)
12. Alexandre Conia (Chartres)
13. Rémi Coudroy (Poitiers)
14. Martin Cour (Lyon)
15. Damien Contou (Argenteuil)
16. Fabrice Daviaud (Corbeil-Essonnes)
17. Vincent Das (Montreuil)
18. Jean Dellamonica (Nice)
19. Nadège Demars (Antoine Beclère, AP-HP)
20. Stephan Ehrmann (Tours)
21. Arnaud Galbois (Quincy sous Sénart)
22. Elodie Gelisse (Reims)
23. Julien Grouille (Blois)
24. Laurent Guérin (Ambroise Paré – AP-HP)
25. Emmanuel Guérot (HEGP, AP-HP)
26. Samir Jaber (Montpellier)
27. Caroline Jannière (Créteil)
28. Sébastien Jochmans (Melun)
29. Mathieu Jozwiak (Kremlin Bicêtre, AP-HP)
30. Pierre Kalfon (Chartres)
31. Antoine Kimmoun (Nancy)
32. Alexandre Lautrette (Clermont Ferrand)
33. Jérémie Lemarié (Nancy)
34. Charlène Le Moal (Le Mans)
35. Christophe Lenclud (Mantes La Jolie)
36. Nicolas Lerolle (Angers)
37. Olivier Leroy (Tourcoing)
38. Antoine Marchalot (Dieppe)
39. Bruno Mégarbane (Lariboisière, AP-HP)
40. Armand Mekontso Dessap (Mondor, AP-HP)
41. Etienne de Montmollin (Saint-Denis)
42. Frédéric Pène (Cochin, AP-HP)
43. Claire Pichereau (Poissy)
44. Gaëtan Plantefève (Argenteuil)
45. Sébastien Préau (Lille)
46. Gabriel Preda (Saint-Antoine, AP-HP)
47. Nicolas de Prost (Henri Mondor, AP-HP)
48. Jean-Pierre Quenot (Dijon)
49. Sylvie Ricome (Aulnay-sous-Bois)
50. Damien Roux (Louis Mourier, AP-HP)
51. Bertrand Sauneuf (Cherbourg)
52. Matthieu Schmidt (Pitié Salpétrière, AP-HP)
53. Guillaume Schnell (Le Havre)
54. Romain Sonneville (Bichat, AP-HP)
55. Jean-Marc Tadié (Rennes)
56. Yacine Tandjaoui (Avicenne, AP-HP)
57. Martial Tchir (Villeneuve Saint Georges)
58. Nicolas Terzi (Grenoble)
59. Xavier Valette (Caen)
60. Lara Zafrani (Saint-Louis, AP-HP)
61. Benjamin Zuber (Versailles)
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