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Abkürzungen
ICU
Intensive care unit
mPF
Meningococcal purpura fulminans
pPF
Pneumococcal purpura fulminans
SOFA
Sequential Organ Failure Assessment
Purpura fulminans (PF) is a rare cause of septic shock characterized by the association of a sudden and extensive purpuric rash together with an acute circulatory failure [1] leading to high rates of intensive care unit (ICU) mortality [1, 2] and long-term sequelae [3]. Clinical presentation of patients with PF differs from that of patients with meningitis since PF patients are commonly admitted to the ICU for hemodynamic impairment exposing them to early death from refractory circulatory failure, as opposed to patients with meningitis who are usually admitted to the ICU for neurological impairment. Among adult patients, Neisseria meningitidis and Streptococcus pneumoniae are the most commonly involved microorganisms accounting for more than 80% of PF [1] and meningitis [4]. While clinical features and outcomes widely differ between adult patients with pneumococcal and meningococcal meningitis [4], it remains unclear whether pneumococcal (pPF) and meningococcal (mPF) PF exhibit different clinical phenotypes and outcomes, although pPF was previously shown to predominantly occur in asplenic patients [5] and carries a higher risk of limb amputation [1]. We therefore compared the clinical, biological presentations and outcome of adult patients with pPF and mPF.
We performed an ancillary analysis of a 17-year multicenter retrospective study conducted in 55 centers in France, which included all consecutive patients (≥ 18 years) admitted to the ICU for an infectious PF (2000–2016) [1]. Patients with non-microbiologically documented PF or a bacterial documentation other than Neisseria meningitidis and Streptococcus pneumoniae were excluded.
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During the study period, 195 patients with mPF and 67 with pPF were included. As compared to patients with mPF, those with pPF were older and had higher ICU severity scores. Chronic alcoholism and asplenia were more frequent in pPF, while the proportion of patients without previous comorbid conditions was lower. The time elapsed between disease onset and ICU admission was longer and purpura was less often noticed before ICU admission in pPF than in mPF. pPF patients also had lower platelet counts, higher serum urea and creatinine levels, and more frequent bacteremia. pPF patients needed more frequent invasive mechanical ventilation support, renal replacement therapy, plasma and platelets transfusions and had higher durations of invasive mechanical ventilation and vasopressor support. ICU mortality and rate of limb amputation were higher in patients with pPF (Table 1).
Table 1
Comparison between meningococcal (n = 195) and pneumococcal (n = 67) purpura fulminans
Meningococcal purpura fulminans n = 195
Pneumococcal purpura fulminans n = 67
p value
Patient’s characteristics and ICU scores
Male gender
97 (50)
37 (55)
0.527
Age, years
24 [19–45]
49 [38–60]
< 0.001
SAPS II
50 [35–66]
63 [58–72]
< 0.001
SOFA
11 [8–14]
14 [11–15]
< 0.001
Main comorbidities
Chronic alcoholism
5 (2)
9 (13)
0.002
Diabetes mellitus
3 (2)
4 (6)
0.073
Asplenia or hyposplenia
3 (2)
34 (51)
< 0.001
Malignant hemopathy
1 (1)
2 (3)
0.162
Chronic respiratory disease
18 (23)
14 (28)
0.625
Immunocompromised status
5 (3)
4 (6)
0.241
No coexisting comorbid conditions
164 (84)
22 (33)
< 0.001
Clinical features upon ICU admission
Days between disease onset and ICU admission, days
4 [4–5]
5 [4–6]
0.003
Headache
99 (51)
26 (39)
0.121
Myalgia
48 (25)
12 (18)
0.338
Digestive signs
124 (64)
41 (61)
0.839
Coma Glasgow score
15 [13–15]
15 [13–15]
0.751
Temperature, °C
38.5 [37–40]
38.5 [37–39]
0.802
Neck stiffness
52 (27)
6 (9)
0.004
Purpuric rash before ICU admission
168 (86)
38 (57)
< 0.001
β-Lactam antibiotic therapy before ICU admission
157 (81)
46 (69)
0.067
β-Lactam antibiotic therapy at ICU admission
195 (100)
67 (100)
–
Biological data upon ICU admission
Leukocytes count, 103 mm−3
10,700 [4000–20,800]
10,655 [2500–19,750]
0.717
Platelets count, 103 mm−3
61,000 [28,500–100,000]
33,000 [19,000–49,500]
< 0.001
C-reactive protein, g/L
148 [90–247]
179 [141–289]
0.095
Procalcitonin, ng/mL
48 [14–100]
102 [55–164]
0.087
Troponin, mg/L
1 [0.10–12]
0.25 [0.13–11]
0.697
Creatine kinase, IU/L
300 [110–852]
812 [365–3460]
0.016
Serum urea, mmol/L
9 [7–11]
13 [11–15]
< 0.001
Serum creatinine, μmoL/L
190 [136–250]
240 [184–310]
< 0.001
Prothrombin time, %
33 [22–44]
29 [15–38]
0.227
Factor V, %
23 [10–49]
21 [9–29]
0.246
Arterial lactate, mmol/L
7.40 [5–11]
8 [6–11]
0.798
Fibrinogen, g/L
1.70 [0.6–3]
1.16 [0.5–2]
0.122
Microbiological data at ICU admission
Bacteremia
99 (51)
56 (84
< 0.001
Lumbar puncture performed
125 (64)
29 (43)
0.004
Positive cerebro-spinal fluid culture
72/125 (58)
11/29 (38)
0.080
Outcome in the ICU
Lowest LVEF, %
33 [20–45]
30 [25–50]
0.870
Inotropic agent
91 (64)
35 (61)
0.894
Platelets transfusion
57 (29)
46 (69)
< 0.001
Plasma transfusion
67 (34)
44 (66)
< 0.001
Steroids for septic shock or meningitis
116 (60)
45 (67)
0.333
Activated protein C
33 (17)
9 (13)
0.632
Invasive mechanical ventilation
152 (78)
65 (97)
0.001
Duration of tracheal intubation, days
4 [2–9]
10 [3–28]
< 0.001
Duration of vasopressors, days
3 [2–5]
5 [3–8]
< 0.001
Renal replacement therapy
69 (36)
45 (67)
< 0.001
Veno-arterial ECMO
7 (4)
6 (9)
0.104
Limb amputation
19 (10)
21 (31)
< 0.001
Limb amputation among ICU survivors
18/125 (14)
19/32 (59)
< 0.001
Death in ICU
70 (36)
35 (52)
0.027
Duration of ICU stay, days
5 [2–11]
14 [3–35]
< 0.001
Duration of hospital stay, days
12 [2–23]
23 [3–78]
0.003
Continuous variables are reported as median [Interquartile range] and compared between groups using the Student t-test. Categorical variables are reported as numbers (percentages) and compared using χ2 test. A p value < 0.05 was considered significant
ICU intensive care unit; IMV Invasive Mechanical Ventilation, ECMO Extracorporeal membrane oxygenation, LVEF Left ventricular ejection fraction, SAPSII Simplified Acute Physiology Score, SOFA Sequential Organ Failure Assessment
The Kaplan–Meier survival analysis did not show significant difference between pPF and mPF patients (p = 0.80 by the log-rank test, Fig. 1).
Fig. 1
Kaplan–Meier survival estimates during the 30 days following ICU admission of patients with pneumococcal (red curve) and meningococcal (blue curve) purpura fulminans
×
By multiple logistic regression adjusting on age, SOFA score, administration of β-lactam antibiotic therapy before ICU admission, platelet counts and arterial lactate levels, pPF was not associated with ICU mortality (adjusted Odds Ratio = 1.15 95% CI 0.45–2.89, p = 0.77).
As already reported in adults patients with bacterial meningitis [4], this study confirms that significant differences exist between mPF and pPF, regarding both the clinical presentation at ICU admission and outcomes. Patients with pPF showed a different clinical phenotype, with less frequent purpura possibly leading to less frequent antibiotic treatment, more comorbidities with a more severe presentation at ICU admission, resulting in a higher rate of organ failures during ICU stay. Whether this more severe presentation should be ascribed to the level of virulence of the causative pathogen or to host-related characteristics is unsettled.
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Our study has several limitations including its retrospective design and its long recruitment period with a high number of centers implying ICU procedures being inevitably heterogeneous. Nevertheless, the clinical presentation as well as the course in the ICU of patients with PF seem to differ according to the causative bacterium. This clinical observation should encourage researchers to better study the pathophysiology of pPF in order to develop targeted innovative therapies as being done for mPF [6].
Acknowledgements
We thank the members of the HOPEFUL Study group (to be searchable through their individual PubMed records). Laurent Argaud (Lyon), François Barbier (Orléans), Amélie Bazire (Brest), Gaëtan Béduneau (Rouen), Frédéric Bellec (Montauban), Pascal Beuret (Roanne), Pascal Blanc (Pontoise), Cédric Bruel (Saint-Joseph), Christian Brun-Buisson (Mondor, AP-HP), Gwenhaël Colin (La Roche-sur-Yon), Delphine Colling (Roubaix), Alexandre Conia (Chartres), Rémi Coudroy (Poitiers), Martin Cour (Lyon), Damien Contou (Henri Mondor – AP-HP and Argenteuil), Fabrice Daviaud (Corbeil-Essonnes), Vincent Das (Montreuil), Jean Dellamonica (Nice), Nadège Demars (Antoine Beclère, AP-HP), Stephan Ehrmann (Tours), Arnaud Galbois (Quincy sous Sénart), Elodie Gelisse (Reims), Julien Grouille (Blois), Laurent Guérin (Ambroise Paré – AP-HP), Emmanuel Guérot (HEGP, AP-HP), Samir Jaber (Montpellier), Caroline Jannière (Créteil), Sébastien Jochmans (Melun), Mathieu Jozwiak (Kremlin Bicêtre, AP-HP), Pierre Kalfon (Chartres), Antoine Kimmoun (Nancy), Alexandre Lautrette (Clermont Ferrand), Jérémie Lemarié (Nancy), Charlène Le Moal (Le Mans), Christophe Lenclud (Mantes La Jolie), Nicolas Lerolle (Angers), Olivier Leroy (Tourcoing), Antoine Marchalot (Dieppe), Bruno Mégarbane (Lariboisière, AP-HP), Armand Mekontso Dessap (Mondor, AP-HP), Etienne de Montmollin (Saint-Denis), Frédéric Pène (Cochin, AP-HP), Claire Pichereau (Poissy), Gaëtan Plantefève (Argenteuil), Sébastien Préau (Lille), Gabriel Preda (Saint-Antoine, AP-HP), Nicolas de Prost (Henri Mondor, AP-HP), Jean-Pierre Quenot (Dijon), Sylvie Ricome (Aulnay-sous-Bois), Damien Roux (Louis Mourier, AP-HP), Bertrand Sauneuf (Cherbourg), Matthieu Schmidt (Pitié Salpétrière, AP-HP), Guillaume Schnell (Le Havre), Romain Sonneville (Bichat, AP-HP), Jean-Marc Tadié (Rennes), Yacine Tandjaoui (Avicenne, AP-HP), Martial Tchir (Villeneuve Saint Georges), Nicolas Terzi (Grenoble), Xavier Valette (Caen), Lara Zafrani (Saint-Louis, AP-HP), Benjamin Zuber (Versailles).
Declarations
Ethics approval and consent to participate
This study was conducted in accordance with the amended Declaration of Helsinki and was approved by the Institutional Review Board (CE 2016–01) of the French Intensive Care Society in March, 2016.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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