Epidémiologie du purpura fulminans Réunion du RENAU- Aix les bains – 2 octobre 2006 Epidémiologie du purpura fulminans Jean-François TIMSIT Réanimation médicale CHU Grenoble Centre de recherche Inserm Institut Albert Bonniot

Purpura fulminans Etat de choc septique associé à la présence d’un purpura extensif et d’une CIVD Méningocoque +++ Pneumocoque Streptocoque bêta hémolytique du gpe A

Purpura fulminans diagnostic + CAT Suspicion de septicémie à méningocoque Méningocoque dans un site normalement stérile Diplocoque gram - à l’examen direct du LCR Purpura fulminans LCR évocateur de méningite bactérienne purulente ET Élément purpurique cutané Ou AG soluble ds LCR sg ou urines Ou PCR + sg ou LCR

Facteurs de risque « classique » Deficit en complément Asplénie (ATCD infection virale) Maladie chronique Tabagisme Nouvel arrivant, nouvelle école Niveau socio-economique bas MMWR May 27, 2005. 54(RRO7); 1-21

Contagiosité Sous le même toit 3-4% de cas secondaires Risque estimé de cas secondaires 2-4 /1000 sous le même toit Peu mais 500-800 fois supérieur à la population générale

Polymorphisme genetique pro coagulantes ou antifibrinolytiques:  les nécroses cutanées Debard AL et al- J. Clin Infect Dis 2005; 40:1679

Diapo: Pr JP Mira, Journée Outcomerea Avril 2006

Diapo: Pr JP Mira, Journée Outcomerea Avril 2006 Higher level of PAI-1 and poor prognosis Diapo: Pr JP Mira, Journée Outcomerea Avril 2006

Polymorphisme genetique Reactions proinflammatoires importantes Debard AL et al- J. Clin Infect Dis 2005; 40:1679

Recurrent Purpura Fulminans 2002/01: 15 yo girl admitted in ICU - Temperature 40°C; HR 125; BP 74/45; RR 38 - Meningitis with purpura fulminans - MOF (Shock, ARDS, ARF, DIC, Lactic acidosis) - Meningococcus type N in the skin biopsy - Survival with multiple finger amputations and skin grafting - 6 month hospitalization 2003/02: - Temperature 39°C; HR 125; BP 83/48; RR: 33 - Meningitis with purpura fulminans - Lumbar punction  meningococcus type Y - Shock and DIC - Survival (Xigris) with new skin grafting - 3 month hospitalization Debard AL et al- J. Clin Infect Dis 2005; 40:1679

Recurrent Purpura Fulminans Genetic predisposition? Innate immunity Inflammation Coagulation Innate Immunity TLR4 CD14 FcgRIIa FcgRIII MBL Complement C7 deficiency Inflammation TNFa LTa IL-1 IL-6 IL-10 ACE Coagulation Tissue Factor Prothrombin Factor V Factor VII Factor XIII PAI-1 Innate Immunity TLR4 CD14 FcgRIIa FcgRIII MBL Complement Inflammation TNFa LTa IL-1 IL-6 IL-10 ACE Coagulation Tissue Factor Prothrombin Factor V Factor VII Factor XIII PAI-1 Debard AL et al- J. Clin Infect Dis 2005; 40:1679

The « challenge » From Genetics to Rationale Therapeutics

Epidemiology (U.S.) MMWR May 27, 2005. 54(RRO7); 1-21

3335 Death (92% as the cause of Death) Median age of death 19 y Sharip et al - Pediatr Infect Dis J 2006;25: 191–194) Death records 3335 Death (92% as the cause of Death) Median age of death 19 y 58% Death <25 y Age adjusted mortality* Afro-americans: 3.32 White: 1.45 Asian-pacific: 1 Season* January 483 (14.5%) August 162 (5%) High mortality rates among African-Americans likely reflect increased incidence of meningococcal disease among African-Americans,11 which could be caused in part by low birth weight,12 poverty and crowded living conditions and by lack of health care access. BACKGROUND: Neisseria meningitidis is a leading cause of bacterial meningitis and septicemia in the United States. Approximately 10-15% of meningococcal patients died despite antimicrobial therapies. METHODS: We used vital records to assess meningococcal disease mortality in the United States during 1990-2002. Meningococcal cases were defined as reported deaths with recorded International Classification of Diseases, 9th revision (ICD-9) codes 036.0-036.9 or ICD-10 codes A39.0-A39.9. Denominator data were obtained from population estimates published by the U.S. Census Bureau. We analyzed the effects of age, sex, race/ethnicity and season of the year on meningococcal disease mortality. RESULTS: We identified 3335 meningococcal deaths. Both the crude and age-adjusted mortality rates were 0.10 death per 100,000 population per year (95% confidence interval, 0.09-0.10). Fifty-eight percent of deaths occurred among persons younger than 25 years old. Mortality was elevated in infants, young adults (15-24 years old), and older adults (older than 74 years old). Mortality rates in African-Americans were 1.45 and 3.32 times higher than mortality rates in whites and Asians/Pacific Islanders, respectively. Mortality caused by meningococcal disease rose in winter months and declined during the summer. Observed mortality rates increased from 1990 to 1997 and decreased from 1997 to 2002. CONCLUSIONS: Meningococcal disease continues to be an important, vaccine-preventable cause of death in the United States. Vaccination and other disease prevention efforts should be augmented for higher risk groups. Meningococcal mortality data can be used to assess the effectiveness of these efforts. PMID: 16511378 [PubMed - indexed for MEDLINE] …The Most important cause of preventable death

Epidemiologie afrique WER - No. 37, 2001, 76, 281–288, http://www. who Surtout A et C Emergence W135 (burkina Faso) Evolution par epidémies Tous les 11-12 ans (Fig: epidemie 2001) Epidémies de méningococcie, ceinture africaine de la méningite, 2001 Avec environ 1,2 million de cas et près de 135 000 décès par an dans le monde, la méningococcie constitue l.une des principales urgences épidémiques. Si l.on rencontre cette maladie partout dans le monde, les épidémies les plus fréquentes et les plus importantes se produisent dans une région connue sous le nom de ceinture africaine de la méningite, qui englobe partiellement ou en totalité 18 pays subsahariens. Dans cette région, la plupart des flambées sont provoquées par Neisseria meningitidis sérogroupe A, et dans une moindre mesure par le sérogroupe C.

Données EPIBAC 2004

France : épidémiologie Taux d’incidence le plus élevé était observé chez les moins de 1 an (15/100000) 2ème pic d’incidence à l’adolescence, supérieur à 2/100000 avec un maximum de 5,2/100000 à 17 ans (meningo C) Perrocheau et al - Euro Surveill 2005;10(12): 238-41

France : épidémiologie B : 59%, en augmentation depuis 1996 C : 32%, augmentation marquée en 2001 et 2002 W135 : 5%, stable depuis 2000 Diminution en 2004 des 3 sérogroupes (site InVS) B C W Autres 360 (51.5) 197 (28.2) 25 (3.6) 117 (16.8) 2004 Perrocheau et al - Euro Surveill 2005;10(12): 238-41

Evolution 2004: (1.46/100 000 hab) Isère Savoie Haute-Savoie Rhone-Alpes France Hautes-Alpes Source: http://www.invs.sante.fr/surveillance/iim/default.htm (1 oct 2006)

Rhone-Alpes : épidémiologie IIM 95-2003 B : 57%, en augmentation depuis 1996 C : 31%, augmentation marquée W135 : 5%, stable depuis 2000 /105 hab.* (*) France: 1,54/100 000 hab http://rhone-alpes.sante.gouv.fr (28 sept 2006)

SP meningitis in adults: penicillin susceptibilities of 1071 isolates* 100% Years (*) CNR 1000 souches * France

Evolution de l’incidence des infections invasives à méningocoque en France

Relations grippe/ Méningocoque en France

BMJ 2006;332;445-450; Case: primary clinical diagnosis of meningococcal infection proven by culture of PCR in 15-19 y olds Control: asked by their general practitioner  Behavior in the preceeding 2-week period + biology

Purpura fulminans critères de mauvais pronostic Jeune age Rapidité d’évolution Absence de syndrome méningé Sévérité du choc Importance des lésions cutanées et des ischémies distales

Facteurs pronostiques

France : épidémiologie 34.2% Perrocheau et al - Euro Surveill 2005;10(12): 238-41

Sérougroupe/lethalité (2004) Total B C W Guéris 555(79) 305(85) 136 (69) 19 (76) Séquelles 35(5) 21 (4) 11 (5.6) 1 (4) DCD 82(12) 22 (6) 40 (20.3) 5 (20) Inconnu 27(4) 12 (3.3) 10 (5) --- 699 360 197 25 Source: http://www.invs.sante.fr/surveillance/iim/default.htm (1 oct 2006)

229 pat, 69 outbreaks, 2% of the UScases Increased Case-Fatality Rate Associated with Outbreaks of Neisseria meningitidis Infection, Compared with Sporadic Meningococcal Disease, in the United States, 1994–2002 Brooks R et al - Clinical Infectious Diseases 2006; 43:49–54 229 pat, 69 outbreaks, 2% of the UScases BACKGROUND: Outbreaks of meningococcal disease are infrequent but important public health events. We characterize outbreak-associated cases in the United States and compare them with sporadic disease. METHODS: Outbreaks of meningococcal disease that occurred during the period of 1 July 1994 through 30 June 2002 were identified through state health departments, Centers for Disease Control and Prevention records, and a review of newspapers and the medical literature. Cases associated with outbreaks were compared with sporadic cases identified through population-based surveillance. RESULTS: We identified 69 outbreaks of Neisseria meningitidis infection (median, 9.5 outbreaks per year; range, 3-14 outbreaks per year), which involved 229 patients from 30 states. Forty-three (62%) of the outbreaks involved N. meningitidis serogroup C, 17 (25%) involved serogroup B, and 9 (13%) involved serogroup Y. Twenty-five outbreaks (36%) occurred in communities, and 44 (64%) were organization based, including 12 that occurred in colleges and universities, 19 that occurred in primary and secondary schools, and 8 that occurred in nursing homes. Vaccination campaigns (with the A/C/Y/W-135 meningococcal polysaccharide vaccine) were conducted for 31 outbreaks (28 involving serogroup C and 3 involving serogroup Y). After controlling for age, serogroup, and clinical presentation, outbreak-associated cases were associated with a higher case-fatality rate than were sporadic cases (21% vs. 11%; odds ratio, 3.3; 95% confidence interval, 2.0-5.5). CONCLUSIONS: Outbreaks remain an important but infrequent public health issue, representing <2% of all cases of meningococcal disease. However, given the increased case-fatality rate found among outbreak-related cases of N. meningitidis infection, additional investigation of factors that favor the transmission and virulence of outbreak-related strains is warranted. Adj OR 3.3 [2-3.5] (Age,Sero, clinical syndrome)

 1ere dose d’antibiotique: 8h55 7h30: Merci de prendre en charge en urgence…ce matin à mon arrivée: TA 9/5, purpura echymotique au niveau du ventre, myalgie diffuse, nuque discretement raide. Dans ce contexte, une hospitalisation d’urgence s’impose…  1ere dose d’antibiotique: 8h55

A l’admission en réanimation ischémies distales purpura extensif ecchymotique intéressant les mb, le tronc et le visage

Evolution SDMV, dysfonction myocardique+++ Syndrome des loges Déficit moteur des mb inférieurs 7 jours de VM

Toutes les études de plus de 10 patients Avec la mention de l’ATB pre-hospitaliere et du pronostic 14 études Objective To review the evidence for effectiveness of treatment with antibiotics before admission in reducing case fatality from meningococcal disease. Design Systematic review. Data sources Cochrane register of trials and systematic reviews, database of abstracts of reviews of effectiveness, health technology assessment, and national research register in England and Wales, Medline, Embase, and CAB Health. Included studies Studies describing vital outcome of at least 10 cases of meningococcal disease classified by whether or not antibiotics were given before admission to hospital. Results 14 observational studies met the review criteria. Oral antibiotic treatment given before admission was associated with reduced mortality among cases (combined risk ratio 0.17, 95% confidence interval 0.07 to 0.44). In seven studies in which al included patients were seen in primary care, the association between parenteral antibiotics before admission and outcome was inconsistent (2 for heterogeneity 11.02, P = 0.09). After adjustment for the proportion given parenteral antibiotics before admission, there was no residual heterogeneity. A higher proportion of patients given parenteral antibiotics before admission was associated with reduced mortality after such treatment and vice versa (P = 0.04). Conclusion Confounding by severity is the most likely explanation both for the beneficial effect of oral antibiotics and the harmful effect observed in some studies of parenteral antibiotics.We cannot conclude whether or not antibiotics given before admission have an effect on case fatality. The data are consistent with benefit when a substantial proportion of cases are treated. ATB oral seulement

     Toutes les études de plus de 10 patients Avec la mention de l’ATB pre-hospitaliere et du pronostic 14 études       reducing case fatality from meningococcal disease. Design Systematic review. Data sources Cochrane register of trials and systematic reviews, database of abstracts of reviews of effectiveness, health technology assessment, and national research register in England and Wales, Medline, Embase, and CAB Health. Included studies Studies describing vital outcome of at least 10 cases of meningococcal disease classified by whether or not antibiotics were given before admission to hospital. Results 14 observational studies met the review criteria. Oral antibiotic treatment given before admission was associated with reduced mortality among cases (combined risk ratio 0.17, 95% confidence interval 0.07 to 0.44). In seven studies in which al included patients were seen in primary care, the association between parenteral antibiotics before admission and outcome was inconsistent (2 for heterogeneity 11.02, P = 0.09). After adjustment for the proportion given parenteral antibiotics before admission, there was no residual heterogeneity. A higher proportion of patients given parenteral antibiotics before admission was associated with reduced mortality after such treatment and vice versa (P = 0.04). Conclusion Confounding by severity is the most likely explanation both for the beneficial effect of oral antibiotics and the harmful effect observed in some studies of parenteral antibiotics.We cannot conclude whether or not antibiotics given before admission have an effect on case fatality. The data are consistent with benefit when a substantial proportion of cases are treated. ATB parenterale (pre-hospitalier seulement) Cas sévère: lésions ecchymotiques, choc

      Toutes les études de plus de 10 patients Avec la mention de l’ATB pre-hospitaliere et du pronostic 12 études ATB parentérale      P=0.02  reducing case fatality from meningococcal disease. Design Systematic review. Data sources Cochrane register of trials and systematic reviews, database of abstracts of reviews of effectiveness, health technology assessment, and national research register in England and Wales, Medline, Embase, and CAB Health. Included studies Studies describing vital outcome of at least 10 cases of meningococcal disease classified by whether or not antibiotics were given before admission to hospital. Results 14 observational studies met the review criteria. Oral antibiotic treatment given before admission was associated with reduced mortality among cases (combined risk ratio 0.17, 95% confidence interval 0.07 to 0.44). In seven studies in which al included patients were seen in primary care, the association between parenteral antibiotics before admission and outcome was inconsistent (2 for heterogeneity 11.02, P = 0.09). After adjustment for the proportion given parenteral antibiotics before admission, there was no residual heterogeneity. A higher proportion of patients given parenteral antibiotics before admission was associated with reduced mortality after such treatment and vice versa (P = 0.04). Conclusion Confounding by severity is the most likely explanation both for the beneficial effect of oral antibiotics and the harmful effect observed in some studies of parenteral antibiotics.We cannot conclude whether or not antibiotics given before admission have an effect on case fatality. The data are consistent with benefit when a substantial proportion of cases are treated.  Biais  Sévérité Effet deletère si traitement rare:  cas plus sevère  inexpérience

Case: 190 fatal cases of meningococcal diseases Control: (3:1) matched for age and region 152 prehospital diag  Reason for AB-:uncertainty of diag. (27/47), rash not hemorrhagic, allergy (7),  delay hosp.  AB+ had more severe disease at hosp adm. GMSPS: 6 vs 4, p=0.0002 GP considered severe if 999 or blue light ambulance call circulatory collapse or loss consciouisness OBJECTIVE: To explore the impact on mortality and morbidity of parenteral penicillin given to children before admission to hospital with suspected meningococcal disease. DESIGN: Retrospective comparison of fatal and non-fatal cases. SETTING: England, Wales, and Northern Ireland; December 1997 to February 1999. PARTICIPANTS: 158 children aged 0-16 years (26 died, 132 survived) in whom a general practitioner had made the diagnosis of meningococcal disease before hospital admission. RESULTS: Administration of parenteral penicillin by general practitioners was associated with increased odds ratios for death (7.4, 95% confidence interval 1.5 to 37.7) and complications in survivors (5.0, 1.7 to 15.0). Children who received penicillin had more severe disease on admission (median Glasgow meningococcal septicaemia prognostic score (GMSPS) 6.5 v 4.0, P = 0.002). Severity on admission did not differ significantly with time taken to reach hospital. CONCLUSIONS: Children who were given parenteral penicillin by a general practitioner had more severe disease on reaching hospital than those who were not given penicillin before admission. The association with poor outcome may be because children who are more severely ill are being given penicillin before admission. 105 AB+ 47 AB- DC 26/158 GP considered severe if 999 or blue light ambulance call circulatory collapse or loss consciouisness

AB+ is associated with a 7-fold increase in the risk of death and a 5-fold increase in complications…? Possible explanation: 1- Endotoxin liberation? But no increase in severity with the delay to hosp. Adm. 2- underestimation of the GP severity by the practitionners 3- Abx already too late OBJECTIVE: To explore the impact on mortality and morbidity of parenteral penicillin given to children before admission to hospital with suspected meningococcal disease. DESIGN: Retrospective comparison of fatal and non-fatal cases. SETTING: England, Wales, and Northern Ireland; December 1997 to February 1999. PARTICIPANTS: 158 children aged 0-16 years (26 died, 132 survived) in whom a general practitioner had made the diagnosis of meningococcal disease before hospital admission. RESULTS: Administration of parenteral penicillin by general practitioners was associated with increased odds ratios for death (7.4, 95% confidence interval 1.5 to 37.7) and complications in survivors (5.0, 1.7 to 15.0). Children who received penicillin had more severe disease on admission (median Glasgow meningococcal septicaemia prognostic score (GMSPS) 6.5 v 4.0, P = 0.002). Severity on admission did not differ significantly with time taken to reach hospital. CONCLUSIONS: Children who were given parenteral penicillin by a general practitioner had more severe disease on reaching hospital than those who were not given penicillin before admission. The association with poor outcome may be because children who are more severely ill are being given penicillin before admission. …« The current discrepancies can be answered only by a randomised controlled trial. » (Accepted 23 February 2006)… SIC!!!!!!!!

Conclusions As with many interventions intended to BMJ 2003 - 327; 20-27 Conclusions As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only observational data.We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute.

Statistics and death of meningococcal diseases in children Statistics and death of meningococcal diseases in children Perera R – BMJ 2006; 332:1297  Patients in whom the diagnosis of IMD was not suspected by the GP were excluded… (*) None of these patients received pre-hospital Penicillin… Children seen by a GP had a lower mortality (18%) than others (37%) Children included Children excluded Crude odds ratio All children 448 0.85 GP suspected only 152 290* 5.96 Comment by the statistician of the Harden study+++ « Population enrolled should have a chance to receive penicillin… ..But the population referred probably to a subgroup with a more slowly progressive disease (time to see the doctor) and in whom signs and symptom were specific enough for a diagnosis »

An earlier diagnosis… Thompson MJ - Lancet 2006; 367: 397–403 Time between onset and adm. Med13 h (<1y) Med 14 h (1-4y) Med 20 h (5-14y) Med 22 h (15-16 y) 113 (25%) sympt of LRTI within 2 weeks Sepsis features abnormal skin colour, cold hands and feet, or leg pain; impaired mental state unconsciousness, confusion or delirium, or seizure; Meningism neck stiffness or photophobia. 190 fatal/755 non fatal cases Background Meningococcal disease is a rapidly progressive childhood infection of global importance. To our knowledge, no systematic quantitative research exists into the occurrence of symptoms before admission to hospital. Methods Data were obtained from questionnaires answered by parents and from primary-care records for the course of illness before admission to hospital in 448 children (103 fatal, 345 non-fatal), aged 16 years or younger, with meningococcal disease. In 373 cases, diagnosis was confirmed with microbiological techniques. The rest of the children were included because they had a purpuric rash, and either meningitis or evidence of septicaemic shock. Results were standardised to UK case-fatality rates. Findings The time-window for clinical diagnosis was narrow. Most children had only non-specific symptoms in the first 4–6 h, but were close to death by 24 h. Only 165 (51%) children were sent to hospital after the first consultation. The classic features of haemorrhagic rash, meningism, and impaired consciousness developed late (median onset 13–22 h). By contrast, 72% of children had early symptoms of sepsis (leg pains, cold hands and feet, abnormal skin colour) that first developed at a median time of 8 h, much earlier than the median time to hospital admission of 19 h. Interpretation Classic clinical features of meningococcal disease appear late in the illness. Recognising early symptoms of sepsis could increase the proportion of children identified by primary-care clinicians and shorten the time to hospital admission. The framework within which meningococcal disease is diagnosed should be changed to emphasise identification of these early symptoms by parents and clinicians.

Antibiothérapie avant l’admission Conseil Supérieur d’Hygiène (10 mars 2000): (devant un purpura fébrile) dès le domicile une dose (IV, IM) de 50mg/kg de ceftriaxone (max 1g enfant, 2 g adulte) ou à défaut 100mg/kg de cefotaxime ou 100mg/kg d’ amoxicilline Faire une HC en pré-hospitalier…(sinon tant pis!!) Données françaises (InVS) 2002-2004: 507 purpura fulminans 41% (206) ont reçu des ATB avant admission. 24% si ATB vs 35% (p=0,01) Perrocheau A et al - Euro Surveill 2005;10(12): 238-41