Marc Leone

Effect of Sex on Coxiella burnetii Infection: Protective Role of 17β-Estradiol

Q fever is a zoonosis caused by Coxiella burnetii and recently has been recognized as a potential agent of bioterrorism. In Q fever, men are symptomatic more often than women, despite equal seroprevalence. We hypothesized that sex hormones play a role in the pathogenesis of C. burnetii infection. When C57/BL6 mice were injected with C. burnetii, bacteria load and granuloma numbers were lower in females than in males. Ovarectomized mice showed increased bacteria load in the spleen and the liver, similar to that found in males. The granuloma number was also increased in ovarectomized mice and reached the levels found in males. Tissue infection and granulomatous response are largely under the control of estrogens: treatment of ovarectomized mice with 17beta-estradiol reduced both bacteria loads and granuloma numbers. These results show that sex hormones control host response to C. burnetii infection and may account for host-dependent clinical presentation of Q fever.

De-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized noninferiority trial

BackgroundIn patients with severe sepsis, no randomized clinical trial has tested the concept of de-escalation of empirical antimicrobial therapy. This study aimed to compare the de-escalation strategy with the continuation of an appropriate empirical treatment in those patients.MethodsThis was a multicenter non-blinded randomized noninferiority trial of patients with severe sepsis who were randomly assigned to de-escalation or continuation of empirical antimicrobial treatment. Recruitment began in February 2012 and ended in April 2013 in nine intensive care units (ICUs) in France. Patients with severe sepsis were assigned to de-escalation (nxa0=xa059) or continuation of empirical antimicrobial treatment (nxa0=xa057). The primary outcome was to measure the duration of ICU stay. We defined a noninferiority margin of 2xa0days. If the lower boundary of the 95xa0% confidence interval (CI) for the difference in patients assigned to the de-escalation group was less than 2xa0days, as compared with that of patients assigned to the continuation group, de-escalation was considered to be noninferior to the continuation strategy. Secondary outcomes included mortality at 90xa0days, occurrence of organ failure, number of superinfections, and number of days with antibiotics during the ICU stay.ResultsThe median duration of ICU stay was 9 [interquartile range (IQR) 5–22] days in the de-escalation group and 8 [IQR 4–15] days in the continuation group, respectively (Pxa0=xa00.71). The mean difference was 3.4 (95xa0% CI −1.7 to 8.5). A superinfection occurred in 16 (27xa0%) patients in the de-escalation group and six (11xa0%) patients in the continuation group (Pxa0=xa00.03). The numbers of antibiotic days were 9 [7–15] and 7.5 [6–13] in the de-escalation group and continuation group, respectively (Pxa0=xa00.03). Mortality was similar in both groups.ConclusionAs compared to the continuation of the empirical antimicrobial treatment, a strategy based on de-escalation of antibiotics resulted in prolonged duration of ICU stay. However, it did not affect the mortality rate.

Sex-Related Differences in Gene Expression Following Coxiella burnetii Infection in Mice: Potential Role of Circadian Rhythm

Background Q fever, a zoonosis due to Coxiella burnetii infection, exhibits sexual dimorphism; men are affected more frequently and severely than women for a given exposure. Here we explore whether the severity of C. burnetii infection in mice is related to differences in male and female gene expression profiles. Methodology/Principal Findings Mice were infected with C. burnetii for 24 hours, and gene expression was measured in liver cells using microarrays. Multiclass analysis identified 2,777 probes for which expression was specifically modulated by C. burnetti infection. Only 14% of the modulated genes were sex-independent, and the remaining 86% were differentially expressed in males and females. Castration of males and females showed that sex hormones were responsible for more than 60% of the observed gene modulation, and this reduction was most pronounced in males. Using functional annotation of modulated genes, we identified four clusters enriched in males that were related to cell-cell adhesion, signal transduction, defensins and cytokine/Jak-Stat pathways. Up-regulation of the IL-10 and Stat-3 genes may account for the high susceptibility of men with Q fever to C. burnetii infection and autoantibody production. Two clusters were identified in females, including the circadian rhythm pathway, which consists of positive (Clock, Arntl) and negative (Per) limbs of a feedback loop. We found that Clock and Arntl were down-modulated whereas Per was up-regulated; these changes may be associated with efficient bacterial elimination in females but not in males, in which an exacerbated host response would be prominent. Conclusion This large-scale study revealed for the first time that circadian rhythm plays a major role in the anti-infectious response of mice, and it provides a new basis for elucidating the role of sexual dimorphism in human infections.

Sex Hormones and Bacterial Infections

Epidemiological and experimental data suggest the association of gender and sex with susceptibility and severity of infectious diseases (Moss, 2005). Gender and sex likely affect viral and parasitic infectious diseases (Morales-Montor et al., 2004; Fish, 2008; Snider et al., 2009). Here we will review the effect of gender and sex on bacterial infectious diseases (sepsis, mycobacterial diseases and Q fever). We will differentiate gender and sex by considering that gender refers to differences determined by cultural and societal factors and sex refers to the biological differences between males and females (Fish, 2008). Indeed, variables such as poverty, occupational status and marital status affect differently men and women in different countries (Theobald et al., 2006), leading to different risks of exposition to infectious pathogens and accesses to efficient treatment. This is illustrated by the decreased prevalence of tuberculosis in industrialized countries associated with socioeconomic changes including reduced malnutrition and overcrowding, improved sanitary conditions in the workplaces before the use of chemotherapy (Davies et al., 1999). Sex-based differences in the susceptibility to pathogens include what is due to chromosome effect and sex hormones. Thus, it is critical to delineate the respective roles of gender and sex on bacterial infections. The present review focuses on four features of the association between sex and bacterial infections with a special attention for bacterial sepsis, mycobacterial infections and Coxiella burnetii infection.

The Patient with Septic Shock

Septic shock may occur during surgery or may be a cause for emergent surgery. The patients with septic shock in the operating room should be managed according to international guidelines. This implies the use of monitoring to assess the need for fluid, vasopressor, and positive inotrope. The choice of hypnotics remains challenging in those patients with an impaired sympathetic tone. Ketamine seems a reasonable choice for induction, whereas sevoflurane or desflurane can be used for maintenance. Surgery should not be a reason for delaying the administration of antibiotics. Each hour of delay is associated with worsening of outcomes. Sampling blood and secretion are mandatory before the initiation of the antimicrobial treatment.

Genetic Aspects of Uncommon Diseases

Genetic or hereditary diseases are the consequence of gene’s sequence modification. They represent 80 % of the so-called “rare” diseases, i.e. with a prevalence below 1/2,000. This chapter presents general data on the pathophysiology of these diseases and their diagnosis. The most frequent hereditary diseases that can be encountered in the ICU are listed with details in summary tables.

Heat and Moister Exchangers and the Booster® System: Technology and Clinical Implications

It is well recognized that delivering warm, humidified gas to patients ventilated through an endotracheal or tracheostomy tube is of primarily importance. The upper airway and the normal heat and moisture exchanging process of inspired gases are bypassed during mechanical ventilation with endotracheal intubation or tracheostomy. A continuous loss of moisture and heat occurs and predisposes patients to serious airway damage. In addition, medical gases are dried to avoid condensation damage to valves and regulators in the distribution network. To prevent complications associated with ventilation with cold and dry gases, the addition of exogenous heat and humidity by the use of heated hot water systems (vaporizers or nebulizers) can be considered. Vaporizing humidifiers have some disadvantages: condensation of water that can be a source of infection, malfunctions, high maintenance costs, and increased workload for nursing staff. Heat and moisture exchangers (HMEs) with microbial filtration capacity (HME filters, HMEFs) may be a simple solution to the problems of conditioning respiratory gases and, eventually, of reducing the contamination of the apparatus and subsequent bacterial pneumonia. An important advance in the design of HMEs was made with the introduction of plastic foam impregnated with a hygroscopic substance as the active element. The hygroscopic substance chemically absorbs a portion of the expired water vapor on the humidifier element, which is collected by dry inspiratory gases. Paper-based condensation surfaces have also become available, and their efficiency is reinforced after impregnation with a hygroscopic substance. The HMEs preserve patients’ heat and water, and globally they recover 70% of expired heat and humidity.

Les rickettsioses en réanimation

Trois familles de maladie sont regroupes sous le terme de rickettsioses: celles causees par des bacteries du genre Rickettsia, les ehrlichioses et la fievre Q. n n nLes quatre principaux symptomes des fievres pourprees ou boutonneuses sont la fievre, l’eruption cutanee, l’escarre noire au site de morsure de l’arthropode et les lymphadenopathies. n n nPlusieurs types de typhus sont decrits. Le pronostic du typhus murin est favorable dans la plupart des cas. La mortalite spontanee du typhus epidemique varie entre 20 et 30 %. n n nLa fievre pourpree des montagnes Rocheuses, la fievre boutonneuse mediterraneenne et le typhus peuvent etre responsables d’un syndrome de defaillance multiviscerale. n n nL’ehrlichiose granulocytique humaine est observee en Europe et aux Etats-Unis. La mortalite est de moins de 1 %. n n nLa fievre Q est causee par Coxiella burnetii qui infecte principalement par aerosols. La fievre peut etre aigue ou chronique. L’evolution peut etre defavorable. n n nLe diagnostic est base sur les examens serologiques. n n nLa doxycycline (200 mg/j) est le traitement de choix. La precocite d’administration conditionne le pronostic. Les femmes enceintes et les patients allergiques recoivent des traitements alternatifs.

Aspects génétiques des maladies rares

Les maladies genetiques representent 80% des maladies rares. n n nElles resultent de la modification pathologique d’un ou plusieurs genes. n n nLe diagnostic, prenatal ou non, est realise par la mise en evidence d’une ou plusieurs mutations. n n nLa base de connaissance Orphanet (http://www.orpha.net) reste la reference mondiale en termes d’informations sur les maladies genetiques

Prise en charge du traumatisé crânien isolé

Les traumatismes cranio-encephaliques expliquent 50 a 70% des morts accidentelles et sont l’une des premieres causes de deces avant l’âge de 20 ans. Leurs sequelles sont frequentes, souvent tres serieuses, et rendent difficiles la reinsertion socio-familiale de ces jeunes victimes. Si, dans certains cas, la mort ou les sequelles sont inevitables, car directement imputables a la severite des lesions cerebrales initiales, ailleurs, elles peuvent et doivent etre evitees par une prise en charge precoce et adaptee des blesses. En effet, le seul moyen d’ameliorer le pronostic vital et fonctionnel est de prevenir l’apparition ou de limiter l’extension des lesions cerebrales secondaires. Au cours de ces trente dernieres annees, l’introduction de la tomodensitometrie (TDM) cerebrale, et la mesure de pression intracrânienne (PIC) ont donne a la « neurotraumatologie » un visage nouveau. Leurs places ont ete bien definies dans les recommandations nord-americaines (1) et francaises (2) comme etant la pierre angulaire de la prise en charge des patients traumatises crâniens fermes.