[Markers of severity and predictors of response to treatment in severe asthma]. / Marqueurs de sévérité et marqueurs prédictifs de réponse au traitement dans l'asthme sévère.

Asthma is a multifactorial disease with complex pathophysiology. Knowledge of its immunopathology and inflammatory mechanisms is progressing and has led to the development over recent years of increasingly targeted therapeutic strategies. The objective of this review is to pinpoint the different predictive markers of asthma severity and therapeutic response. Obesity, nasal polyposis, gastroesophageal reflux disease and intolerance to aspirin have all been considered as clinical markers associated with asthma severity, as have functional markers such as bronchial obstruction, low FEV1, small daily variations in FEV1, and high FeNO. While sinonasal polyposis and allergic comorbidities are associated with better response to omalizumab, nasal polyposis or long-term systemic steroid use are associated with better response to antibodies targeting the IL5 pathway. Elevated total IgE concentrations and eosinophil counts are classic biological markers regularly found in severe asthma. Blood eosinophils are predictive biomarkers of response to anti-IgE, anti-IL5, anti-IL5R and anti-IL4R biotherapies. Dupilumab is particularly effective in a subgroup of patients with marked type 2 inflammation (long-term systemic corticosteroid therapy, eosinophilia≥150/µl or FENO>20 ppb). Chest imaging may help to identify severe patients by seeking out bronchial wall thickening and bronchial dilation. Study of the patient's environment is crucial insofar as exposure to tobacco, dust mites and molds, as well as outdoor and indoor air pollutants (cleaning products), can trigger asthma exacerbation. Wider and more systematic use of markers of severity or response to treatment could foster increasingly targeted and tailored approaches to severe asthma.

A global phylogenomic and metabolic reconstruction of the large intestine bacterial community of domesticated cattle.

BACKGROUND: The large intestine is a colonization site of beneficial microbes complementing the nutrition of cattle but also of zoonotic and animal pathogens. Here, we present the first global gene catalog of cattle fecal microbiomes, a proxy of the large intestine microbiomes, from 436 metagenomes from six countries. RESULTS: Phylogenomics suggested that the reconstructed genomes and their close relatives form distinct branches and produced clustering patterns that were reminiscent of the metagenomics sample origin. Bacterial taxa had distinct metabolic profiles, and complete metabolic pathways were mainly linked to carbohydrates and amino acids metabolism. Dietary changes affected the community composition, diversity, and potential virulence. However, predicted enzymes, which were part of complete metabolic pathways, remained present, albeit encoded by different microbes. CONCLUSIONS: Our findings provide a global insight into the phylogenetic relationships and the metabolic potential of a rich yet understudied bacterial community and suggest that it provides valuable services to the host. However, we tentatively infer that members of that community are not irreplaceable, because similar to previous findings, symbionts of complex bacterial communities of mammals are expendable if there are substitutes that can perform the same task. Video Abstract.

Prevalence and determinants of home delivery among reproductive age women, Margibi County, Liberia.

BACKGROUND: The use of institutional delivery services is essential for improving maternal and child health. However, studies in Liberia reveal over 20% of women still deliver at home. We assessed the prevalence and associated factors of home delivery among women of reproductive age in Margibi County, Liberia. METHODS: We conducted a cross-sectional study among 438 women of reproductive age in Margibi County. Data were obtained using a semi-structured questionnaire. A simple random sampling approach was used to select the participants for the study. We performed binary logistic regression to identify factors influencing home delivery. Findings were summarized into tables displaying the frequencies, percentages, crude, and adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Prevalence of home delivery in the County was 90.6% (95% CI = 87.5 - 93.0). Women who were ≥ 31 years (aOR = 6.74, 95%CI = 2.86-15.90), women who had two or more children (aOR = 9.68, 95%CI = 4.07-22.99) and those who had rapid onset of labor (aOR = 6.35, 95%CI = 1.59 - 25.27) were associated with increased odds of home delivery. Good attitude of health workers (aOR = 0.01, 95%CI = 0.001 - 0.08) and the availability of transport to the nearest health facility (aOR = 0.01, 95%CI = 0.003 - 0.03) were factors associated with a decreased odds of home delivery among the study participants. CONCLUSION: The high prevalence of home delivery in the county is a call for urgent interventions by the government of Liberia and various non-governmental organizations. The government may need to supply the county with ambulances and ensure in-service training of health workers on good attitudes.

[Cardiopulmonary exercise testing in the management of systemic sclerosis]. / La place de l'Exploration Fonctionnelle (cardio-)respiratoire d'eXercice (EFX) dans la prise en charge de la sclérodermie systémique.

Cardiopulmonary complications are the leading cause of mortality in patients with systemic sclerosis (SSc) requiring an early identification. A global and comprehensive approach is needed due to the complexity of the overlapping aetiologies of dyspnoea in SSc. Through its integrative approach of ventilatory, metabolic, cardiovascular, skeletal muscular and gas exchange findings, cardiopulmonary exercise testing (CPET) has been known to identify and sort competing mechanisms of exercise limitation in scleroderma patients presenting with dyspnoea. CPET may be used to screen for pulmonary arterial hypertension, suspect interstitial lung disease and guide therapeutic strategies including exercise rehabilitation. This review focuses on the clinical value of CPET in the decision-making processes for a more personalised diagnostic approach to SSc-related complications.

[The role of hyponatremia in the rapid onset of coma after Cyclophosphamide]. / Rôle de l'hyponatrémie dans la survenue rapide d'un coma après Cyclophosphamide.

INTRODUCTION: Cyclophosphamide is an alkylating agent used in routine pulmonary practice, particularly in the management of connectivitis-related diffuse interstitial lung disease. Common side effects are gastrointestinal disorders and immunosuppression, and a sudden and exceptional adverse effect is severe hyponatremia. OBSERVATION: A 78-year-old female patient treated for NSIP-OP in the context of an anti-synthetase syndrome was treated with Cyclophosphamide 15mg/kg. Twenty-four hours after the end of the infusion, she was diagnosed at home in a coma with comitial seizures. Biological assessment revealed severe hyponatremia at 109 mmol/l with blood hypo-osmolarity. The patient's condition rapidly improved following correction of the ionic disorder. CONCLUSION: Hyponatremia induced by low-dose Cyclophosphamide is a rare but serious adverse effect that requires special attention.

Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury.

Acetaminophen (N-acetyl-p-aminophenol; APAP) toxicity is a common cause of liver damage. In the mouse model of APAP-induced liver injury (AILI), interleukin 11 (IL11) is highly up-regulated and administration of recombinant human IL11 (rhIL11) has been shown to be protective. Here, we demonstrate that the beneficial effect of rhIL11 in the mouse model of AILI is due to its inhibition of endogenous mouse IL11 activity. Our results show that species-matched IL11 behaves like a hepatotoxin. IL11 secreted from APAP-damaged human and mouse hepatocytes triggered an autocrine loop of NADPH oxidase 4 (NOX4)-dependent cell death, which occurred downstream of APAP-initiated mitochondrial dysfunction. Hepatocyte-specific deletion of Il11 receptor subunit alpha chain 1 (Il11ra1) in adult mice protected against AILI despite normal APAP metabolism and glutathione (GSH) depletion. Mice with germline deletion of Il11 were also protected from AILI, and deletion of Il1ra1 or Il11 was associated with reduced c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activation and quickly restored GSH concentrations. Administration of a neutralizing IL11RA antibody reduced AILI in mice across genetic backgrounds and promoted survival when administered up to 10 hours after APAP. Inhibition of IL11 signaling was associated with the up-regulation of markers of liver regenerations: cyclins and proliferating cell nuclear antigen (PCNA) as well as with phosphorylation of retinoblastoma protein (RB) 24 hours after AILI. Our data suggest that species-matched IL11 is a hepatotoxin and that IL11 signaling might be an effective therapeutic target for APAP-induced liver damage.

Lung function in Birt-Hogg-Dubé syndrome: a retrospective analysis of 96 patients.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the FLCN gene coding for folliculin. Its clinical expression includes cutaneous fibrofolliculomas, renal tumors, multiple pulmonary cysts, and recurrent spontaneous pneumothoraces. Data on lung function in BHD are scarce and it is not known whether lung function declines over time. We retrospectively assessed lung function at baseline and during follow-up in 96 patients with BHD. RESULTS: Ninety-five percent of BHD patients had multiple pulmonary cysts on computed tomography and 59% had experienced at least one pneumothorax. Mean values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and total lung capacity were normal at baseline. Mean (standard deviation) residual volume (RV) was moderately increased to 116 (36) %pred at baseline, and RV was elevated > 120%pred in 41% of cases. Mean (standard deviation) carbon monoxide transfer factor (DLco) was moderately decreased to 85 (18) %pred at baseline, and DLco was decreased < 80%pred in 33% of cases. When adjusted for age, gender, smoking and history of pleurodesis, lung function parameters did not significantly decline over a follow-up period of 6 years. CONCLUSIONS: Cystic lung disease in BHD does not affect respiratory function at baseline except for slightly increased RV and reduced DLco. No significant deterioration of lung function occurs in BHD over a follow-up period of 6 years.

Staphylococcus pseudoxylosus sp. nov., isolated from bovine mastitis.

Strain S04009T, a Gram-stain-positive, coagulase-negative staphylococcus, was isolated from bovine mastitis in France. 16S rRNA gene analysis revealed it to be closely related to the coagulase-negative species Staphylococcusxylosus, Staphylococcussaprophyticus, Staphylococcuscaeli and Staphylococcus edaphicus. At the whole-genome level, strain S04009T had an average nucleotide identity value <95 % and an inferred DNA-DNA hybridization value <70 % when compared to these species. Furthermore, phenotypic characteristics distinguished S04009T from those species. From these related species only strain S04009T and S. xylosus are able to ferment xylose and these two can be distinguished by the inability of strain S04009T to express urease activity. Based on the genotypic and phenotypic results, it is proposed that this isolate is a novel species, with the name Staphylococcus pseudoxylosus sp. nov. The type strain is S04009T (=DSM 107950T=CCUG 72763T=NCTC 14184T).

Hypothesis: Fever control, a niche for alpha-2 agonists in the setting of septic shock and severe acute respiratory distress syndrome?

During severe septic shock and/or severe acute respiratory distress syndrome (ARDS) patients present with a limited cardio-ventilatory reserve (low cardiac output and blood pressure, low mixed venous saturation, increased lactate, low PaO2/FiO2 ratio, etc.), especially when elderly patients or co-morbidities are considered. Rescue therapies (low dose steroids, adding vasopressin to noradrenaline, proning, almitrine, NO, extracorporeal membrane oxygenation, etc.) are complex. Fever, above 38.5-39.5°C, increases both the ventilatory (high respiratory drive: large tidal volume, high respiratory rate) and the metabolic (increased O2 consumption) demands, further limiting the cardio-ventilatory reserve. Some data (case reports, uncontrolled trial, small randomized prospective trials) suggest that control of elevated body temperature ("fever control") leading to normothermia (35.5-37°C) will lower both the ventilatory and metabolic demands: fever control should simplify critical care management when limited cardio-ventilatory reserve is at stake. Usually fever control is generated by a combination of general anesthesia ("analgo-sedation", light total intravenous anesthesia), antipyretics and cooling. However general anesthesia suppresses spontaneous ventilation, making the management more complex. At variance, alpha-2 agonists (clonidine, dexmedetomidine) administered immediately following tracheal intubation and controlled mandatory ventilation, with prior optimization of volemia and atrio-ventricular conduction, will reduce metabolic demand and facilitate normothermia. Furthermore, after a rigorous control of systemic acidosis, alpha-2 agonists will allow for accelerated emergence without delirium, early spontaneous ventilation, improved cardiac output and micro-circulation, lowered vasopressor requirements and inflammation. Rigorous prospective randomized trials are needed in subsets of patients with a high fever and spiraling toward refractory septic shock and/or presenting with severe ARDS.

[Pulmonary intravascular talcosis: A case report]. / Talcose intravasculaire pulmonaire : à propos d'un cas.

INTRODUCTION: Pulmonary intravascular talcosis is a rare condition occurring in intravenous drug users injecting oral medications. Talc results in a foreign-body granulomatous reaction giving a radiological haematogenic miliary appearance mimicking miliary tuberculosis. Drug users represent a population at risk for both these conditions and their distinction may be challenging. CASE REPORT: We reported the case of a man, 33 year-old, intravenous drug addict, detected by the health services because he was the partner of a person who died of contagious and multi-resistant tuberculosis. Chest X-ray and CT scan showed a typical miliary appearance. Despite negative microbiology, clinical diagnosis of miliary tuberculosis was retained. Due to the lack of radiological improvement despite appropriate antibiotic treatment, re-evaluation and trans-bronchial biopsy were undertaken. The presence of granulomas centered by birefringent foreign bodies in polarized light led to a diagnosis of pulmonary intravascular talcosis. CONCLUSION: In the presence of pulmonary miliary in an intravenous drug addict, intravascular talcosis should be suspected.

Sources of variability in quantifying circulating thymosin beta-4: literature review and recommendations.

INTRODUCTION: Thymosin beta-4 (TB4) is an endogenous peptide with protective and regenerative effects in models of cellular and organ injury. TB4 is increasingly measured as a potential plasma or serum biomarker in human cardiovascular, liver, infectious, and autoimmune disease. AREAS COVERED: The focus of this review is the quantification of TB4 in clinical cohort studies and whether reported TB4 concentrations differ with respect to method of sample preparation. We survey current literature for studies measuring TB4 in human serum or plasma and compare reported concentrations in healthy controls. EXPERT OPINION: We find substantial intra- and inter- study variability in healthy controls, and a lack of protocol standardization. We further highlight three factors that may confound TB4 clinical measurements and should be considered in future study design: 1) residual platelets remaining in suspension after centrifugation, 2) TB4 release following ex vivo platelet activation, and 3) specificity of assays towards posttranslational modifications. Accordingly, we put forth our recommendations to minimize residual and activated platelets during sample collection, and to cross-validate TB4 measurements using both antibody-based and mass spectrometry-based methods.

[The biological rationale for immunotherapy in cancer]. / Rationnel biologique de l'immunothérapie des cancers.

INTRODUCTION: Immunotherapy aims to promote the immune system's activity against malignant cells by stimulating the response to several tumor antigens. STATE OF THE ART: Immunosurveillance may adjust the immunogenicity of tumors. To be effective, immunity must induce the specific activation of CD4+ and CD8+ T lymphocytes, as well as activation of innate immunity. Activator and inhibitory costimulatory molecules regulate T lymphocyte activation at immunity checkpoints such as PD-1/PD-L1 and CTLA-4. Adaptive immune resistance confers tumour resistance to immunosurveillance through these immune checkpoints. PERSPECTIVES: Approaches involving the combination of several immunotherapies with each other or with chemotherapy and radiotherapy and antibodies against other molecules of costimulation are under development. The development of biomarkers, which can select a targeted population and predict therapeutic response, represents a major challenge. Tumour high-throughput sequencing could refine "immunoscore". Intratumoral T cell receptor seems to represent a promising biomarker. CONCLUSIONS: Numerous challenges still remain in developing research approaches for the development of immunotherapies.

[Emphysema, did you say emphysema?] / Emphysème, vous avez dit emphysème ?

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a common condition that may initially look simple but may conceal other diseases capable of accelerating its natural history or even simulating it. We describe four cases presenting as COPD with emphysema that were reclassified on the basis of certain clinical characteristics and the radiological pattern. CASE REPORTS: A 52 year old never smoking woman presenting with emphysema was eventually diagnosed as having lymphangioleiomyomatosis on the basis of an abdominal CT scan showing kidney angiomyolipomas. A 44 years old smoker presenting with rapidly evolving emphysema was eventually diagnosed as having Langerhans cell histiocytosis on the basis of a previous chest CT (four years earlier) showing cavitating nodules. An airport refueler, 73 years old, with severe emphysema despite never having smoked, was eventually diagnosed as suffering from alpha-1 antitrypsin deficiency. The last patient was a 54 year old man, a never smoker, who presented with severe airflow limitation and multilobar hyperlucency, with bronchiectasis in the same areas. He was eventually diagnosed as having a severe form of the Swyer-James-MacLeod syndrome. CONCLUSION: These four case reports underline the importance of questioning the diagnosis of COPD when certain particular phenotypic characteristics are identified.

Detection of PD-L1 in circulating tumor cells and white blood cells from patients with advanced non-small-cell lung cancer.

Background: Expression of PD-L1 in tumor cells and tumor-infiltrating immune cells has been associated with improved efficacy to anti-PD-1/PD-L1 inhibitors in patients with advanced-stage non-small-cell lung cancer (NSCLC) and emerged as a potential biomarker for the selection of patients to cancer immunotherapies. We investigated the utility of circulating tumor cells (CTCs) and circulating white blood cells (WBCs) as a noninvasive method to evaluate PD-L1 status in advanced NSCLC patients. Patients and methods: CTCs and circulating WBCs were enriched from peripheral blood samples (ISET® platform; Rarecells) from 106 NSCLC patients. PD-L1 expression on ISET filters and matched-tumor tissue was evaluated by automated immunostaining (SP142 antibody; Ventana), and quantified in tumor cells and WBCs. Results: CTCs were detected in 80 (75%) patients, with levels ranging from 2 to 256 CTCs/4 ml, and median of 60 CTCs/4 ml. Among 71 evaluable samples with matched-tissue and CTCs, 6 patients (8%) showed ≥1 PD-L1-positive CTCs and 11 patients (15%) showed ≥1% PD-L1-positive tumor cells in tumor tissue with 93% concordance between tissue and CTCs (sensitivity = 55%; specificity = 100%). From 74 samples with matched-tissue and circulating WBCs, 40 patients (54%) showed ≥1% PD-L1-positive immune infiltrates in tumor tissue and 39 patients (53%) showed ≥1% PD-L1 positive in circulating WBCs, with 80% concordance between blood and tissue (sensitivity = 82%; specificity = 79%). We found a trend for worse survival in patients receiving first-line cisplatin-based chemotherapy treatments, whose tumors express PD-L1 in CTCs or immune cells (progression-free and overall survival), similar to the effects of PD-L1 expression in matched-patient tumors. Conclusions: These results demonstrated that PD-L1 status in CTCs and circulating WBCs correlate with PD-L1 status in tumor tissue, revealing the potential of CTCs assessment as a noninvasive real-time biopsy to evaluate PD-L1 expression in patients with advanced-stage NSCLC.

Thymosin Beta-4 Is Elevated in Women With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Thymosin beta-4 (TB4) is an X-linked gene product with cardioprotective properties. Little is known about plasma concentration of TB4 in heart failure (HF), and its relationship with other cardiovascular biomarkers. We sought to evaluate circulating TB4 in HF patients with preserved (HFpEF) or reduced (HFrEF) ejection fraction compared to non-HF controls. METHODS AND RESULTS: TB4 was measured using a liquid chromatography and mass spectrometry assay in age- and sex-matched HFpEF (n=219), HFrEF (n=219) patients, and controls (n=219) from a prospective nationwide study. Additionally, a 92-marker multiplex proximity extension assay was measured to identify biomarker covariates. Compared with controls, plasma TB4 was elevated in HFpEF (985 [421-1723] ng/mL versus 1401 [720-2379] ng/mL, P<0.001), but not in HFrEF (1106 [556-1955] ng/mL, P=0.642). Stratifying by sex, only women (1623 [1040-2625] ng/mL versus 942 [386-1891] ng/mL, P<0.001), but not men (1238.5 [586-1967] ng/mL versus 1004 [451-1538] ng/mL, P=1.0), had significantly elevated TB4 in the setting of HFpEF. Adjusted for New York Heart Association class, N-terminal pro B-type natriuretic peptide, age, and myocardial infarction, hazard ratio to all-cause mortality is significantly higher in women with elevated TB4 (1.668, P=0.036), but not in men (0.791, P=0.456) with HF. TB4 is strongly correlated with a cluster of 7 markers from the proximity extension assay panel, which are either X-linked, regulated by sex hormones, or involved with NF-κB signaling. CONCLUSIONS: We show that plasma TB4 is elevated in women with HFpEF and has prognostic information. Because TB4 can preserve EF in animal studies of cardiac injury, the relation of endogenous, circulating TB4 to X chromosome biology and differential outcomes in female heart disease warrants further study.

Immunotherapy in Non-Small Cell Lung Cancer: Biological Principles and Future Opportunities.

Immunotherapy aims to amplify the anticancer immune response through reactivation of the lymphocytic response raised against several tumor neo-antigens. To obtain an effective immune response, this therapeutic approach requires that a number of immunological checkpoints be passed, such as the activation of excitatory costimulatory signals or the avoidance of coinhibitory molecules. Among the immune checkpoints, the interaction of the membrane-bound ligand PD-1 and its receptor PD-L1 has received much attention because of remarkable efficacy in numerous clinical trials for various cancer types, including non-small cell lung cancer (NSCLC). However, several limitations exist with these therapeutic agents when used as monotherapy, with objective responses observed in only 30-40% of patients, with the majority of patients demonstrating innate resistance, and approximately 25% of responders later demonstrating disease progression. Recent developments in the understanding of cancer immunology have the potential to identify mechanisms of innate and acquired resistance to immune checkpoint inhibitors through translational research in human samples. This review focuses on the biological basic principles for immunological checkpoint blockade, and highlights the current status and the perspectives of this therapeutic approach in NSCLC patients.

Pulmonary sarcoid-like granulomatosis induced by nivolumab.

The use of antibodies against programmed death (PD)1, such as nivolumab and pembrolizumab, has dramatically improved the prognosis of patients with advanced melanoma. Nivolumab is also approved in advanced squamous cell nonsmall-cell lung cancer. These immunotherapies are associated with a unique set of toxicities termed immune-related adverse events, which are different from toxicities observed with conventional cytotoxic chemotherapy. We report the case of a 56-year-old man who was diagnosed with metastatic melanoma and who received nivolumab. One week after the second infusion, he developed pulmonary symptoms, dry eye syndrome and a bilateral swelling of the parotid glands. Investigations were negative for infection. The bronchoalveolar lavage differential cell count showed 32% lymphocytes with an increased CD4 : CD8 ratio, and bronchial biopsies revealed noncaseating epithelioid granulomas, without malignant cells. The clinical and radiological courses were rapidly favourable with oral corticosteroid. This case illustrates that sarcoidosis can be induced by nivolumab treatment. With the increasing use of anti-PD1 inhibitors in patients with advanced melanoma and squamous cell nonsmall-cell lung cancer, clinicians should be aware of this potential associated immune-related adverse event.

Comparison of different blood compartments for the detection of circulating DNA using a rat model of Pneumocystis pneumonia.

Pneumocystis is mostly found in the alveolar spaces, but circulation of viable organisms also occurs and suggests that the detection of DNA in blood could be used as a noninvasive procedure to improve the diagnosis of Pneumocystis pneumonia (PcP). In order to determine the optimal compartment for Pneumocystis DNA detection, we used a rat model of PcP and tested the presence of Pneumocystis with a quantitative mtLSU targeting real-time PCR in four blood compartments: whole blood, clot, serum and Platelet-Rich-Plasma (PRP). All samples from 4 Pneumocystis-free control rats were negative. Pneumocystis was detected in 79, 64, 57, and 57% of samples from 14 PcP rats, respectively, but DNA release was not related to pulmonary loads. These data confirm the potential usefulness of Pneumocystis DNA detection in the blood for PcP diagnosis and suggest that whole blood could be the most appropriate compartment for Pneumocystis detection.

Pressor Response to Noradrenaline in the Setting of Septic Shock: Anything New under the Sun-Dexmedetomidine, Clonidine? A Minireview.

Progress over the last 50 years has led to a decline in mortality from ≈70% to ≈20% in the best series of patients with septic shock. Nevertheless, refractory septic shock still carries a mortality close to 100%. In the best series, the mortality appears related to multiple organ failure linked to comorbidities and/or an intense inflammatory response: shortening the period that the subject is exposed to circulatory instability may further lower mortality. Treatment aims at reestablishing circulation within a "central" compartment (i.e., brain, heart, and lung) but fails to reestablish a disorganized microcirculation or an adequate response to noradrenaline, the most widely used vasopressor. Indeed, steroids, nitric oxide synthase inhibitors, or donors have not achieved overwhelming acceptance in the setting of septic shock. Counterintuitively, α 2-adrenoceptor agonists were shown to reduce noradrenaline requirements in two cases of human septic shock. This has been replicated in rat and sheep models of sepsis. In addition, some data show that α 2-adrenoceptor agonists lead to an improvement in the microcirculation. Evidence-based documentation of the effects of alpha-2 agonists is needed in the setting of human septic shock.