title: Effects of level of social contact on dairy calf behavior and health

text: Housing preweaned dairy calves in pairs rather than individually has been found to positively affect behavioral responses in novel social and environmental situations, but concerns have been raised that close contact among very young animals may impair their health. In previous studies, the level of social contact permitted in individual housing has been auditory, visual, or physical contact. It is unclear how these various levels of social contact compare with each other and to pair housing, when their effects on behavior and health are considered, and whether the timing of pair housing has an effect. To investigate this, 110 Holstein calves (50 males, 60 females) in 11 blocks were paired according to birth date. Within 60 h of birth, each pair of calves was allocated to 1 of 5 treatments: individual housing with auditory contact (I), individual housing with auditory and visual contact (V), individual housing with auditory, visual, and tactile contact (T), pair housing (P), or individual housing with auditory and visual contact the first 2 wk followed by pair housing (VP). At 6 wk of age, calves were subjected to a social test and a novel environment test. In the social test, all pair-housed calves (P and VP) had a shorter latency to sniff an unfamiliar calf than did individually housed calves (I, V, and T), whereas calves with physical contact (T, P, and VP) sniffed the unfamiliar calf for longer than calves on the remaining treatments (I and V). In the novel environment test, calves with physical contact (T, P, and VP) had a lower heart rate, and more of these calves vocalized during the test compared with calves without physical contact (I and V). No effect of treatment was found for clinical scores, levels of the 5 most common pathogens in feces, or in development of serum antibodies against the 3 most common respiratory pathogens. Calves housed individually are more fearful of unfamiliar calves than are pair-housed calves. Contrary to common belief, the allowance of physical contact and pair housing had no effects on the health of the calves.


COPD Exacerbations: To X-ray or Not To X-ray


EMERGING INFECTIOUS DISEASES – OVERVIEW


title: Virus Entry: Looking Back and Moving Forward

text: Research over a period of more than half a century has provided a reasonably accurate picture of mechanisms involved in animal virus entry into their host cells. Successive steps in entry include binding to receptors, endocytosis, passage through one or more membranes, targeting to specific sites within the cell, and uncoating of the genome. For some viruses, the molecular interactions are known in great detail. However, as more viruses are analyzed, and as the focus shifts from tissue culture to in vivo experiments, it is evident that viruses display considerable redundancy and flexibility in receptor usage, endocytic mechanism, location of penetration, and uncoating mechanism. For many viruses, the picture is still elusive because the interactions that they engage in rely on sophisticated adaptation to complex cellular functions and defense mechanisms.


title: Blood Transfusion Therapy

text: Transfusion of red blood cells (RBCs) is a balance between providing benefit for patients while avoiding risks of transfusion. Randomized, controlled trials of restrictive RBC transfusion practices have shown equivalent patient outcomes compared with liberal transfusion practices, and meta-analyses have shown improved in-hospital mortality, reduced cardiac events, and reduced bacterial infections. This body of level 1 evidence has led to substantial, improved blood utilization and reduction of inappropriate blood transfusions with implementation of clinical decision support via electronic medical records, along with accompanying educational initiatives.


American College of Chest Physicians and American Association for Bronchology Consensus Statement: Prevention of Flexible Bronchoscopy-Associated Infection


title: RNA interference-mediated control of hepatitis B virus and emergence of resistant mutant

text: Background & Aims Present therapy for chronic hepatitis B attains control only in limited proportions. Small interfering RNA (siRNA) offers a new tool with potential therapeutic applications for hepatitis B virus (HBV). Given the importance of sequence identity in the effectiveness of siRNA and the heterogeneity of HBV sequences among different isolates, a short hairpin RNA (shRNA)-expressing plasmid, pSuper/HBVS1, was developed to target a region conserved among major HBV genotypes and assess its effectiveness control of HBV. Methods HBV replication-competent plasmid was cotransfected with pSuper/HBVS1 to HuH-7 cells or to mice. The levels of viral proteins, RNA, and DNA were examined in transfected cells and animals. The effects of pSuper/HBVS1 on clinical isolates with genotypes B and C were also determined. Results pSuper/HBVS1 significantly decreased levels of viral proteins, RNA, and DNA for HBV genotype A in cell culture and in mice. Comparable suppressive effects were observed on clinical isolates of genotypes B and C. A clone with a silent mutation in the target region was identified from a patient with genotype C. This mutant revealed diminished sensitivity to pSuper/HBVS1 and could be selected out in the presence of pSuper/HBVS1 in cell culture. Conclusions These findings indicated that shRNA could suppress HBV expression and replication for genotypes A, B, and C, promising an advance in treatment of HBV. However, the emergence of resistant mutants in HBV quasispecies should be considered.


title: Alterations in Pulmonary Function Following Respiratory Viral Infection

text: Respiratory viral illness is a major cause of morbidity in both adults and children. This report focuses on both the acute and chronic effects on respiratory function of these ubiquitous infections. Infant airways are particularly vulnerable due to the relatively low conductance in immature peripheral airways. Bronchiolitis, caused predominantly by respiratory syncytial virus, is the most important of these viral illnesses and is emerging as a major risk factor for the subsequent development of obstructive airway disease in adults, possibly by interference with normal alveolar proliferation. The basic pathogenic mechanism involved in adult respiratory viral infection is bronchial hyperreactivity, presumably secondary to epithelial damage and resultant sensitization of rapidly adapting airway receptors. In addition, there may be virus-related alterations in the autonomic and humoral regulation of airway tone. Viral infections may alter the effects of common air pollutants on respiratory function.


title: Non-neutral evolution of the major histocompatibility complex class II gene DRB1 in the sac-winged bat Saccopteryx bilineata

text: The immune genes of the major histocompatibility complex (MHC) are classical examples for high levels of genetic diversity and non-neutral evolution. This is particularly true for the regions containing the antigen-binding sites as, for instance, in the exon 2 of the MHC class II gene DRB. We surveyed, for the first time in the order Chiroptera, the genetic diversity within this exon in the sac-winged bat Saccopteryx bilineata. We detected 11 alleles among 85 bats, of which 79 were sampled in one population. Pairwise comparisons revealed that interallelic sequence differences ranged between 3 and 22%, although nucleotide substitutions were not evenly distributed along the exon sequence. This was most probably the result of intragenic recombination. High levels of sequence divergence and significantly more nonsynonymous than synonymous substitutions (d(N)/d(S)>1) suggest long-term balancing selection. Thus, the data are consistent with the hypothesis that recombination gives rise to new alleles at the DRB locus of the sac-winged bat, and these are maintained in the population through balancing selection. In this respect, the sac-winged bat closely resembles other mammalian species.


title: BiP/GRP78 Mediates ERAD Targeting of Proteins Produced by Membrane-Bound Ribosomes Stalled at the STOP-Codon

text: Translational stalling of ribosome bound to endoplasmic reticulum (ER) membrane requires an accurate clearance of the associated polypeptides, which is not completely understood in mammals. We characterized in mammalian cells the model of ribosomal stalling at the STOP-codon based on proteins tagged at the C-terminus with the picornavirus 2A peptide followed by a termination codon instead of the Proline (2A*). We exploited the 2A* stalling model to characterize the pathway of degradation of ER-targeted polypeptides. We report that the ER chaperone BiP/GRP78 is a new main factor involved. Moreover, degradation of the ER-stalled polypeptides required the activities of the AAA-ATPase VCP/p97, its associated deubiquitinylase YOD1, the ribosome-associated ubiquitin ligase Listerin and the proteasome. In human proteome, we found two human C-terminal amino acid sequences that cause similar stalling at the STOP-codon. Our data suggest that translational stalling at the ER membrane activates protein degradation at the interface of ribosomal- and ER-associated quality control systems.


title: Pulmonary complications in hematopoietic SCT: a prospective study

text: Pulmonary complications are common and often lethal in hematopoietic SCT recipients. The objective of this prospective interventional study was to evaluate the etiology, diagnostic procedures, risk factors and outcome of pulmonary complications in a cohort of hematopoietic SCT recipients followed up for 1 year. For patients suffering from a pulmonary complication, a diagnostic algorithm that included non-invasive and bronchoscopic procedures was performed. We identified 73 pulmonary complications in 169 patients: 50 (68%) were pneumonias; 21 (29%) were non-infectious complications and 2 (3%) were undiagnosed. Viruses (particularly Rhinovirus) and bacteria (particularly P. aeruginosa) (28 and 26%, respectively) were the most common causes of pneumonia. A specific diagnosis was obtained in 83% of the cases. A non-invasive test gave a specific diagnosis in 59% of the episodes. The diagnostic yield of bronchoscopy was 67 and 78% in pulmonary infections. Early bronchoscopy (⩽5 days) had higher diagnostic yield than late bronchoscopy (78 vs 23%; P=0.02) for pulmonary infections. Overall mortality was 22 and 32% of all fatalities were due to pulmonary complications. Pulmonary complications are common and constitute an independent risk factor for mortality, stressing the importance of an appropriate clinical management. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/bmt.2014.151) contains supplementary material, which is available to authorized users.


title: The therapeutic potential of RNA interference

text: In recent years, we have witnessed the discovery of a new mechanism of gene regulation called RNA interference (RNAi), which has revitalized interest in the development of nucleic acid-based technologies for therapeutic gene suppression. This review focuses on the potential therapeutic use of RNAi, discussing the theoretical advantages of RNAi-based therapeutics over previous technologies as well as the challenges involved in developing RNAi for clinical use. Also reviewed, are the in vivo proof-of principle experiments that provide the preclinical justification for the continued development of RNAi-based therapeutics.


Osler-Weber-Rendu Syndrome


Hypertrophic pulmonary osteoarthropathy: an unusual manifestation of lung cancer


title: Peptide-Based Vaccines: Current Progress and Future Challenges

text: [Image: see text] Vaccines have had a profound impact on the management and prevention of infectious disease. In addition, the development of vaccines against chronic diseases has attracted considerable interest as an approach to prevent, rather than treat, conditions such as cancer, Alzheimer’s disease, and others. Subunit vaccines consist of nongenetic components of the infectious agent or disease-related epitope. In this Review, we discuss peptide-based vaccines and their potential in three therapeutic areas: infectious disease, Alzheimer’s disease, and cancer. We discuss factors that contribute to vaccine efficacy and how these parameters may potentially be modulated by design. We examine both clinically tested vaccines as well as nascent approaches and explore current challenges and potential remedies. While peptide vaccines hold substantial promise in the prevention of human disease, many obstacles remain that have hampered their clinical use; thus, continued research efforts to address these challenges are warranted.


title: Sensitivity of bats to urbanization: a review

text: In this article we review the current knowledge of the effects of urban expansion on bats and assess the potential of these mammals as bioindicators of urbanization. The response of bats to this process is highly species-specific: some species tolerate urban habitat or are even favoured by its roosting or foraging opportunities, others are affected by the loss or fragmentation of key natural habitat, or by the physical and chemical pollution associated with urbanization. Species responses generally translate into altered community structures, with few markedly dominating species. We propose different hypothetical models of bat fitness along an urbanization gradient and discuss why bat population density may not be an effective fitness proxy to assess the reactions of these mammals to urban expansion. We also suggest that urban habitat may act as an ecological trap even for apparently synurbic species. Overall, bat sensitivity to urbanization makes these mammals promising candidates to track the effects of this process of land use change on the biota, but more studies, specifically tailored to explore this role, are needed.


title: Recent advances in computational simulation of macro-, meso-, and micro-scale biomimetics related fluid flow problems

text: Over the last decade, computational methods have been intensively applied to a variety of scientific researches and engineering designs. Although the computational fluid dynamics (CFD) method has played a dominant role in studying and simulating transport phenomena involving fluid flow and heat and mass transfers, in recent years, other numerical methods for the simulations at meso- and micro-scales have also been actively applied to solve the physics of complex flow and fluid-interface interactions. This paper presents a review of recent advances in multi-scale computational simulation of biomimetics related fluid flow problems. The state-of-the-art numerical techniques, such as lattice Boltzmann method (LBM), molecular dynamics (MD), and conventional CFD, applied to different problems such as fish flow, electro-osmosis effect of earthworm motion, and self-cleaning hydrophobic surface, and the numerical approaches are introduced. The new challenging of modelling biomimetics problems in developing the physical conditions of self-clean hydrophobic surfaces is discussed.


title: Pathogenesis and transmission of avian influenza A (H7N9) virus in ferrets and mice

text: On 29 March 2013, the Chinese Center for Disease Control and Prevention confirmed the first reported case of human infection with an avian influenza A(H7N9) virus(1). The recent human infections with H7N9 virus, totalling over 130 cases with 39 fatalities to date, have been characterized by severe pulmonary disease and acute respiratory distress syndrome (ARDS)(2). This is concerning because H7 viruses have typically been associated with ocular disease in humans, rather than severe respiratory disease(3). This recent outbreak underscores the need to better understand the pathogenesis and transmission of these viruses in mammals. Here we assess the ability of A/Anhui/1/2013 and A/Shanghai/1/2013 (H7N9) viruses, isolated from fatal human cases, to cause disease in mice and ferrets and to transmit to naive animals. Both H7N9 viruses replicated to higher titre in human airway epithelial cells and in the respiratory tract of ferrets compared to a seasonal H3N2 virus. Moreover, the H7N9 viruses showed greater infectivity and lethality in mice compared to genetically related H7N9 and H9N2 viruses. The H7N9 viruses were readily transmitted to naive ferrets through direct contact but, unlike the seasonal H3N2 virus, did not transmit readily by respiratory droplets. The lack of efficient respiratory droplet transmission was corroborated by low receptor-binding specificity for human-like α2,6-linked sialosides. Our results indicate that H7N9 viruses have the capacity for efficient replication in mammals and human airway cells and highlight the need for continued public health surveillance of this emerging virus. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nature12391) contains supplementary material, which is available to authorized users.


title: Human genetics of life-threatening influenza pneumonitis

text: Influenza viruses infect millions of people around the globe annually, usually causing self-limited upper respiratory tract infections. However, a small but non-negligible proportion of patients suffer from life-threatening pulmonary disease. Those affected include otherwise healthy individuals, and children with primary infections in particular. Much effort has been devoted to virological studies of influenza and vaccine development. By contrast, the enormous interindividual variability in susceptibility to influenza has received very little attention. One interesting hypothesis is that interindividual variability is driven largely by the genetic makeup of the infected patients. Unbiased genomic approaches have been used to search for genetic lesions in children with life-threatening pulmonary influenza. Four monogenic causes of severe influenza pneumonitis—deficiencies of GATA2, IRF7, IRF9, and TLR3—have provided evidence that severe influenza pneumonitis can be genetic and often in patients with no other severe infections. These deficiencies highlight the importance of human type I and III IFN-mediated immunity for host defense against influenza. Clinical penetrance is incomplete, and the underlying mechanisms are not yet understood. However, human genetic studies have clearly revealed that seemingly sporadic and isolated life-threatening influenza pneumonitis in otherwise healthy individuals can be genetic.


Severe ARDS in a critically ill influenza patient with invasive pulmonary aspergillosis


WHO issues rallying cry to keep fight against SARS on track


title: Impact of fluid balance on outcome of adult patients treated with extracorporeal membrane oxygenation

text: PURPOSE: To assess the relationship between early daily fluid balance (FB) and 90-day outcome in adult patients treated with extracorporeal membrane oxygenation (ECMO). DESIGN: Retrospective observational study. SETTING: Tertiary referral centre for ECMO. PATIENTS: 115 patients treated with ECMO for refractory heart failure and 57 patients treated with ECMO for refractory respiratory failure. METHODS: We analysed the association between early daily FB versus hospital and 90-day mortality using multivariable logistic regression model, Cox proportional-hazards model and propensity score. RESULTS: We obtained detailed demographic, clinical, and biochemical data, daily FB, and continuous renal replacement days. Fifty-seven per cent of patients had acute kidney injury (AKI) at ECMO initiation, and 60 % (n = 103) of patients received continuous renal replacement therapy (CRRT) during ECMO course, beginning at a median of 1 (0–3.5) days after ECMO initiation. Overall 90-day mortality was 24 %. Survivors exhibited lower daily FB from day 3 to day 5. After adjustments, Acute Physiology and Chronic Health Evaluation (APACHE) III, CRRT during the first 3 days, major bleeding event at day 1 and positive FB on day 3 were independent predictors of 90-day mortality. Positive FB at ECMO day 3 remained an independent predictor of hospital and 90-day mortality, regardless of the statistical model used or the inclusion of a propensity score to have positive FB. CONCLUSIONS: Positive FB at ECMO day 3 is an independent predictor of 90-day mortality. Further interventional studies aimed at testing the value of strategy of tight control of FB during the early ECMO period are now warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00134-014-3360-2) contains supplementary material, which is available to authorized users.


Critics slam treatment for SARS as ineffective and perhaps dangerous


Biologists seek to revamp biowarfare register


title: Macrolide-based regimens in absence of bacterial co-infection in critically ill H1N1 patients with primary viral pneumonia

text: PURPOSE: To determine whether macrolide-based treatment is associated with mortality in critically ill H1N1 patients with primary viral pneumonia. METHODS: Secondary analysis of a prospective, observational, multicenter study conducted across 148 Intensive Care Units (ICU) in Spain. RESULTS: Primary viral pneumonia was present in 733 ICU patients with pandemic influenza A (H1N1) virus infection with severe respiratory failure. Macrolide-based treatment was administered to 190 (25.9 %) patients. Patients who received macrolides had chronic obstructive pulmonary disease more often, lower severity on admission (APACHE II score on ICU admission (13.1 ± 6.8 vs. 14.4 ± 7.4 points, p < 0.05), and multiple organ dysfunction syndrome less often (23.4 vs. 30.1 %, p < 0.05). Length of ICU stay in survivors was not significantly different in patients who received macrolides compared to patients who did not (10 (IQR 4–20) vs. 10 (IQR 5–20), p = 0.9). ICU mortality was 24.1 % (n = 177). Patients with macrolide-based treatment had lower ICU mortality in the univariate analysis (19.2 vs. 28.1 %, p = 0.02); however, a propensity score analysis showed no effect of macrolide-based treatment on ICU mortality (OR = 0.87; 95 % CI 0.55–1.37, p = 0.5). Moreover, the sensitivity analysis revealed very similar results (OR = 0.91; 95 % CI 0.58–1.44, p = 0.7). A separate analysis of patients under mechanical ventilation yielded similar results (OR = 0.77; 95 % CI 0.44–1.35, p = 0.4). CONCLUSION: Our results suggest that macrolide-based treatment was not associated with improved survival in critically ill H1N1 patients with primary viral pneumonia.


title: The PRESERVE mortality risk score and analysis of long-term outcomes after extracorporeal membrane oxygenation for severe acute respiratory distress syndrome

text: PURPOSE: This study was designed to identify factors associated with death by 6 months post-intensive care unit (ICU) discharge and to develop a practical mortality risk score for extracorporeal membrane oxygenation (ECMO)-treated acute respiratory distress syndrome (ARDS) patients. We also assessed long-term survivors’ health-related quality of life (HRQL), respiratory symptoms, and anxiety, depression and post-traumatic stress disorder (PTSD) frequencies. METHODS: Data from 140 ECMO-treated ARDS patients admitted to three French ICUs (2008–2012) were analyzed. ICU survivors contacted >6 months post-ICU discharge were assessed for HRQL, psychological and PTSD status. RESULTS: Main ARDS etiologies were bacterial (45 %), influenza A[H(1)N(1)] (26 %) and post-operative (17 %) pneumonias. Six months post-ICU discharge, 84 (60 %) patients were still alive. Based on multivariable logistic regression analysis, the PRESERVE (PRedicting dEath for SEvere ARDS on VV-ECMO) score (0–14 points) was constructed with eight pre-ECMO parameters, i.e. age, body mass index, immunocompromised status, prone positioning, days of mechanical ventilation, sepsis-related organ failure assessment, plateau pressure andpositive end-expiratory pressure. Six-month post-ECMO initiation cumulative probabilities of survival were 97, 79, 54 and 16 % for PRESERVE classes 0–2, 3–4, 5–6 and ≥7 (p < 0.001), respectively. HRQL evaluation in 80 % of the 6-month survivors revealed satisfactory mental health but persistent physical and emotional-related difficulties, with anxiety, depression or PTSD symptoms reported, by 34, 25 or 16 %, respectively. CONCLUSIONS: The PRESERVE score might help ICU physicians select appropriate candidates for ECMO among severe ARDS patients. Future studies should also focus on physical and psychosocial rehabilitation that could lead to improved HRQL in this population. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00134-013-3037-2) contains supplementary material, which is available to authorized users.


title: Asynchrony, neural drive, ventilatory variability and COMFORT: NAVA versus pressure support in pediatric patients. A non-randomized cross-over trial

text: PURPOSE: To determine if neurally adjusted ventilatory assist (NAVA) improves asynchrony, ventilatory drive, breath-to-breath variability and COMFORT score when compared to pressure support (PS). METHODS: This is a non-randomized short-term cross-over trial in which 12 pediatric patients with asynchrony (auto-triggering, double triggering or non-triggered breaths) were enrolled. Four sequential 10-min periods of data were recorded after 20 min of ventilatory stabilization (wash-out) at each of the following settings: baseline PS with the ventilator settings determined by the attending physician (1-PS(b)); PS after optimization (2-PS(opt)); NAVA level set so that maximum inspiratory pressure (P (max)) equaled P (max) in PS (3-NAVA); same settings as in 2-PS(opt) (4-PS(opt)). RESULTS: The median asynchrony index was significantly lower during NAVA (2.0 %) than during 2-PS(opt) (8.5 %, p = 0.017) and 4-PS(opt) (7.5 %, p = 0.008). In NAVA mode, the NAVA trigger accounted on average for 66 % of triggered breaths. The median trigger delay with respect to neural inspiratory time was significantly lower during NAVA (8.6 %) than during 2-PS(opt) (25.2 %, p = 0.003) and 4-PS(opt) (28.2 %, p = 0.0005). The median electrical activity of the diaphragm (EAdi) change during trigger delay normalized to maximum inspiratory EAdi difference was significantly lower during NAVA (5.3 %) than during 2-PS(opt) (21.7 %, p = 0.0005) and 4-PS(opt) (24.6 %, p = 0.001). The coefficient of variation of tidal volume was significantly higher during NAVA (44.2 %) than during 2-PS(opt) (19.8 %, p = 0.0002) and 4-PS(opt) (23.0 %, p = 0.0005). The median COMFORT score during NAVA (15.0) was lower than that during 2-PS(opt) (18.0, p = 0.0125) and 4-PS(opt) (17.5, p = 0.039). No significant changes for any variable were observed between 1-PS(b) and 2-PS(opt). CONCLUSIONS: Neurally adjusted ventilatory assist as compared to optimized PS results in improved synchrony, reduced ventilatory drive, increased breath-to-breath mechanical variability and improved patient comfort. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00134-012-2535-y) contains supplementary material, which is available to authorized users.


Year in review in Intensive Care Medicine, 2008: I. Brain injury and neurology, renal failure and endocrinology, metabolism and nutrition, sepsis, infections and pneumonia


Nuclear factor k B: a pivotal role in the systemic inflammatory response syndrome and new target for therapy


Antimicrobial treatment guidelines for acute bacterial rhinosinusitis()()()()


title: Experience with ARDS caused by tuberculosis in a respiratory intensive care unit

text: OBJECTIVE: Acute respiratory distress syndrome (ARDS) is an important cause of morbidity and mortality in intensive care units. Tuberculosis (TB) commonly causes respiratory failure in patients with extensive pulmonary parenchymal involvement, but it is a rare cause of ARDS. We report our experience of TB presenting with ARDS. METHODS: Retrospective analysis of 187 patients admitted with a diagnosis of ARDS over the previous 7 years. Data are presented in a descriptive fashion using mean±SD or median (range). RESULTS: Nine (4.9%) of 187 patients had ARDS secondary to tuberculosis. All patients were mechanically ventilated. The diagnosis was made on clinico-radiological grounds and confirmed later using fiberoptic bronchoscopy and transbronchial biopsy in seven patients, and lymph node biopsy and examination of the joint aspirate in the remaining two. All patients were empirically started on anti-tubercular therapy with a median time to initiation of therapy being 3 days (range 2–8 days). Three patients had multi-organ dysfunction syndrome (MODS) without any evidence of bacterial infection. Seven of nine (77.8%) patients survived; two died because of severe ARDS, MODS, and respiratory failure. CONCLUSIONS: Tuberculosis is an uncommon but definite cause of ARDS, and in patients with ARDS of obscure aetiology where the clinical features suggest tuberculosis as the inciting cause, antitubercular therapy should be started empirically and the diagnosis actively pursued later.


title: Point-of-care lung ultrasound in neonatology: classification into descriptive and functional applications

text: Lung ultrasound (LUS) is the latest amongst imaging techniques: it is a radiation-free, inexpensive, point-of-care tool that the clinician can use at the bedside. This review summarises the rapidly growing scientific evidence on LUS in neonatology, dividing it into descriptive and functional applications. We report the description of the main ultrasound features of neonatal respiratory disorders and functional applications of LUS aiming to help a clinical decision (such as surfactant administration, chest drainage etc). Amongst the functional applications, we propose SAFE (Sonographic Algorithm for liFe threatening Emergencies) as a standardised protocol for emergency functional LUS in critical neonates. SAFE has been funded by a specific grant issued by the European Society for Paediatric Research. Future potential development of LUS in neonatology might be linked to its quantitative evaluation: we also discuss available data and research directions using computer-aided diagnostic techniques. Finally, tools and opportunities to teach LUS and expand the research network are briefly presented.


title: Clinical Features of Fatal Pandemic Influenza A/H1N1 Infection Complicated by Invasive Pulmonary Fungal Infection

text: BACKGROUND: Severe pneumonia caused by influenza virus infection can be secondary to invasive pulmonary fungal (IPF) infection. OBJECTIVES: This study aimed to summarize the incidence of IPF infection secondary to influenza virus infection and further explore its etiologic mechanism and high-risk factors. METHODS: All adult patients with confirmed influenza A (H1N1) virus infection admitted to the intensive care units (ICUs) of Nanjing Drum Hospital from November 2017 to March 2018 were retrospectively selected. The differences in baseline factors, risk factors, immune function and outcome parameters were studied between patients with and without IPF. RESULTS: Of the 19 critically ill patients with H1N1 infection, 11 (57.9%) developed IPF infection after 7 days of ICU admission. Two patients had proven and nine probable IPF infection. A difference in human leukocyte antigen–DR isotype (△HLA-DR; day 7–day 1) was found between the two groups. △HLA-DR (day 7–day 1) was higher in patients with no IPF infection than in those with IPF infection [(14.52 ± 14.21)% vs ( − 11.74 ± 20.22)%, P = 0.019]. The decline in HLA-DR indicated impaired immune function secondary to fungal infection in patients with H1N1 infection. CONCLUSIONS: IPF infection was diagnosed in 57.9% of critically ill patients with H1N1 virus infection after a median of 7 days following ICU admission. A continuous decline in immune function could lead to the development of IPF infections. Dynamic monitoring of immune function may help in the early detection of IPF infection.


Non-invasive management of acute respiratory distress syndrome related to Influenza A (H1N1) virus pneumonia in a pregnant woman


title: Gene patents and the public good

text: A race to claim patents on the SARS virus raises questions about the patent system's ability to cope with genomics.


title: Respiratory syncytial virus triggered adult respiratory distress syndrome in infants: A report of two cases

text: Two infants with severe respiratory syncytial virus infection which resulted eventually in classical adult respiratory distress syndrome (ARDS) are presented. Both infants had severe apneic spells, necessitating intubation and mechanical ventilation (MV). Chest radiographs changed after a few days after institution of MV from initial bronchopneumonia like pattern to severe ARDS. Assessment of respiratory system mechanics (single breath occlusion technique) revealed severe restrictive disease in both cases. The first patient recovered with residual restrictive changes determined during a follow-up 2.5 months later, whereas the second infant died because of ARDS, pulmonary interstitial emphysema and hypoxemic hypoxia.


Vital signs: the first step in prevention and management of critical illness in resource-limited settings


title: Relocating: Middle Eastern promise

text: Countries on the Arabian Peninsula are vying to attract young scientists to their universities.


Researchers get to grips with cause of pneumonia epidemic


title: Defective translation of measles virus matrix protein in a subacute sclerosing panencephalitis cell line

text: Subacute sclerosing panencephalitis (SSPE) is a slowly progressing fatal human disease of the central nervous system (CNS) that is associated with measles virus persistence. Virus nucleocapsids are present in the brain(1,2) and the patient is in a state of hyperimmunization towards this agent. However, although all other structural polypeptides are recognized by the immune system, there is a markedly decreased antibody response towards virus matrix or membrane protein(3,4). Matrix protein has not been detected in brain cells(5) and infectious virus is not present. The absence of this virus structural polypeptide is thought to account for the apparent restriction in virus maturation both in vivo and in vitro. SSPE viruses can only rarely be rescued from brain tissue by co-cultivation or cell fusion techniques using tissue culture cell lines susceptible to measles virus infection(6). Often this procedure fails to yield a lytic budding virus but produces instead a carrier cell line in which the agent is cell associated. These lines (known as SSPE cell lines) also do not contain matrix protein(7,8). However, the reason for this deficiency is unknown. We have therefore now examined an SSPE cell line which does not yield infectious virus in order to define this process further. We found that although messenger RNA for membrane protein was present, it was unable to form normal matrix protein in translation reactions.


title: Surfactant adjunctive therapy forPneumocystis carinii pneumonitis in an infant with acute lymphoblastic leukaemia

text: We report successful treatment of adult respiratory distress syndrome (ARDS) with artificial surfactant (40mg/kg, Colfosceril Palmitate, ‘Exosurf’, Wellcome) in an infant with severePneumocystis carinii pneumonitis.


title: Acute hypoxemic respiratory failure in children: case mix and the utility of respiratory severity indices

text: Objective: Acute hypoxemic respiratory failure (AHRF) is a common reason for emergency pediatric intensive care. An objective assessment of disease severity from acute physiological parameters would be of value in clinical practice and in the design of clinical trials. We hypothesised that there was a difference in the best early respiratory indices in those who died compared with those who survived. Design: A prospective observational study of 118 consecutive AHRF admissions with data analysis incorporating all blood gases. Setting: A pediatric intensive care unit in a national children’s hospital. Interventions: None. Results: Mortality was 26/118,22% (95% confidence interval 18–26%). There were no significant differences in the best alveolar-arterial oxygen tension gradient (A-aDO(2), torr), oxygenation index (OI), ventilation index (VI), or PaO(2)/FIO(2) during the first 2 days of intensive care between the survivors and non-survivors. Only the mean airway pressure (MAP, cm H(2)O) used for supportive care was significantly different on days 0 and 1 (p≤0.05) with higher pressure being used in non-survivors. Multiple logistic regression analysis did not identify any gas exchange or ventilator parameter independently associated with mortality. Rather, all deaths were associated with coincident pathology or multi-organ system failure, or perceived treatment futility due to pre-existing diagnoses instead of unsupportable respiratory failure. When using previously published predictors of outcome (VI>40 and OI>40; A-aDO(2)>450 for 24 h; A-aDO(2)>470 or MAP>23; or A-aDO(2)>420) the risk of mortality was overestimated significantly in the current population. Conclusion: The original hypothesis was refuted. It appears that the outcome of AHRF in present day pediatric critical care is principally related to the severity of associated pathology and now no longer solely to the severity of respiratory failure. Further studies in larger series are needed to confirm these findings.


An interdisciplinary approach for renal transplant recipients with severe pneumonia: a single ICU experience


title: Etiologies and outcome of acute respiratory failure in HIV-infected patients

text: OBJECTIVE: To assess the etiologies and outcome of acute respiratory failure (ARF) in HIV-infected patients over the first decade of combination antiretroviral therapy (ART) use. METHODS: Retrospective study of all HIV-infected patients (n = 147) admitted to a single intensive care unit (ICU) for ARF between 1996 and 2006. RESULTS: ARF revealed the diagnosis of HIV infection in 43 (29.2%) patients. Causes of ARF were bacterial pneumonia (n = 74), Pneumocystis jirovecii pneumonia (PCP, n = 52), other opportunistic infections (n = 19), and noninfectious pulmonary disease (n = 33); the distribution of causes did not change over the 10-year study period. Two or more causes were identified in 33 patients. The 43 patients on ART more frequently had bacterial pneumonia and less frequently had opportunistic infections (P = 0.02). Noninvasive ventilation was needed in 49 patients and endotracheal intubation in 42. Hospital mortality was 19.7%. Factors independently associated with mortality were mechanical ventilation [odds ratio (OR) = 8.48, P < 0.0001], vasopressor use (OR, 4.48; P = 0.03), time from hospital admission to ICU admission (OR, 1.05 per day; P = 0.01), and number of causes (OR, 3.19; P = 0.02). HIV-related variables (CD4 count, viral load, and ART) were not associated with mortality. CONCLUSION: Bacterial pneumonia and PCP remain the leading causes of ARF in HIV-infected patients in the ART era. Hospital survival has improved, and depends on the extent of organ dysfunction rather than on HIV-related characteristics.


title: Current management and outcome of tracheobronchial malacia and stenosis presenting to the paediatric intensive care unit

text: Objective: To identify factors associated with mortality and prolonged ventilatory requirements in patients admitted to our paediatric intensive care unit (PICU) with tracheobronchial malacia and stenosis diagnosed by dynamic contrast bronchograms. Design: Retrospective review. Setting: Tertiary paediatric intensive care unit. Patients: Forty-eight cases admitted to our PICU over a 5-year period in whom a diagnosis of tracheobronchial malacia or stenosis was made by dynamic contrast bronchography (1994–1999). Interventions: Conservative management, tracheostomy and long-term ventilation, surgical correction, internal or external airway stenting. Measurements and results: Recording of clinical details, length of invasive ventilation and appearance at contrast bronchography. Five groups of patients were defined: isolated primary airway pathology (n=7), ex-premature infants (n=11), vascular rings (n=9), complex cardiac and/or syndromic pathology (n=17) and tracheo-oesophageal fistulae (n=4). The overall mortality was 29%. Median length of invasive ventilation in survivors was 38 days and in patients who died 45. Mortality was highest in the patients with complex cardiac and/or syndromic pathology (p=0.039 Cox regression analysis) but was not related to any other factor. Patients with stenosis required a significantly longer period of ventilatory support (median length of ventilation 59 days) than patients with malacia (39 days). Conclusions: Length of ventilation and bronchographic diagnosis did not predict survival. The only factor found to contribute significantly to mortality was the presence of complex cardiac and/or syndromic pathology. However, patients with stenosis required longer ventilatory support than patients with malacia.


title: High survival in adult patients with acute respiratory distress syndrome treated by extracorporeal membrane oxygenation, minimal sedation, and pressure supported ventilation

text: Objectives: To evaluate the results of treatment of severe acute respiratory distress syndrome (ARDS) with extracorporeal membrane oxygenation (ECMO), minimal sedation, and pressure supported ventilation. Design and setting: Observational study in a tertiary referral center, Intensive Care Unit, Astrid Lindgren Children's Hospital at Karolinska Hospital, Stockholm, Sweden. Subjects and methods: Seventeen adult patients with ARDS were treated with venovenous or venoarterial ECMO after failure of conventional therapy. The Murray score of pulmonary injury averaged 3.5 (3.0–4.0) and the mean PaO(2)/FIO(2) ratio was 46 (31–65). A standard ECMO circuit with nonheparinized surfaces was used. The patients were minimally sedated and received pressure-supported ventilation. High inspiratory pressures were avoided and arterial saturation as low as 70% was accepted on venovenous bypass. Results: In one patient a stable bypass could not be established. Among the remaining 16 patients 13 survived (total survival rate 76%) after 3–52 days (mean 15) on bypass. Major surgical procedures were performed in several patients. The cause of death in the three nonsurvivors was intracranial complications leading to total cerebral infarction. Conclusion: A high survival rate can be obtained in adult patients with severe ARDS using ECMO and pressure-supported ventilation with minimal sedation. Surgical complications are amenable to surgical treatment during ECMO. Bleeding problems can generally be controlled but require immediate and aggressive approach. It is difficult or impossible to decide when a lung disease is irreversible, and prolonged ECMO treatment may be successful even in the absence of any detectable lung function.


Hemophagocytic syndrome in the critically ill


title: Challenges in severe community-acquired pneumonia: a point-of-view review

text: PURPOSE: Severe community-acquired pneumonia (SCAP) is still associated with substantial morbidity and mortality. In this point-of-view review paper, a group of experts discuss the main controversies in SCAP: the role of severity scores to guide patient settings of care and empiric antibiotic therapy; the emergence of pathogens outside the core microorganisms of CAP; viral SCAP; the best empirical treatment; septic shock as the most lethal complication; and the need for new antibiotics. METHODS: For all topics, the authors describe current controversies and evidence and provide recommendations and suggestions for future research. Evidence was based on meta-analyses, most recent RCTs and recent interventional or observational studies. Recommendations were reached by consensus of all the authors. RESULTS AND CONCLUSIONS: The IDSA/ATS criteria remain the most pragmatic tool to predict ICU admission. The authors recommend a combination of a beta-lactam/beta-lactamase inhibitor or a third G cephalosporin plus a macrolide in most SCAP patients, and to empirically cover PES (P. aeruginosa, extended spectrum beta-lactamase producing Enterobacteriaceae, methicillin-resistant S. aureus) pathogens when at least two specific risk factors are present. In patients with influenza CAP, the authors recommend the use of oseltamivir and avoidance of the use of steroids. Corticosteroids can be used in case of refractory shock and high systemic inflammatory response.


title: Influence of prothrombin complex concentrates on plasma coagulation in critically ill patients

text: Objective: To evaluate thrombogenicity of prothrombin complex concentrates (PCCs) in critically ill patients.¶Design: Prospective clinical study.¶Setting: Medical intensive care unit at a university hospital.¶Patients: 16 consecutive patients suffering from acquired deficiencies of coagulation factors and with either overt bleeding from any site or a planned invasive procedure.¶Interventions: 2000 factor IX units of PCCs intravenously.¶Measurements and results: Prothrombin time (PT), activated partial prothrombin time, fibrinogen, platelet count, plasma levels of coagulation factors II, V, VII, VIII, IX, X, antithrombin, protein C, thrombin-antithrombin complex (TAT), prothrombin fragment F(1+2), and the fibrin degradation product D-dimer were measured prior to and 1, 3, and 24 h after administration of PCCs. PT as well as coagulation factors II, VII, IX, and X, TAT, and F(1+2) showed a significant increase after administration of PCCs. All other parameters remained unchanged.¶Conclusions: Administration of PCCs induces thrombin generation. No evidence for induction of disseminated intravascular coagulation in biochemical terms could be found. When rapid correction of acquired coagulation factor disturbances is warranted, the use of PCCs seems reasonable, but the elevated risk of intravascular thrombus formation should be kept in mind.


title: Associations between ventilator settings during extracorporeal membrane oxygenation for refractory hypoxemia and outcome in patients with acute respiratory distress syndrome: a pooled individual patient data analysis: Mechanical ventilation during ECMO

text: PURPOSE: Extracorporeal membrane oxygenation (ECMO) is a rescue therapy for patients with acute respiratory distress syndrome (ARDS). The aim of this study was to evaluate associations between ventilatory settings during ECMO for refractory hypoxemia and outcome in ARDS patients. METHODS: In this individual patient data meta-analysis of observational studies in adult ARDS patients receiving ECMO for refractory hypoxemia, a time-dependent frailty model was used to determine which ventilator settings in the first 3 days of ECMO had an independent association with in-hospital mortality. RESULTS: Nine studies including 545 patients were included. Initiation of ECMO was accompanied by significant decreases in tidal volume size, positive end-expiratory pressure (PEEP), plateau pressure, and driving pressure (plateau pressure − PEEP) levels, and respiratory rate and minute ventilation, and resulted in higher PaO(2)/FiO(2), higher arterial pH and lower PaCO(2) levels. Higher age, male gender and lower body mass index were independently associated with mortality. Driving pressure was the only ventilatory parameter during ECMO that showed an independent association with in-hospital mortality [adjusted HR, 1.06 (95 % CI, 1.03–1.10)]. CONCLUSION: In this series of ARDS patients receiving ECMO for refractory hypoxemia, driving pressure during ECMO was the only ventilator setting that showed an independent association with in-hospital mortality. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00134-016-4507-0) contains supplementary material, which is available to authorized users.


Health concerns prompt US review of exotic-pet trade


title: Is influenza A(H1N1) pneumonia more severe than other community-acquired pneumonias? Results of the GiViTI survey of 155 Italian ICUs

text: PURPOSE: Uncertainty about the severity of the A(H1N1) pandemia persists. Information about disease severity can be obtained by investigating intensive care unit (ICU) admissions, especially when historical comparisons can be made with cases of community-acquired pneumonia (CAP). METHODS: This prospective observational study was conducted in 155 ICUs contributing to the GiViTI national database. To assess the impact on ICU workload, the occupancy rate during the epidemic phase was compared with influenza periods in previous years. A logistic regression model was developed to assess the prognostic importance of A(H1N1) influenza. RESULTS: The characteristics of the 319 A(H1N1) cases were similar to those reported in other studies, confirming the young age of patients (mean 43 years) and the higher prevalence among pregnant women and obese people. At the epidemic’s peak (October–December 2009) the occupancy rate did not significantly differ from the same period of the previous year, and was significantly lower than the 2009 seasonal influenza outbreak (January–March 2009). Compared with CAP of other origin (3,678 patients), A(H1N1) pneumonia was associated with a lower risk of death. However, after adjusting for confounding this was no longer the case (OR 0.88; 95% CI 0.59–1.31; p = 0.52). CONCLUSION: This study confirmed the specific features of critically ill A(H1N1) patients (i.e., young age, pregnancy, obesity). The pandemic did not increase ICU workload compared with other periods. A(H1N1) pneumonia did not have a higher risk of death than CAP of different origin among patients admitted to the ICU. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00134-011-2339-5) contains supplementary material, which is available to authorized users.


title: ECLS in pertussis: does it have a role?

text: Objectives: To investigate the value of extracorporeal circulatory life support (ECLS) in paediatric patients with severe Bordetella pertussis infection. Design: Single case report and a review of the ECLS database. Setting: Tertiary referral hospital paediatric intensive care unit. Patients and participants: A single case report of an infant with B. pertussis infection is described. Despite receiving ECLS, this infant died from overwhelming cardiac and cerebral insults. Outcome for children receiving ECLS registered on the Extracorporeal Life Support Organization database is reviewed. Measurements and results: The mortality of infants receiving ECLS for B. pertussis infection is high, with only 5 survivors reported among 22 registered cases. The majority of nonsurvivors had evidence of circulatory collapse in addition to severe respiratory failure, and these patients commonly died of hypoxic-ischaemic cerebral insult. These data suggest the existence of a subgroup of patients with respiratory failure only, who may benefit from ECLS, and a larger subgroup who suffer ischaemic cardiac and cerebral insults which are unlikely to be improved by ECLS. Conclusions: The value of ECLS in patients with B. pertussis infection who present with major cardiac dysfunction is questionable. Such patients almost invariably have a poor outcome despite maximal therapy.


Viral particles induce Ia antigen expression on astrocytes


Paracetamol absorption test to detect poor enteric absorption of oseltamivir in intensive care unit patients with severe influenza: a pilot study


title: The phosphatidylinositol cycle and the regulation of arachidonic acid production

text: An increase in the metabolism of phosphatidylinositol occurs in a wide variety of tissues by the action of specific ligands(1–3). In platelets, the interaction of thrombin with its receptor initiates the degradation of phosphatidylinositol by the action of a specific phospholipase C (refs 4–8). In normal conditions of stimulation, the resultant 1,2-diacylglycerol is rapidly and completely phosphorylated to phosphatidic acid(4–11). The formation of phosphatidic acid precedes the release of arachidonic acid from the phospholipids of stimulated platelets(5). This early appearence of phosphatidate might result in the initial production of arachidonic acid and lysophosphatidic acid by the action of a phospholipase A(2) specific for phosphatidate(12). Phosphatidate/lysophosphatidate could induce calciumgating(13–15) and subsequently stimulate phospholipases of the A(2)-type(8), that degrade phosphatidylcholine, phosphatidyl-ethanolamine and a further fraction of phosphatidylinositol(6). Alternatively, the lysophosphatidate produced may serve as a substrate for the transfer of arachidonate directly from other phospholipids(16,17) to form new phosphatidate which in turn can release more arachidonate. Overall, such a sequence would be equivalent to phospholipase A(2) activation of other phospholipids. Our present data indicate that when the release of arachidonic acid is completely inhibited by cyclic AMP or quinacrine, phosphatidic acid is redirected entirely to phosphatidylinositol and there is no production of arachidonate. In these conditions, the availability of calcium might be profoundly restricted. The correlation in platelets of a phosphatidylinositol by a specific phospholipase A(2) might suggest that these phenomena are applicable to activations in other cell systems.


ISNV Meeting Supplement


title: Evaluation by polymerase chain reaction of cytomegalovirus reactivation in intensive care patients under mechanical ventilation

text: OBJECTIVE: The study was undertaken to determine if critically ill patients under mechanical ventilation could reactivate latent cytomegalovirus (CMV) in either lung or blood. DESIGN: Prospective study in critically ill patients. SETTING: The study was performed in a multidisciplinary intensive care unit in a university hospital. PATIENTS: 23 non-immunocompromised, mechanically ventilated patients who were anti-CMV immunoglobulin G-positive. Ten immunocompromised patients with active CMV infection and 16 asymptomatic CMV seropositive non-immunocompromised patients constituted the positive and negative control groups. MEASUREMENTS AND RESULTS: The presence of CMV in blood and bronchoalveolar lavage (BAL) was evaluated by both viral cultures and polymerase chain reaction (PCR). Thirty-seven blood and 22 BAL samples were investigated. Sequential samples were evaluated in 8 patients. For PCR, a 290 bp fragment in the first exon of the immediate early 1 gene was amplified. In order to exclude inhibitors of PCR amplification, a 268 bp fragment of the β-globin gene was concurrently amplified in all samples. Viral cultures of blood and BAL were negative in all 23 non-immunocompromised, mechanically ventilated patients. Moreover, no CMV DNA could be amplified in blood or BAL samples, whereas a β-globin amplification was observed in all samples. CONCLUSION: In a series of 23 critically ill patients under mechanical ventilation who were seropositive for CMV, no reactivation of CMV in blood or lung was demonstrated.


title: Acquired neuromuscular disorders in critically ill patients: a systematic review

text: Objective: To summarize the prospective clinical studies of neuromuscular abnormalities in intensive care unit (ICU) patients. Study identification and selection: Studies were identified through MEDLINE, EMBASE, references in primary and review articles, personal files, and contact with authors. Through duplicate independent review, we selected prospective cohort studies evaluating ICU-acquired neuromuscular disorders. Data abstraction: In duplicate, independently, we abstracted key data regarding design features, the population, clinical and laboratory diagnostic tests, and clinical outcomes. Results: We identified eight studies that enrolled 242 patients. Inception cohorts varied; some were mechanically ventilated patients for ≥ 5 days, others were based on a diagnosis of sepsis, organ failure, or severe asthma while others were selected on the basis of exposure to muscle relaxants, or because of participation in muscle biochemistry studies. Weakness was systematically assessed in two of the eight studies, concerning patients with severe asthma, with a reported frequency of 36 and 70 %, respectively. Electrophysiologic and histologic abnormalities consisted of both peripheral nerve and muscle involvement and were frequently reported, even in non-selected ICU patients. In a population of patients mechanically ventilated for more than 5 days, electrophysiologic abnormalities were reported in 76 % of cases. Two studies showed a clinically important increase (5 and 9 days, respectively) in duration of mechanical ventilation and a mortality twice as high in patients with critical illness neuromuscular abnormalities, compared to those without. Conclusions: Prospective studies of ICU-acquired neuromuscular abnormalities include a small number of patients with various electrophysiologic findings but insufficiently reported clinical correlations. Evaluation of risk factors for these disorders and studies examining their contribution to weaning difficulties and long-term disability are needed.


title: Bird flu data languish in Chinese journals

text: Health authorities in the dark as warnings go untranslated


title: Increase in lung volume originated by extrinsic PEEP in patients with auto-PEEP: The role of static lung complicance

text: The use of extrinsic positive end expiratory pressure (PEEPe) in patients with auto-PEEP (AP) can reduce the respiratory work during weaning from mechanical ventilation. However, the application of PEEPe produce a certain level of hyperinflation, an undesirable effect which can limit the efficacy of the reduction of respiratory work. The objective of the present study has been to determine if the encrease in end expiratory lung volume (EELV) originated by the PEEPe is related to static lung compliance (SLC). We have studied 14 patients on mechanical ventilation in whom an AP of between 4 and 12 cmH(2)O was detected. On applying PEEPe equal to half the AP, the EELV increased slightly (77±64 ml) and was not related to pulmonary compliance. When PEEPe equal to the AP was applied, the EELV increased by 178±110 ml (range 45–375 ml,p<0.05), and there was a significant correlation with SLC (r=0.659,p<0.05). In conclusion, the application of PEEPe equal to the AP causes a moderate increace in EELV. However, in patients with high pulmonary compliance this increase can be more important and must be taken into account when considering the use of PEEPe during weaning.


title: The epidemiology of the systemic inflammatory response

text: Objective: To examine the incidence, risk factors, aetiologies and outcome of the various forms of the septic syndromes (the systemic inflammatory response syndrome [SIRS] sepsis, severe sepsis, and septic shock) and their relationships with infection.¶Design: Review of published cohort studies examining the epidemiology of the septic syndromes, with emphasis on intensive care unit (ICU) patients.¶Results: The prevalence of SIRS is very high, affecting one-third of all in-hospital patients, and > 50 % of all ICU patients; in surgical ICU patients, SIRS occurs in > 80 % patients. Trauma patients are at particularly high risk of SIRS, and most these patients do not have infection documented. The prevalence of infection and bacteraemia increases with the number of SIRS criteria met, and with increasing severity of the septic syndromes. About one-third of patients with SIRS have or evolve to sepsis. Sepsis may occur in approximately 25 % of ICU patients, and bacteraemic sepsis in 10 %. In such patients, sepsis evolves to severe sepsis in > 50 % of cases, whereas evolution to severe sepsis in non-ICU patients is about 25 %. Severe sepsis and septic shock occur in 2 %–3 % of ward patients and 10 %–15 % or more ICU patients, depending on the case-mix; 25 % of patients with severe sepsis have shock. There is a graded severity from SIRS to sepsis, severe sepsis and septic shock, with an associated 28-d mortality of approximately 10 %, 20 %, 20 %–40 %, and 40 %–60 %, respectively. Mortality rates are similar within each stage, whether infection is documented or not, and microbiological characteristics of infection do not substantially influence outcome, although the source of infection does. While about three of four deaths occur during the first months after sepsis, the septic syndromes significantly impact on long-term outcome, with an estimated 50 % reduction of life expectancy over the following five years. The major determinants of outcome, both short-term and long-term, of patients with sepsis are the severity of underlying diseases and comorbidities, the presence of shock and organ failures at onset of sepsis or evolving thereafter. It has been estimated that two-thirds of the overall mortality can be attributed to sepsis.¶Conclusions: The prevalence of sepsis in ICU patients is very high, and most patients have clinically or microbiologically documented infection, except in specific subset of patients. The prognosis of septic syndromes is related to underlying diseases and the severity of the inflammatory response and its sequelae, reflected in shock and organ dysfunction/failures.


title: The spread of epidemiology

text: With the United States on high alert over the possibility of bioterror attacks, epidemiologists are in huge demand, says Virginia Gewin.


title: Tumor necrosis factor-alpha in normal and diseased brain: Conflicting effects via intraneuronal receptor crosstalk?

text: Tumor necrosis factor-alpha (TNF-α) is pleiotropic mediator of a diverse array of physiological and neurological functions, including both normal regulatory functions and immune responses to infectious agents. Its role in the nervous system is prominent but paradoxical. Studies on uninflamed or “normal” brain have generally attributed TNF-α a neuromodulatory effect. In contrast, in inflamed or diseased brain, the abundance of evidence suggests that TNF-α has an overall neurotoxic effect, which may be particularly pronounced for virally mediated neurological disease. Still others have found TNF-α to be protective under some conditions of neurological insult. It is still uncertain exactly how TNF-α is able to induce these opposing effects through receptor activation of only a limited set of cell signaling pathways. In this paper, we provide support from the literature to advance our hypothesis that one mechanism by which TNF-α can exert its paradoxical effects in the brain is via crosstalk with signaling pathways of growth factors or other cytokines.


title: Clinical identification of cognitive impairment in ICU survivors: insights for intensivists

text: BACKGROUND: A growing body of research has demonstrated the presence of ongoing cognitive impairment in large numbers of ICU survivors. OBJECTIVE: This review offers a practical framework for practicing intensivists and those following patients after their ICU stay for the identification of cognitive impairment in ICU survivors. CONCLUSIONS: Early detection of cognitive impairment in critically ill patients is an important and achievable goal, but overt cognitive impairment remains unrecognized in most cases. However, it can be identified by objective (test scores) or subjective evidence (clinical judgment, patient observation, family interaction).


title: Leukocytes: friend or foe

text: Leukocytes have a fundamental role in innate and adaptive immunity, wound healing, tumour surveillance and in tissue remodelling. It is their function in the inflammatory response however that is of most interest to us in the intensive care setting. Over the last three decades we have gained significant insights into leukocyte activation, recruitment and mediator secretion and the contribution of these agents to both the onset and resolution of sepsis and inflammation.¶The body relies on the inflammatory response for protection. Leukocytes occupy a pivotal position in this but to maintain these cells in a state of permanent activation would be unsustainable, with widespread microvascular plugging, uncontrolled free radical release and an excessive metabolic demand. Leukocytes thus circulate in a quiescent state and are rapidly activated by invading pathogens and other stimuli. A direct consequence of this protective strategy is that the inflammatory response may be inadequate, with the risk of overwhelming sepsis, or excessive, leading to rampant systemic inflammation and consequent multiple organ damage.¶It is now becoming apparent however that in addition to leukocytes other cells have important roles both in defence against invading pathogens and in driving malignant inflammation. This review will focus on two new facets of the innate immune system, the Toll family of proteins as the signal transduction element for endotoxin, and the antimicrobial peptides. These exemplify potential damaging and protective response elements but importantly neither are restricted to leukocytes. The capacity of cells and tissues other than the leukocytes to participate and even lead in the inflammatory responses will also be explored.


title: Epidemiology, antibiotic therapy and clinical outcomes of healthcare-associated pneumonia in critically ill patients: a Spanish cohort study

text: PURPOSE: Information about healthcare-associated pneumonia (HCAP) in critically ill patients is scarce. METHODS: This prospective study compared clinical presentation, outcomes, microbial etiology, and treatment of HCAP, community-acquired pneumonia (CAP), and immunocompromised patients (ICP) with severe pneumonia admitted to 34 Spanish ICUs. RESULTS: A total of 726 patients with pneumonia (449 CAP, 133 HCAP, and 144 ICP) were recruited during 1 year from April 2011. HCAP patients had more comorbidities and worse clinical status (Barthel score). HCAP and ICP patients needed mechanical ventilation and tracheotomy more frequently than CAP patients. Streptococcus pneumoniae was the most frequent pathogen in all three groups (CAP, 34.2 %; HCAP, 19.5 %; ICP, 23.4 %; p = 0.001). The overall incidence of Gram-negative pathogens, methicillin-resistant Staphylococcus aureus (MRSA), and Pseudomonas aeruginosa was low, but higher in HCAP and ICP patients than CAP. Empirical treatment was in line with CAP guidelines in 73.5 % of patients with CAP, in 45.5 % of those with HCAP, and in 40 % of those with ICP. The incidence of inappropriate empirical antibiotic therapy was 6.5 % in CAP, 14.4 % in HCAP, and 21.8 % in ICP (p < 0.001). Mortality was highest in ICP (38.6 %) and did not differ between CAP (18.4 %) and HCAP (21.2 %). CONCLUSIONS: HCAP accounts for one-fifth of cases of severe pneumonia in patients admitted to Spanish ICUs. The empirical antibiotic therapy recommended for CAP would be appropriate for 90 % of patients with HCAP in our population, and consequently the decision to include coverage of multidrug-resistant pathogens for HCAP should be cautiously judged in order to prevent the overuse of antimicrobials. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00134-014-3239-2) contains supplementary material, which is available to authorized users.


title: Avian influenza A H7N9 virus infects human astrocytes and neuronal cells and induces inflammatory immune responses

text: Seasonal, pandemic, and avian influenza virus infections may be associated with central nervous system pathology, albeit with varying frequency and different mechanisms. Here, we demonstrate that differentiated human astrocytic (T98G) and neuronal (SH-SY5Y) cells can be infected by avian H7N9 and pandemic H1N1 viruses. However, infectious progeny viruses can only be detected in H7N9 virus infected human neuronal cells. Neither of these viral strains can generate infectious progeny virus in human astrocytes despite replication of viral genome was observed. Furthermore, H7N9 virus triggered high pro-inflammatory cytokine expression, while pandemic H1N1 virus induced only low cytokine expression in either brain cell type. The experimental finding here is the first data to demonstrate that avian H7N9 virus can infect, transcribe, and replicate its viral genome; induce cytokine upregulation; and cause cytopathic effects in human brain cells, which may potentially lead to profound central nervous system injury. Observation for neurological problems due to H7N9 virus infection deserves further attention when managing these patients.


title: Reversible induction of natural killer cell activity in cloned murine cytotoxic T lymphocytes

text: Natural killer (NK) activity is a poorly understood component of the immune system, generally identified as the ability to kill certain tumour cells(1,2). Perhaps the most controversial issue has been the lineage to which cells displaying this activity belong. Extensive studies of surface antigens on cells with NK activity in both mouse and man have led to enigmatic results, such cells apparently bearing markers of both T-cell (Thy-1 and E receptor) and myeloid (Mac-1 and OKM1) lineages(3–6). A fresh approach to this problem would be to take cells of known lineage and test whether they express, or could be induced to express, NK cell function. Using this approach we show here that monoclonal cytotoxic T lymphocyte (CTL) lines can be induced, by culture in high concentrations of spleen cell supernatant, to express a new lytic activity apparently identical with that of splenic cells NK activity. Preliminary evidence implicates both interleukin-2(IL-2) and interferon (IFN) as mediators of this phenomenon. These findings clearly demonstrate that cells of T cell lineage have the capacity to express NK activity.


title: Predictive factors of death in primary lung cancer patients on admission to the intensive care unit

text: Objective: To assess the lung cancer patient's prognosis in the intensive care unit with early predictive factors of death. Design: Retrospective study from July 1986 to February 1996. Setting: Medical intensive care unit at a university hospital. Patients: Fifty-seven patients with primary lung cancer admitted to our medical intensive care unit (MICU). Measurements and results: Data collection included demographic data (age, sex, underlying diseases, MICU admitting diagnosis) and evaluation of tumor (pathologic subtypes, metastases, lung cancer staging, treatment options). Three indexes were calculated for each patient: Karnofsky performance status, Simplified Acute Physiology Score (SAPS) II, and multisystem organ failure score (ODIN score). Mortality was high in the MICU: 66% of patients died during their MICU stay, and hospital mortality reached 75%. In multivariate analysis, acute pulmonary disease and Karnofsky performance status <70 were associated with a poor MICU and post-MICU prognosis. For the survivors, long-term survival after MICU discharge depended exclusively on the severity of the lung cancer. Conclusions: We confirmed the high mortality rate of lung cancer patients admitted to the MICU. Two predictive factors of death in MICU were identified: performance status <70 and acute pulmonary disease.


title: 4′,6-Dichloroflavan (BW683C), a new anti-rhinovirus compound

text: Derivatives of flavan have been synthesized as chemical intermediates, but the only reported biological action is the ability of certain alkyl and alkoxy derivatives to lower blood cholesterol concentrations(1). It was therefore surprising to discover that flavan itself (Table 1) is a highly effective inhibitor of the replication of certain serotypes of rhinovirus, and that a simple derivative, BW683C (4′,6-dichloroflavan), is the most potent antiviral compound yet reported. The present work examines the antiviral activity of flavan derivatives with a view to selecting the compound most suitable for trial in volunteers infected with a common cold virus.


title: Lack of nitric oxide synthase type 2 (NOS2) results in reduced neuronal apoptosis and mortality following mouse hepatitis virus infection of the central nervous system

text: The role of nitric oxide synthase type-2 (NOS2)-derived nitric oxide (NO) in the pathogenesis of mouse hepatitis virus (MHV)-induced central nervous system disease was examined. Infection of NOS2 knockout ((−/−)) and NOS2(+/+) mice with MHV resulted in similar kinetics of viral clearance from the brain and comparable levels of demyelination. MHV-infected NOS2(−/−) mice displayed a marked decrease in mortality as compared to infected NOS2(+/+) mice that correlated with a significant decrease (P ≤ 0.001) in the number of apoptotic cells (determined by TUNEL staining) present in the brain. Confocal microscopy revealed that the majority of cells (>70%) undergoing apoptosis were neurons. These studies indicate that NOS2-generated NO contributes to apoptosis of neurons but not demyelination following MHV infection.


8th international symposium on neurovirology: Speakers


A code of conduct for data on epidemics


Tale of two serines


title: Hepatitis C Screening in Community-Based Voluntary Counselling and Testing Services in Europe: An Observational Study from the COBATEST Network 2014–2018

text: The COBATEST Network links community-based voluntary counselling and testing (CBVCT) services in the European region and collects testing data using standardised data collection tools. This study aims to describe the population being screened for anti-HCV antibodies in the COBATEST Network and identify risk factors associated with a reactive HCV screening test result in the period 2014–2018. Clients aged > 16 screened for HCV in the period 2014–2018 at one of the Network’s CBVCT services were included in the study. In the 5 year period, 7426 clients were screened for HCV in 22 centres in 10 countries and anti-HCV antibodies were detected in 113 (1.5%). The majority of people screened were aged 25–44, men who have sex with men (MSM), not HIV+ , not reporting a history of injecting drug use or sex work. Detection of anti-HCV antibodies was associated with being HIV + MSM (aOR 9.1, 95% CI 3.8; 21.8 compared to HIV-clients) and being a person who injects drugs (PWID, aOR 28.1, 95% CI 17.6; 45.0, compared to people with no history of injecting drug use). This study demonstrates that HIV-MSM with no history of injection drug use are using CBVCT services for HCV screening, but reactive screening test is associated with being HIV+ or PWID. The integration of HCV screening into the CBVCT service model may widen access to testing for populations that may otherwise not be tested. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10900-019-00780-0) contains supplementary material, which is available to authorized users.


title: Gene therapy for acute lung injury

text: The remarkable transition of biological science into the age of molecular biology held great promise for development of new therapies for treatment of human disease. The fact that the technology exists for analyzing genetic material in exquisite detail and constructing DNA in virtually any desired form was the basis for promising rapid translation into clinical medicine and the final cure for genetically determined diseases; cystic fibrosis is the prime example of such a lung disease. The promise was not kept, at least not in a time frame which was expected. That result is neither because the rationale was faulty nor because the tools of molecular biology were wanting. The devil was and is in the details. How do you deliver DNA to the desired cell targets in amounts sufficient to accomplish the desired effect? Viral vectors have received the most attention, but viral vectors have proven to have both theoretical and practical problems. In the lungs, these vectors have not fulfilled their original promise. Non-viral based strategies work in a general sense, but efficiency of gene delivery in vivo has been a limitation. In addition, the experimental end points in both clinical and preclinical investigation have been most often designed to demonstrate phenomenology rather than potential efficacy. And, why limit the potential of gene therapy to inherited disease? In fact, treatment of acquired diseases by increasing or decreasing expression of a given gene in the lungs that would hasten recovery from an acquired disease might be easier than treating inherited disease because the requirements for duration of transgene expression would be less stringent. Over the past two decades, we have learned enough about the pathogenesis of acute lung injury to predict that increased (or decreased) production of certain biologically active mediators should be beneficial. Genes encoding some of these mediators have been cloned and constructs made which express the genes. It is now possible using either viral or non-viral strategies to deliver expression constructs to the lungs and, since acute lung injury has a dismal prognosis and no effective drugs have been identified, this seems a good clinical target for gene therapy. In preclinical studies, we have shown that increased expression of the gene encoding the constitutive form of the cyclooxygenase gene (COX-1) results in increased production of prostacyclin and PGE(2) by the lungs and inhibits endotoxin induced pulmonary hypertension and edema. Additional studies demonstrate that increased expression of the alpha-1 antitrypsin gene in human respiratory epithelium in culture and in vivo has anti-viral and anti-inflammatory effects that are not predicted by extracellular concentrations of the transgene product. Thus, acute lung injury is a reasonable target for gene therapy, and evidence to date indicates that current technology is sufficiently robust to pursue this novel area for treatment of this devastating disease.


title: Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children

text: OBJECTIVES: To develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction. DESIGN: A panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process. METHODS: The panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, “in our practice” statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate. RESULTS: The panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 49 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, “in our practice” statements were provided. In addition, 52 research priorities were identified. CONCLUSIONS: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research.


Adjuvant therapies in critical care: steroids in community-acquired pneumonia


title: Outcome of acute respiratory distress syndrome patients treated with extracorporeal membrane oxygenation and brought to a referral center

text: PURPOSE: Patients with severe acute respiratory distress syndrome (ARDS) are candidates for extracorporeal membrane oxygenation (ECMO) therapy. The evaluation of organ severity is difficult in patients considered for cannulation in a distant hospital. This study was designed to identify early factors associated with hospital mortality in ARDS patients treated with ECMO and retrieved from referring hospitals. METHODS: Data from 85 consecutive ARDS patients equipped with ECMO by our mobile team and consequently admitted to our ICU were prospectively collected and analyzed. RESULTS: The main ARDS etiologies were community-acquired bacterial pneumonia (35 %), influenza pneumonia (23 %) (with 12 patients having been treated during the first half of the study period), and nosocomial pneumonia (14 %). The median (interquartile range) time between contact from the referring hospital and patient cannulation was 3 (1–4) h. ECMO was venovenous in 77 (91 %) patients. No complications occurred during transport by our mobile unit. Forty-eight patients died at the hospital (56 %). Based on a multivariate logistic regression, a score including age, SOFA score, and a diagnosis of influenza pneumonia was constructed. The probability of hospital mortality following ECMO initiation was 40 % in the 0–2 score class (n = 58) and 93 % in the 3–4 score class (n = 27). Patients with an influenza pneumonia diagnosis and a SOFA score before ECMO of less than 12 had a mortality rate of 22 %. CONCLUSIONS: Age, SOFA score, and a diagnosis of influenza may be used to accurately evaluate the risk of death in ARDS patients considered for retrieval under ECMO from distant hospitals.


title: Life in the danger zone

text: Instruments for studying microbes under biological containment cannot be readily removed from labs for servicing. A US facility is finding ways around that problem.


title: Significance of pathologic oxygen supply dependency in critically ill patients: Comparison between measured and calculated methods

text: OBJECTIVE: Oxygen supply dependency at normal or high oxygen delivery rate has been increasingly proposed as a hallmark and a risk factor in critical illnesses. We hypothesized that as fas as an adequate oxygen delivery is provided, oxygen consumption, when determined by indirect calorimetry, is not dependent on oxygen delivery in critically ill patients whereas calculated oxygen consumption is associated with artefactual correlation of oxygen consumption and delivery. DESIGN: Oxygen delivery, oxygen consumption and their relationship were analyzed prospectively. Metabolic data gained from both measured and calculated methods were obtained simultaneously before and after volume loading. SETTING: The study was completed in the intensive care unit as part of the management protocol of the patients. PATIENTS: 32 consecutive patients entered the study and were divided into 3 groups according to a clinical condition known to favour oxygen supply dependency: sepsis syndrome, adult respiratory distress syndrome and acute primary liver failure. INTERVENTION: The rise in oxygen delivery was obtained by colloid infusion (oxygen flux test) performed in hemodynamically and metabolically stable patients. All were mechanically ventilated. No change in therapy was allowed during the test. MEASUREMENTS AND RESULTS: Oxygen consumption was simultaneously evaluated by calculation (Fick Principle) and direct measurement using indirect calorimetry. Oxygen delivery was derived from the cardiac output (thermodilution) and arterial content of oxygen. Oxygen supply dependency was considered while observing an increase in oxygen delivery greater than 45 ml/min·m(2). Irrespective of patient's clinical diagnosis and outcome, measured oxygen uptake remained unaltered by volume infusion whereas both oxygen delivery and calculated oxygen consumption increased significantly. Arterial lactate level>2 mmol/l and measured oxygen extraction ratio>25% failed to identify oxygen supply dependency when measured data were considered. CONCLUSION: Analysis of oxygen uptake, when measured by indirect calorimetry, failed to substantiate oxygen supply dependency in the vast majority of the critically ill patients irrespective of diagnosis and outcome. Mathematical coupling of shared variables accounted for the correlation between oxygen delivery and calculated oxygen consumption.


title: Transplantation of Killer Endosymbionts in Paramecium

text: SEVERAL syngens or breeding groups of Paramecium aurelia contain endosymbionts which may result in the development of the killer trait(1). The symbionts are of different morphological types and it has been suggested that these are non-randomly distributed between syngens(2). Experiments involving crosses between paramecia with and without symbionts showed that each endosymbiont required a specific nuclear gene for its maintenance. A single gene controlled the presence or absence of endosymbionts as shown by segregation in the F(2) generation. The pattern of loss of symbionts in some of those F(2) clones varies, generally extending over a number of asexual fissions which for different endosymbionts can be from two to over sixty. Infection experiments also demonstrate the requirement for a specific gene. Infection of endosymbionts from homogenates or purified preparations occurs via the medium but only into particular cells possessing a specific gene(1,3). Finally, some endosymbionts growing in vitro retain their infectivity into certain paramecia (author's laboratory).


title: Guangzhou

text: Prone to infectious disease outbreaks, Guangzhou this year experienced one of its worst for dengue fever. By exploiting the data from thousands of clinical cases, researchers hope to reveal new approaches for prevention and control.


title: Life-threatening hemoptysis in adults with community-acquired pneumonia due to Panton-Valentine leukocidin-secreting Staphylococcus aureus

text: Three new consecutive cases of life-threatening hemoptysis in adults with community-acquired pneumonia due to Panton-Valentine leukocidin-secreting Staphylococcus aureus are presented, focusing on the particular clinical presentation of this new entity. Between December 1999 and March 2001, three adults aged from 23 to 67 years were admitted to our respiratory intensive care unit for massive hemoptysis and septic shock associated with community-acquired Staphylococcus aureus pneumonia. Isolates were sent to the Centre National de Référence des Toxémies Staphylococciques in Lyon, France, where they were found to secrete Panton-Valentive leukocidin. The clinical course was similar in the three patients, with massive hemoptysis and septic shock necessitating mechanical ventilation. Two patients died rapidly; necropsy showed pulmonary vascular necrosis in one of them. The third patient recovered after appropriate antibiotic therapy. Leukocidin/neutrophil interactions in the pulmonary vasculature may cause severe hemoptysis in patients with community-acquired Staphylococcus aureus pneumonia secreting Panton-Valentine leukocidin. Adult patients with massive hemoptysis and suspected community-acquired pneumonia should receive antibiotic regimens covering Staphylococcus aureus.


Noninvasive ventilation routine therapy for community-acquired pneumonia? Not so fast!


title: Incidence and costs of hospitalized adult influenza patients in The Netherlands: a retrospective observational study

text: OBJECTIVE: Influenza virus infections cause a high disease and economic burden during seasonal epidemics. However, there is still a need for reliable disease burden estimates to provide a more detailed picture of the impact of influenza. Therefore, the objectives of this study is to estimate the incidence of hospitalisation for influenza virus infection and associated hospitalisation costs in adult patients in the Netherlands during two consecutive influenza seasons. METHODS: We conducted a retrospective study in adult patients with a laboratory confirmed influenza virus infection in three Dutch hospitals during respiratory seasons 2014–2015 and 2015–2016. Incidence was calculated as the weekly number of hospitalised influenza patients divided by the total population in the catchment populations of the three hospitals. Arithmetic mean hospitalisation costs per patient were estimated and included costs for emergency department consultation, diagnostics, general ward and/or intensive care unit admission, isolation, antibiotic and/or antiviral treatment. These hospitalisation costs were extrapolated to national level and expressed in 2017 euros. RESULTS: The study population consisted of 380 hospitalised adult influenza patients. The seasonal cumulative incidence was 3.5 cases per 10,000 persons in respiratory season 2014–2015, compared to 1.8 cases per 10,000 persons in 2015–2016. The arithmetic mean hospitalisation cost per influenza patient was €6128 (95% CI €4934–€7737) per patient in 2014–2015 and €8280 (95% CI €6254–€10,665) in 2015–2016, potentially reaching total hospitalisation costs of €28 million in 2014–2015 and €20 million in 2015–2016. CONCLUSIONS: Influenza virus infections lead to 1.8–3.5 hospitalised patients per 10,000 persons, with mean hospitalisation costs of €6100–€8300 per adult patient, resulting in 20–28 million euros annually in The Netherlands. The highest arithmetic mean hospitalisation costs per patient were found in the 45–64 year age group. These influenza burden estimates could be used for future influenza cost-effectiveness and impact studies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10198-020-01172-1) contains supplementary material, which is available to authorized users.


title: Preparing for emerging infections

text: New infectious diseases continue to emerge, yet there is no clear strategy for managing them. A model response should be devised in the light of past events such as the recent US outbreak of a previously unknown hantavirus.


title: Management of HIV-infected patients in the intensive care unit

text: The widespread use of combination antiretroviral therapies (cART) has converted the prognosis of HIV infection from a rapidly progressive and ultimately fatal disease to a chronic condition with limited impact on life expectancy. Yet, HIV-infected patients remain at high risk for critical illness due to the occurrence of severe opportunistic infections in those with advanced immunosuppression (i.e., inaugural admissions or limited access to cART), a pronounced susceptibility to bacterial sepsis and tuberculosis at every stage of HIV infection, and a rising prevalence of underlying comorbidities such as chronic obstructive pulmonary diseases, atherosclerosis or non-AIDS-defining neoplasms in cART-treated patients aging with controlled viral replication. Several patterns of intensive care have markedly evolved in this patient population over the late cART era, including a steady decline in AIDS-related admissions, an opposite trend in admissions for exacerbated comorbidities, the emergence of additional drivers of immunosuppression (e.g., anti-neoplastic chemotherapy or solid organ transplantation), the management of cART in the acute phase of critical illness, and a dramatic progress in short-term survival that mainly results from general advances in intensive care practices. Besides, there is a lack of data regarding other features of ICU and post-ICU care in these patients, especially on the impact of sociological factors on clinical presentation and prognosis, the optimal timing of cART introduction in AIDS-related admissions, determinants of end-of-life decisions, long-term survival, and functional outcomes. In this narrative review, we sought to depict the current evidence regarding the management of HIV-infected patients admitted to the intensive care unit.


title: The 1918 flu virus is resurrected

text: The recreation of one of the deadliest diseases known could help us to prevent another pandemic. Or it might trigger one, say critics. Andreas von Bubnoff investigates whether the benefits outweigh the risks.


title: Association of social deprivation with 1-year outcome of ICU survivors: results from the FROG-ICU study

text: PURPOSE: Intensive care unit survivors suffer from prolonged impairment, reduced quality of life, and higher mortality rates after discharge compared to the general population. Socioeconomic status may play a partial but important role in mortality and recovery. Therefore, the detection of factors that are responsible for poor long-term outcomes would be beneficial in designing targeted interventions for at-risk populations. METHODS: For an endpoint analysis, 1834 intensive care unit patients with known French Deprivation Index (FDep) scores were included from the French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) study, which was a prospective, observational, multicenter cohort study performed in 20 French intensive care units in 13 different hospitals. Socioeconomic status was defined by using the FDep score [represented as quintiles when referring to the general French population, as quintiles when referring to the FROG-ICU cohort, or as dichotomized data (which was defined as a FDep ≤ 0 for nondeprived patients)] and by using a detailed social questionnaire that was completed 3 months after discharge. The primary outcome included an all-cause, 1-year mortality after ICU discharge when regarding socioeconomic status. The secondary outcomes included both ICU and hospital lengths of stay, both short- and medium-term mortality, and the quality of life, as assessed during the 1-year follow-up by using the Medical Outcome Survey Short Form-36 (SF-36). The Revised Impact of Event Scale (IES-R) was used to evaluate the symptoms of post-traumatic stress disorder, and the Hospital Anxiety and Depression Scale (HADS) was used to screen for anxiety and depression. RESULTS: Of the 1447 patients who were discharged alive from the ICU, 19.2% died over the following year. No association was found between 1-year mortality and socioeconomic status, regardless of whether this association was analyzed in quintiles (p = 0.911 in the quintiles of the general French population; p = 0.589 in the quintiles of the FROG-ICU cohort itself) or as dichotomized data [nondeprived (n = 177; 1-year mortality of 18.2%) versus deprived (n = 97; 1-year mortality of 20.5%; p = 0.304)]. Moreover, no differences were found between the nondeprived and the deprived patients in the ICU and hospital lengths of stay, ICU mortalities, in-hospital mortalities, or 28-day mortalities. The SF-36 was below the score for the normal French population throughout the follow-up period. Socially deprived patients showed significantly lower median scores in the physical function subscale [55, interquartile range (IQR) (28.8–80) vs. 65, IQR (35–90); p = 0.014], the physical role subscale [25, IQR (0–75) vs. 33.3, IQR (0–100); p = 0.022], and the overall physical component scale [47.5, IQR (30–68.8) vs. 54.4, IQR (35–78.8); p = 0.010]. Up to 31.6% of survivors presented symptoms that indicated post-traumatic stress disorder, and up to 31.5% of survivors reported clinically meaningful symptoms of anxiety or depression. CONCLUSIONS: A lower socioeconomic status was associated with lower self-reported physical component scores in the nondeprived patients. Psychiatric symptoms are frequently reported after an ICU stay, and subsequent interventions should target those fields. TRIAL REGISTRATION: ClinicalTrials.gov NCT01367093; registered on June 6, 2011. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00134-018-5412-5) contains supplementary material, which is available to authorized users.


title: Plasma cortisol levels before and during "low-dose" hydrocortisone therapy and their relationship to hemodynamic improvement in patients with septic shock

text: Objectives: To compare cortisol levels during "low-dose" hydrocortisone therapy to basal and ACTH-stimulated endogenous levels and to assess whether clinical course and the need for catecholamines depend on cortisol levels and/or pretreatment adrenocortical responsiveness. Design and setting: Prospective observational study in a medical ICU of a university hospital. Patients: Twenty consecutive patients with septic shock and a cardiac index of 3.5 l/min or higher, started on "low-dose" hydrocortisone therapy (100 mg bolus, 10 mg/h for 7 days and subsequent tapering) within 72 h of the onset of shock. Measurements and results: Basal total and free plasma cortisol levels ranged from 203 to 2169 and from 17 to 372 nmol/l. In 11 patients cortisol production was considered "inadequate" because there was neither a response to ACTH of at least 200 nmol/l nor a baseline level of at least 1000 nmol/l. Following the initiation of hydrocortisone therapy total and free cortisol levels increased 4.2- and 8.5-fold to median levels of 3587 (interquartile range 2679–5220) and 1210 (interquartile range 750–1846) nmol/l on day 1, and thereafter declined to median levels of 1310 nmol/l and 345 nmol/l on day 7. Patients with "inadequate" steroid production could be weaned from vasopressor therapy significantly faster, although their plasma free cortisol concentrations during the hydrocortisone treatment period did not differ. Conclusions: (a) During proposed regimens of "low-dose" hydrocortisone therapy, initially achieved plasma cortisol concentrations considerably exceed basal and ACTH stimulated levels. (b) Cortisol concentrations decline subsequently, despite continuous application of a constant dose. (c) "Inadequate" endogenous steroid production appears to sensitize patients to the hemodynamic effects of a "therapeutic rise" in plasma cortisol levels.


ESPNIC 2013: 24th Annual Meeting of the European Society of Paediatric and Neonatal Intensive Care