Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes.

People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. 1), whose mechanism remains unknown. In acquired and genetic mouse models of diabetes, induced with an acute pulmonary viral infection, we demonstrate that hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell (DC) subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. Mechanistically, hyperglycaemia induces an altered metabolic DC circuitry characterized by increased glucose-to-acetyl-CoA shunting and downstream histone acetylation, leading to global chromatin alterations. These, in turn, drive impaired expression of key DC effectors including central antigen presentation-related genes. Either glucose-lowering treatment or pharmacological modulation of histone acetylation rescues DC function and antiviral immunity. Collectively, we highlight a hyperglycaemia-driven metabolic-immune axis orchestrating DC dysfunction during pulmonary viral infection and identify metabolic checkpoints that may be therapeutically exploited in mitigating exacerbated disease in infected diabetics.

Gene expression profile in cases of infectious death in infancy.

BACKGROUND: Genetic predispositions in cases suffering sudden unexpected infant death have been a research focus worldwide during the past decade. Despite large efforts, there is still uncertainty concerning the molecular pathogenesis of these deaths. With genetic technology in constant development, the possibility of an alternative approach into this research field has become available, like mRNA expression studies. METHODS: In this study, we investigated mRNA gene expression in 14 cases who died suddenly and unexpectedly from infection without a history of severe illness prior to death. The control group included eight accidents, two cases of natural death, one undetermined, one case of medical malpractice, and two homicides. The study included tissue from liver, heart, and brain using Illumina whole-genome gene expression assay. RESULTS: From the array, 19 genes showed altered expression in the infectious deaths compared to controls. Tissue from the heart showed 15 genes with altered mRNA expression compared to the control group. CONCLUSIONS: Downregulation of KCNE5 in heart tissue from cases of infectious death was of particular interest. Variants of KCNE5 are associated with Brugada syndrome and sudden death and could be responsible for the fatal outcome in the group of infectious death. IMPACT: KCNE5 is downregulated in tissue from the heart in cases of infectious death in infancy. This study provides knowledge about the gene expression profile in cases of infectious death. Variants of a gene known to give increased risk of cardiac arrhythmia is downregulated in cases of infectious death in infancy. The results could give us better knowledge as to why some infants do not survive an infection. This study provides a candidate gene for future studies.

Myocarditis Presenting as Sudden Death in Infants and Children: A Single Centre Analysis by ESGFOR Study Group.

BACKGROUND: Acute myocarditis is an inflammatory disease of the heart mostly diagnosed in young people, which can present as sudden death. The etiology includes infectious agents (mostly viruses), systemic diseases and toxins. We aim to characterize infants and children with myocarditis at post-mortem presenting as sudden deaths. METHODS: Retrospective evaluation of 813 post-mortems in infants and children dying suddenly and unexpectedly between 2009-2019. Data retrieved included histological features, microbiology and clinical history. RESULTS: 23 of 813 post-mortems reviewed corresponded to acute myocarditis and 1 to dilated cardiomyopathy related to remote Parvovirus infection. PCR identified enterovirus (7), parvovirus (7 cases, 2 also with HHV6 and 1 case with EVB), Influenza A (1), Parainfluenza type 3 (1). Two cases corresponded to hypersensitivity myocarditis, 1 was Group A Streptococcus and 5 idiopathic myocarditis. Enterovirus was frequent in infants (7/10), and in newborns was associated with meningoencephalitis or congenital myocarditis. More than 50% were less than 2 years of age and all remained clinically unsuspected. CONCLUSION: Myocarditis represents almost 3% of all sudden pediatric deaths. Enterovirus and parvovirus were the most common viruses. This retrospective analysis showed that patients experienced viral symptoms but remained unsuspected, highlighting the need for more clinical awareness of myocarditis.

Delaying haematopoietic stem cell transplantation in children with viral respiratory infections reduces transplant-related mortality.

Viral respiratory infections (VRIs) contribute to the morbidity and transplant-related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and strategies to prevent and treat VRIs are warranted. We monitored VRIs before and after transplant in children undergoing allogeneic HSCT with nasopharyngeal aspirates (NPA) and assessed the impact on clinical outcome. Between 2007 and 2017, 585 children underwent 620 allogeneic HSCT procedures. Out of 75 patients with a positive NPA screen (12%), transplant was delayed in 25 cases (33%), while 53 children started conditioning with a VRI. Patients undergoing HSCT with a positive NPA screen had a significantly lower overall survival (54% vs. 79%) and increased TRM (26% vs. 7%) compared to patients with a negative NPA. Patients with a positive NPA who delayed transplant and cleared the virus before conditioning had improved overall survival (90%) and lower TRM (5%). Pre-HSCT positive NPA was the only significant risk factor for progression to a lower respiratory tract infection and was a major risk factor for TRM. Transplant delay, whenever feasible, in case of a positive NPA screen for VRIs can positively impact on survival of children undergoing HSCT.

Responding to global stimulant use: challenges and opportunities.

We did a global review to synthesise data on the prevalence, harms, and interventions for stimulant use, focusing specifically on the use of cocaine and amphetamines. Modelling estimated the effect of cocaine and amphetamine use on mortality, suicidality, and blood borne virus incidence. The estimated global prevalence of cocaine use was 0·4% and amphetamine use was 0·7%, with dependence affecting 16% of people who used cocaine and 11% of those who used amphetamine. Stimulant use was associated with elevated mortality, increased incidence of HIV and hepatitis C infection, poor mental health (suicidality, psychosis, depression, and violence), and increased risk of cardiovascular events. No effective pharmacotherapies are available that reduce stimulant use, and the available psychosocial interventions (except for contingency management) had a weak overall effect. Generic approaches can address mental health and blood borne virus infection risk if better tailored to mitigate the harms associated with stimulant use. Substantial and sustained investment is needed to develop more effective interventions to reduce stimulant use.

Detection of community-acquired respiratory viruses in allogeneic stem-cell transplant recipients and controls-A prospective cohort study.

BACKGROUND: Community-acquired respiratory viruses (CARV) cause upper and lower respiratory tract infections (URTI/LRTI) and may be life-threatening for recipients of an allogeneic stem cell transplantation (allo-SCT). METHODS: In a prospective study encompassing 4 winter-seasons, we collected throat gargles (TG) at random time points from allo-SCT recipients (patients) and controls and followed them up for at least 3 weeks including repetitive sampling and documentation of symptoms. A Multiplex-PCR system to identify 20 CARV and Mycoplasma pneumoniae was used to detect CARV. RESULTS: One hundred ninety-four patients with 426 TG and 273 controls with 549 TG were included. There were more patients with a positive test result (25% vs 11% in the controls), and the patients had a higher number of positive TG (70 = 16%) compared to controls (32 = 6%) (P < .001). Altogether, 115 viruses were detected. Multiple viruses in one TG (11/48, 34%) and prolonged shedding were only observed in patients (13/48, 27%). Patients had more RSV (18/83, 26%) and adenovirus (15/83, 21%) than controls (both viruses 2/32, 6%). Independent risk factors for the detection of CARV included age >40 years (OR 3.38, 95% CI 1.8-6.4, P < .001) and presence of URTI-symptoms (OR 3.22, 95% CI 1.9-5.5, P < .001). No controls developed a LRTI or died whereas 4/48 (8%) patients developed a LRTI (coronavirus in 2, RSV in 1 and influenza A H1N1 in 1 patient). One patient died of CARV (influenza A H1N1). CONCLUSION: Allo-SCT-recipients have more CARV-infections, exhibit a different epidemiology, have more cases of co-infection or prolonged shedding and have a higher rate of LRTI and mortality.

Hematopoietic stem cell transplantation does not increase the risk of infection-related complications for pediatric patients with Hodgkin and non-Hodgkin lymphomas: A multicenter nationwide study.

BACKGROUND: Hodgkin (HL) and non-Hodgkin lymphoma (NHL) represent a spectrum of lymphoid malignancies that are often curable with currently applied treatment regimens; however, 15%-30% of lymphoma patients still suffer from relapsed or refractory (rel/ref) disease. Although hematopoietic stem cell transplantation (HSCT) improves outcomes of second-line therapy for lymphoma in childhood, the complication rates in this group of patients, especially infectious complications (IC), remain unclear. OBJECTIVE: The aim of this population-based cohort study was a retrospective analysis of incidence, epidemiology and profile of bacterial infections (BI), invasive fungal disease (IFD), and viral infections (VI) in primary or rel/ref lymphoma patients, both HL and NHL. PATIENTS AND METHODS: We subdivided lymphoma patients into three groups: patients with primary conventional chemotherapy/radiotherapy regimens (group A), patients with rel/ref lymphoma treated with second-line chemotherapy (group B), and rel/ref lymphoma patients who underwent HSCT (group C). The medical records of the patients were biannually reported by each pediatric oncology center, and the data were analyzed centrally. RESULTS: Within 637 patients with primary lymphoma, at least one IC was diagnosed in 255 (40.0%), among 52 patients with rel/ref lymphoma 24 (46.2%) ICs were observed, and in transplanted group, 28 (57.1%) out of 49 children were diagnosed with IC (P = .151). The distribution of etiology of IC differed between the patient groups (A, B, C), with a predominance of BI in group A (85.6% vs 72.0% and 47.9%, respectively), VI in group C (9% and 16.0% vs 46.6%, respectively), and IFD in group B (5.4% vs 12.0% vs 5.5%, respectively). Overall, 500 (68.0%) episodes of bacterial IC were diagnosed in the entire group. Apart from HL patients treated with chemotherapy, in all the other subgroups of patients Gram-positives were predominant. The rate of multidrug-resistant bacteria was high, especially for Gram-negatives (41.1% in group A, 62.5% in group B, and 84.6% in group C). The infection-related mortality was comparable for each group. CONCLUSIONS: The incidence of IC was comparable during first- and second-line chemotherapy and after HSCT, but their profile was different for primary or re/ref lymphoma and depended on the type of therapy.

Intravenous immunoglobulin for presumed viral myocarditis in children and adults.

BACKGROUND: This is an update of a previous review. Case reports and case series have described dramatic responses to intravenous immunoglobulin (IVIG) in people with presumed viral myocarditis, and its administration has become commonplace. OBJECTIVES: The primary objective of this review was to compare event-free (death, requirement for a cardiac transplant, or placement of a left ventricular assist device) or overall (death) survival of adults and children with presumed viral myocarditis treated with IVIG versus those who did not receive IVIG. A secondary objective was to determine if a group of patients with presumed viral myocarditis could be identified (on the basis of age, duration of symptoms, acuity of onset of symptoms, cardiac function at presentation, virological results, or the presence or absence of histological evidence of acute myocarditis on cardiac biopsy in patients in whom a biopsy was performed) who would be the most likely to benefit from IVIG. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, DARE, CINAHL, Web of Science Core Collection, and LILACS in July 2019, and two trial registries in November 2019. We contacted authors of trials and checked reference lists of relevant papers. We applied no language restrictions. SELECTION CRITERIA: We included studies if (1) participants had a clinical diagnosis of acute myocarditis with a left ventricular ejection fraction (LVEF) ≤ 0.45, left ventricular end-diastolic diameter (LVEDD) > 2 standard deviations (SDs) above the norm, or a left ventricular shortening fraction (LVSF) > 2 SDs below the mean, with duration of cardiac symptoms < 6 months; (2) participants had no evidence of non-infectious or bacterial cardiac disease; and (3) participants were randomly assigned to receive at least 1 g/kg of IVIG versus no IVIG or placebo. We excluded studies if (1) participants had received immunosuppression before outcome assessment; or (2) onset of myocarditis was reported to have occurred < 6 months postpartum. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results and extracted data. We assessed risk of bias with the Cochrane 'Risk of bias' tool. We conducted meta-analysis for two outcomes (overall survival and improvement in LVEF) with two adult trials. Other meta-analyses were not possible because only three relevant trials were included, and researchers analysed markedly different populations and used different outcome measures. MAIN RESULTS: In this update we added two trials to the two previously included trials. A quasi-randomised trial was previously included due to a paucity of evidence from randomised trials; however, with the addition of two new randomised trials, it was removed from this update. For two adult trials, the overall risk of bias was unclear with very low-certainty evidence for all outcomes. The first trial studied 62 adults with recent-onset dilated cardiomyopathy randomly assigned to receive IVIG or an equivalent volume of 0.1% albumin in a blinded fashion. The effect on event-free survival between groups was uncertain (risk ratio (RR) of any event 1.76, 95% confidence interval (CI) 0.48 to 6.40). The second trial studied 41 adults with acute myocarditis randomised to either high-dose IVIG (1 to 2 g/kg over two days) or no treatment. The IVIG group reported greater survival time after 60 days (no raw data, P < 0.01), but the evidence is uncertain. We pooled the reported number of deaths in both trials, with no evidence of a difference between groups (RR 0.91, 95% CI 0.23 to 3.62, I2 = 31%, very low-certainty evidence). The evidence on the effect of IVIG treatment on LVEF (pooled mean difference (MD) -0.01, 95% CI -0.06 to 0.05) after 12 months and an unknown time frame is uncertain. The results for functional capacity, assessed by peak oxygen consumption at 12 months, were uncertain (MD -0.80, 95% CI -4.57 to 2.97). The results for infusion-related side effects were also uncertain due to a very large CI (RR 20.29, 95% CI 1.25 to 329.93). Lastly, there was uncertain evidence addressing failure to attain complete recovery (RR 0.46, 95% CI 0.19 to 1.14).  Evidence for improvement in LVEDD, left ventricular shortening fraction, and hospitalisation status in adults was not reported.  In the single included paediatric trial, the overall risk of bias was low with very low-certainty evidence for all outcomes. The trial included 86 children in Egypt presenting with acute myocarditis. Children were randomly assigned to 1 g/kg IVIG daily for two consecutive days or placebo followed by echocardiography one and six months post randomisation for recording of LVEDD and LVSF. The evidence for overall survival after six months was uncertain (risk of death RR 0.48, 95% CI 0.20 to 1.15). The evidence was also uncertain for improvement in LVEDD and LVSF after six months (LVEDD MD -4.00, 95% CI -9.52 to 1.52; LVSF no raw data).  Evidence for improvement in LVEF, functional capacity, side effects, complete recovery, and hospitalisation status in children was not reported.  AUTHORS' CONCLUSIONS: Evidence from two trials of very low certainty and with unclear risk of bias provides contradictory evidence on the use of IVIG in the treatment of adults with presumed viral myocarditis. One trial reported that use of IVIG results in longer survival time after 60 days, whilst the other trial found that IVIG does not provide an appreciable benefit. The evidence of a difference in event-free or overall survival, LVEDD, or LVSF is of very low certainty in a single paediatric trial with a low risk of bias. Until higher-quality studies with low risk of bias and larger sample sizes have demonstrated benefit in a particular group of patients, the evidence for treatment with IVIG for presumed viral myocarditis is uncertain. Further studies of the pathophysiology of myocarditis would lead to improved diagnostic criteria, which would facilitate future research.

Systemic lupus erythematosus and infections.

Systemic lupus erythematosus (SLE) is an inflammatory and multi-systemic autoimmune disorder, characterized by an uncontrolled auto-reactivity of B and T lymphocytes, leading to the production of autoantibodies against self-directed antigens and tissue damage. The life expectancy in patients with SLE has improved tremendously in the last two decades, but the mortality rates still remain three times greater compared to those of the general population. Despite increased awareness and improved management, infections remain a major source of morbidity, mortality, hospitalization, and death in patients with SLE. The infections in SLE patients widely range from opportunistic to common bacterial and viral infections with typical or atypical presentations. Moreover, SLE patients exhibit an increased susceptibility to hospital-acquired infections. Factors associated with increased risk of infections include high disease activity, specific immune dysregulation, drug-induced immune deficiency, and organ failure with irreversible damage. Furthermore, immunosuppressive agents may make patients more susceptible to opportunistic infections. A big challenge faced by physicians in these patients is to distinguish between infections and flares of SLE, as infections may mimic them, leading to predicament in diagnosis and appropriate management. Immunosuppression used to treat severe flares of lupus can have catastrophic complications in patients with active infections. There is an urgent need for biomarkers to make an accurate differential diagnosis in this situation. In spite of increased understanding of SLE, many questions remain unanswered. Further research is needed to determine specific immune dysregulation underlying the increased susceptibility to specific infections, predictors of infection in SLE such as genetic markers, and biomarkers that discriminate between disease activity and active infections. Also, measures must be evaluated appropriately to prevent infections, and their complications in SLE.

Low pre-transplant levels of mannose-binding lectin are associated with viral infections and mortality after haematopoietic allogeneic stem cell transplantation.

BACKGROUND: Mannose-binding lectin (MBL) is a key component of innate immunity. Low serum MBL levels, related to promoter polymorphism and structural variants, have been associated with an increased risk of infection. The aim of this work was to analyse the incidence and severity of infections and mortality in relation to the MBL2 genotype and MBL levels in patients underwent allogeneic haematopoietic stem cell transplantation (Allo-HSCT). RESULTS: This was a prospective cohort study of 72 consecutive patients underwent Allo-HSCT between January 2007 and June 2009 in a tertiary referral centre. Three periods were considered in the patients' follow-up: the early period (0-30 days after Allo-HSCT), the intermediate period (30-100 days after Allo-HSCT) and the late period (> 100 days after Allo-HSCT). A commercial line probe assay for MBL2 genotyping and an ELISA Kit were used to measure MBL levels. A total of 220 episodes of infection were collected in the 72 patients. No association between donor or recipient MBL2 genotype and infection was found. The first episode of infection presented earlier in patients with pre-transplant MBL levels of < 1000 ng/ml (median 6d vs 8d, p = 0.036). MBL levels < 1000 ng/ml in the pre-transplant period (risk ratio (RR) 2.48, 95% CI 1.00-6.13), neutropenic period (0-30 days, RR 3.28, 95% CI 1.53-7.06) and intermediate period (30-100 days, RR 2.37, 95% CI 1.15-4.90) were associated with increased risk of virus infection. No association with bacterial or fungal disease was found. Mortality was associated with pre-transplant MBL levels < 1000 ng/ml (hazard ratio 5.55, 95% CI 1.17-26.30, p = 0.03) but not with MBL2 genotype. CONCLUSIONS: Patients who underwent Allo-HSCT with low pre-transplant MBL levels presented the first episode of infection earlier and had an increased risk of viral infections and mortality in the first 6 months post-transplant. Thus, pre-transplant MBL levels would be important in predicting susceptibility to viral infections and mortality and might be considered a biomarker to be included in the pre-transplantation risk assessment.

Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort study.

BACKGROUND: More than 500 000 neonatal deaths per year result from possible serious bacterial infections (pSBIs), but the causes are largely unknown. We investigated the incidence of community-acquired infections caused by specific organisms among neonates in south Asia. METHODS: From 2011 to 2014, we identified babies through population-based pregnancy surveillance at five sites in Bangladesh, India, and Pakistan. Babies were visited at home by community health workers up to ten times from age 0 to 59 days. Illness meeting the WHO definition of pSBI and randomly selected healthy babies were referred to study physicians. The primary objective was to estimate proportions of specific infectious causes by blood culture and Custom TaqMan Array Cards molecular assay (Thermo Fisher, Bartlesville, OK, USA) of blood and respiratory samples. FINDINGS: 6022 pSBI episodes were identified among 63 114 babies (95·4 per 1000 livebirths). Causes were attributed in 28% of episodes (16% bacterial and 12% viral). Mean incidence of bacterial infections was 13·2 (95% credible interval [CrI] 11·2-15·6) per 1000 livebirths and of viral infections was 10·1 (9·4-11·6) per 1000 livebirths. The leading pathogen was respiratory syncytial virus (5·4, 95% CrI 4·8-6·3 episodes per 1000 livebirths), followed by Ureaplasma spp (2·4, 1·6-3·2 episodes per 1000 livebirths). Among babies who died, causes were attributed to 46% of pSBI episodes, among which 92% were bacterial. 85 (83%) of 102 blood culture isolates were susceptible to penicillin, ampicillin, gentamicin, or a combination of these drugs. INTERPRETATION: Non-attribution of a cause in a high proportion of patients suggests that a substantial proportion of pSBI episodes might not have been due to infection. The predominance of bacterial causes among babies who died, however, indicates that appropriate prevention measures and management could substantially affect neonatal mortality. Susceptibility of bacterial isolates to first-line antibiotics emphasises the need for prudent and limited use of newer-generation antibiotics. Furthermore, the predominance of atypical bacteria we found and high incidence of respiratory syncytial virus indicated that changes in management strategies for treatment and prevention are needed. Given the burden of disease, prevention of respiratory syncytial virus would have a notable effect on the overall health system and achievement of Sustainable Development Goal. FUNDING: Bill & Melinda Gates Foundation.

Psychological distress and infectious disease mortality in the general population.

There is a paucity of studies examining the relation between high psychological distress and infectious disease in the general population. We examined this association in a large multi-cohort study drawn from the general population. The analytic sample comprised 104,923 men and women (age, 47.3 ±â€¯17.4 year; 45.7% men) in which psychological distress symptoms was assessed using the 12-item version of the General Health Questionnaire. There were 1535 deaths attributed to infectious diseases during 971,220 person-years of follow up (mean 9.3; range 0.1-17.1 years). A dose-response association between GHQ-12 score and all infectious disease mortality was observed after adjusting for age, sex, survey year, occupational social class, longstanding illness, smoking, alcohol, and physical activity (per SD increase, hazard ratio = 1.24; 95% CI, 1.20-1.28). A similar pattern was apparent for viral infections (1.23; 1.14, 1.33) and pneumonia (1.20; 1.13, 1.28), but weaker for bacterial infections (1.09; 1.00, 1.19). In conclusion, psychological distress is associated with higher risk of infectious disease.

Using machine learning to estimate survival curves for patients receiving an increased risk for disease transmission heart, liver, or lung versus waiting for a standard organ.

INTRODUCTION: Over 19% of deceased organ donors are labeled increased risk for disease transmission (IRD) for viral blood-borne disease transmission. Many potential organ recipients need to decide between accepting an IRD organ offer and waiting for a non-IRD organ. METHODS: Using machine learning and simulation, we built transplant and waitlist survival models and compared the survival for patients accepting IRD organ offers or waiting for non-IRD organs for the heart, liver, and lung. The simulation consisted of generating 20 000 different scenarios of a recipient either receiving an IRD organ or waiting and receiving a non-IRD organ. RESULTS: In the simulations, the 5-year survival probabilities of heart, liver, and lung recipients who accepted IRD organ offers increased on average by 10.2%, 12.7%, and 7.2%, respectively, compared with receiving a non-IRD organ after average wait times (190, 228, and 223 days, respectively). When the estimated waitlist time was at least 5 days for the liver, and 1 day for the heart and lung, 50% or more of the simulations resulted in a higher chance of 5-year survival when the patient received an IRD organ versus when the patient remained on the waitlist. We also developed a simple equation to estimate the benefits, in terms of 5-year survival probabilities, of receiving an IRD organ versus waiting for a non-IRD organ, for a particular set of recipient/donor characteristics. CONCLUSION: For all three organs, the majority of patients are predicted to have higher 5-year survival accepting an IRD organ offer compared with waiting for a non-IRD organ.

Viral prevalence, clinical profiles and comparison of severity scores for predicting the mortality of adults with severe acute respiratory infections

Background/aim: The aim of this study was to determine the accuracy of severity scores for predicting the 28-day mortality among adults with severe acute respiratory infection (SARI) admitted to the emergency department. Materials and methods: This study included 159 consecutive adult patients with SARI admitted to the emergency department of a tertiary hospital. A standard form was filled out in order to record demographic information, clinical parameters, laboratory tests, and radiographic findings of the patients. CURB-65, PSI, SIRS, qSOFA, SOFA and APACHE II scores were compared between the survivor and nonsurvivor groups. Results: Of 159 patients included in the study, 38.4% were positive for respiratory viruses and 28.3% were positive for influenza viruses. 35.8% of the patients were admitted to an intensive care unit (ICU) and the mortality rate was 36.5%. The area under the receiver operating characteristic curve of CURB-65, PSI, SIRS criteria, qSOFA, SOFA and APACHE II scores were 0.717, 0.712, 0.607, 0.683, 0.755, and 0.748, respectively in predicting mortality and 0.759, 0.744, 0.583, 0.728, 0.741, and 0.731, respectively in predicting ICU admission. Conclusion: SOFA and APACHE II were more accurate than SIRS in predicting the 28-day mortality among adults with SARI. There was no significant difference among these scores in terms of other multivariate comparisons.

History of Mosquitoborne Diseases in the United States and Implications for New Pathogens.

The introduction and spread of West Nile virus and the recent introduction of chikungunya and Zika viruses into the Americas have raised concern about the potential for various tropical pathogens to become established in North America. A historical analysis of yellow fever and malaria incidences in the United States suggests that it is not merely a temperate climate that keeps these pathogens from becoming established. Instead, socioeconomic changes are the most likely explanation for why these pathogens essentially disappeared from the United States yet remain a problem in tropical areas. In contrast to these anthroponotic pathogens that require humans in their transmission cycle, zoonotic pathogens are only slightly affected by socioeconomic factors, which is why West Nile virus became established in North America. In light of increasing globalization, we need to be concerned about the introduction of pathogens such as Rift Valley fever, Japanese encephalitis, and Venezuelan equine encephalitis viruses.

Detection of Respiratory Viruses in Deceased Persons, Spain, 2017.

During the 2016-17 influenza season in Spain, we tested specimens from 57 elderly deceased persons for respiratory viruses. Influenza viruses were detected in 18% of the specimens and any respiratory virus in 47%. Only 7% of participants had received a diagnosis of infection with the detected virus before death.

Respiratory Viruses in Invasively Ventilated Critically Ill Patients-A Prospective Multicenter Observational Study.

OBJECTIVES: The presence of respiratory viruses and the association with outcomes were assessed in invasively ventilated ICU patients, stratified by admission diagnosis. DESIGN: Prospective observational study. SETTING: Five ICUs in the Netherlands. PATIENTS: Between September 1, 2013, and April 30, 2014, 1,407 acutely admitted and invasively ventilated patients were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Nasopharyngeal swabs and tracheobronchial aspirates were collected upon intubation and tested for 14 respiratory viruses. Out of 1,407 patients, 156 were admitted because of a severe acute respiratory infection and 1,251 for other reasons (non-severe acute respiratory infection). Respiratory viruses were detected in 28.8% of severe acute respiratory infection patients and 17.0% in non-severe acute respiratory infection (p < 0.001). In one third, viruses were exclusively detected in tracheobronchial aspirates. Rhinovirus and human metapneumovirus were more prevalent in severe acute respiratory infection patients (9.6% and 2.6% vs 4.5 and 0.2%; p = 0.006 and p < 0.001). In both groups, there were no associations between the presence of viruses and the number of ICU-free days at day 28, crude mortality, and mortality in multivariate regression analyses. CONCLUSIONS: Respiratory viruses are frequently detected in acutely admitted and invasively ventilated patients. Rhinovirus and human metapneumovirus are more frequently found in severe acute respiratory infection patients. Detection of respiratory viruses is not associated with worse clinically relevant outcomes in the studied cohort of patients.

A novel locus on mouse chromosome 7 that influences survival after infection with tick-borne encephalitis virus.

BACKGROUND: Tick-borne encephalitis (TBE) is the main tick-borne viral infection in Eurasia. Its manifestations range from inapparent infections and fevers with complete recovery to debilitating or fatal encephalitis. The basis of this heterogeneity is largely unknown, but part of this variation is likely due to host genetic. We have previously found that BALB/c mice exhibit intermediate susceptibility to the infection of TBE virus (TBEV), STS mice are highly resistant, whereas the recombinant congenic strain CcS-11, carrying 12.5% of the STS genome on the background of the BALB/c genome is even more susceptible than BALB/c. Importantly, mouse orthologs of human TBE controlling genes Oas1b, Cd209, Tlr3, Ccr5, Ifnl3 and Il10, are in CcS-11 localized on segments derived from the strain BALB/c, so they are identical in BALB/c and CcS-11. As they cannot be responsible for the phenotypic difference of the two strains, we searched for the responsible STS-derived gene-locus. Of course the STS-derived genes in CcS-11 may operate through regulating or epigenetically modifying these non-polymorphic genes of BALB/c origin. METHODS: To determine the location of the STS genes responsible for susceptibility of CcS-11, we analyzed survival of TBEV-infected F2 hybrids between BALB/c and CcS-11. CcS-11 carries STS-derived segments on eight chromosomes. These were genotyped in the F2 hybrid mice and their linkage with survival was tested by binary trait interval mapping. We have sequenced genomes of BALB/c and STS using next generation sequencing and performed bioinformatics analysis of the chromosomal segment exhibiting linkage with TBEV survival. RESULTS: Linkage analysis revealed a novel suggestive survival-controlling locus on chromosome 7 linked to marker D7Nds5 (44.2 Mb). Analysis of this locus for polymorphisms between BALB/c and STS that change RNA stability and genes' functions led to detection of 9 potential candidate genes: Cd33, Klk1b22, Siglece, Klk1b16, Fut2, Grwd1, Abcc6, Otog, and Mkrn3. One of them, Cd33, carried a nonsense mutation in the STS strain. CONCLUSIONS: The robust genetic system of recombinant congenic strains of mice enabled detection of a novel suggestive locus on chromosome 7. This locus contains 9 candidate genes, which will be focus of future studies not only in mice but also in humans.

Treatment-related mortality in relapsed childhood acute lymphoblastic leukemia.

BACKGROUND: Treatment of relapsed childhood acute lymphoblastic leukemia (ALL) is particularly challenging due to the high treatment intensity needed to induce and sustain a second remission. To improve results, it is important to understand how treatment-related toxicity impacts survival. PROCEDURE: In this retrospective population-based study, we described the causes of death and estimated the risk for treatment-related mortality in patients with first relapse of childhood ALL in the Nordic Society of Paediatric Haematology and Oncology ALL-92 and ALL-2000 trials. RESULTS: Among the 483 patients who received relapse treatment with curative intent, we identified 52 patients (10.8%) who died of treatment-related causes. Twelve of these died before achieving second remission and 40 died in second remission. Infections were the cause of death in 38 patients (73.1%), predominantly bacterial infections during the chemotherapy phases of the relapse treatment. Viral infections were more common following hematopoietic stem cell transplantation (HSCT) in second remission. Independent risk factors for treatment-related mortality were as follows: high-risk stratification at relapse (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.3-3.9; P < 0.01), unfavorable cytogenetic aberrations (HR 3.4; 95% CI 1.3-9.2; P = 0.01), and HSCT (HR 4.64; 95% CI 2.17-9.92; P < 0.001). In contrast to previous findings, we did not observe any statistically significant sex or age differences. Interestingly, none of the 17 patients with Down syndrome died of treatment-related causes. CONCLUSIONS: Fatal treatment complications contribute significantly to the poor overall survival after relapse. Implementation of novel therapies with reduced toxicity and aggressive supportive care management are important to improve survival in relapsed childhood ALL.

Investigating pathogen burden in relation to a cumulative deficits index in a representative sample of US adults.

Pathogen burden is a construct developed to assess the cumulative effects of multiple, persistent pathogens on morbidity and mortality. Despite the likely biological wear and tear on multiple body systems caused by persistent infections, few studies have examined the impact of total pathogen burden on such outcomes and specifically on preclinical markers of dysfunction. Using data from two waves of the National Health and Nutrition Examination Survey, we compared three alternative methods for measuring pathogen burden, composed of mainly persistent viral infections, using a cumulative deficits index (CDI) as an outcome: single pathogen associations, a pathogen burden summary score and latent class analyses. We found significant heterogeneity in the distribution of the CDI by age, sex, race/ethnicity and education. There was an association between pathogen burden and the CDI by all three metrics. The latent class classification of pathogen burden showed particularly strong associations with the CDI; these associations remained after controlling for age, sex, body mass index, smoking, race/ethnicity and education. Our results suggest that pathogen burden may influence early clinical indicators of poor health as measured by the CDI. Our results are salient since we were able to detect these associations in a relatively young population. These findings suggest that reducing pathogen burden and the specific pathogens that drive the CDI may provide a target for preventing the early development of age-related physiological changes.