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Background The modifications to the standard intensive care unit (ICU) organization that had to be urgently implemented worldwide to overcome the surge of ICU admissions due to patients with a severe coronavirus disease 2019 (COVID-19) have resulted in increased workload and patients-to-nurse ratio. The aim of this study was to investigate whether level of critical care staffing could be associated with an increased risk of ICU mortality (primary endpoint), length of stay, mechanical ventilation and the evolution of disease (secondary study endpoints) in critically ill patients with COVID-19. Methods Retrospective multicenter analysis of the international Risk Stratification in COVID-19 patients in the Intensive Care Unit (RISC-19-ICU) registry that prospectively enrolls patients developing critical illness due to COVID-19 in several countries worldwide. The analysis was limited to the period between March 1st, 2020 and May 31st, 2020, to ICUs in Switzerland that have collected additional data on nurse and physician staffing. Hierarchical regression models were used to investigate crude and adjusted effects of critical care staffing ratio on study endpoints. We adjusted for diseases severity and weekly caseload. Results Among the 38 Swiss participating ICUs, 17 recorded critical care staffing information. The study population included 437 patients and 2342 daily assessments of patient-to-nurse/physician ratio. Median of daily patient-to-nurse ratio started at 1.0 ([IQR] 0.5–1.5; calendar week 9) and peaked at 2.4 (IQR 0.4-2.0; calendar week 16), while the median of daily patient-to-physician ratio started at 4.0 (IQR 2.1-5.0; calendar week 9) and peaked at 6.8 (IQR 6.3–7.3; calendar week 19). Neither the patient-to-nurse ratio [adjusted Odds Ratio (OR) 1.28, 95% confidence interval (CI) 0.85–1.94; doubling of ratio] nor the patient-to-physician ratio [adjusted OR 1.08, 95% CI 0.87–1.32; doubling of ratio] was associated with ICU mortality. We found no association of critical care staffing on the investigated secondary study endpoints in adjusted models. COnclusion The Swiss health care system successfully overcame the first wave of the COVID-19 pandemic with regards to the unprecedented demand for ICU treatments. The reduced availability of critical care staffing resources per critically ill patient in Swiss ICUs did not translate in an overall increased risk of mortality.

SummaryBackgroundDifficult-to-treat infections caused by antibiotic susceptible strains have been linked with the occurrence of persisters. Persisters are a subpopulation of dormant bacteria that tolerate antibiotic exposure despite lacking genetic resistance. They can be identified phenotypically upon plating on nutrient agar because of their altered growth dynamics, resulting in colony size heterogeneity. The occurrence of within-patient bacterial phenotypic heterogeneity in various infections and clinical determinants of persister formation remain unknown.MethodsWe plated bacteria derived from 132 patient-samples of difficult-to-treat infections directly on nutrient-rich agar and monitored colony growth by time-lapse imaging. Of these, we retained 36 Staphylococcus aureus mono-cultures for further analysis. We investigated clinical factors potentially associated with increased colony growth-delay with regression analyses. Additionally, we corroborated the clinical findings using in vitro grown static biofilms, exposed to distinct antibiotics.ResultsThe extent of phenotypic heterogeneity of patient-derived S. aureus varied substantially between patients. Increased heterogeneity coincided with increased median growth-delay. Multivariable regression showed that rifampicin treatment was significantly associated with increased median growth-delay. S. aureus grown in biofilms and exposed to high concentrations of rifampicin or a combination of rifampicin with either clindamycin or levofloxacin exhibited prolonged growth-delay, correlating with a strain-dependent increase in antibiotic tolerance.ConclusionsUpon direct cultivation on nutrient-rich agar, S. aureus from difficult-to-treat infections commonly exhibited colony size heterogeneity. This was due to heterogeneous delays in growth resumption, with delays larger than two days in the most extreme cases. Since bacteria in a dormant state are tolerant to antibiotics, the observation of large growth-delays might have direct clinical implications. Future studies are needed to assess the potential of bacterial phenotypic heterogeneity quantification for staphylococcal infections prognosis.

Delirium in the general intensive care unit (ICU) population is common, associated with adverse outcomes and well studied. However, knowledge on delirium in the increasing number of ICU patients with malignancy is scarce. The aim was to assess the frequency of delirium and its impact on resource utilizations and outcomes in ICU patients with malignancy. This retrospective, single-center longitudinal cohort study included all patients with malignancy admitted to ICUs of a University Hospital during one year. Delirium was diagnosed by an Intensive Care Delirium Screening Checklist (ICDSC) score ≥ 4. Of 488 ICU patients with malignancy, 176/488 (36%) developed delirium. Delirious patients were older (66 [55–72] vs. 61 [51–69] years, p = 0.001), had higher SAPS II (41 [27–68] vs. 24 [17–32], p p p p p p p p p p p = 0.074). In conclusion, delirium was a frequent complication in ICU patients with malignancy independently associated with high resource utilizations, however, it was not independently associated with in-hospital mortality.

Background: Whereas delirium in the general intensive care unit (ICU) population is common and well studied, knowledge on ICU delirium in patients with malignancy is scarce. The aim was to assess the frequency of delirium and its impact on resource utilizations and outcomes in ICU patients with malignancy.Methods: This retrospective, single-center longitudinal cohort study included all patients with malignancy admitted to ICUs of a University Hospital during one year. Delirium was diagnosed by an Intensive Care Delirium Screening Checklist (ICDSC) score ≥ 4. Groups were compared with Fisher’s exact and Mann-Whitney U tests. Multivariate analysis included binary logistic regression, Cox regression and multiple linear regression. Results are given as number (percentage; confidence interval (CI)) and median (interquartile range).Results: Of 488 ICU patients with malignancy, 176/488 (36%) developed delirium. Frequencies were high in patients with hepatic (13/21 [62%]; 95% CI 41-82%), lung (29/65 [45%]; 95% CI 33-56%) and colorectal malignancies (15/37 [41%]; 95% CI 24-56%). Delirious patients were older (66 [55-72] vs 61 [51-69] years, p = 0.001), had higher SAPS II (41 [27-68] vs 24 [17-32], p < 0.001) and more frequently sepsis (26/176 [15%] vs 6/312 [1.9%], p < 0.001) and / or shock (30/176 [6.1%] vs 6/312 [1.9%], p < 0.001). In multivariate analysis, delirium was independently associated with lower discharge home (OR [95% CI] 0.366 [0.236-0.567], p < 0.001), longer ICU (HR [95% CI] 0.295 [0.234-0.371], p < 0.001) and hospital length of stay (HR [95% CI] 0.619 [0.500-0.765], p < 0.001), longer mechanical ventilation (HR [95% CI] 0.401 [0.282-0.572], p < 0.001), higher ICU nursing workload (B [95% CI] 1.917 [1.665-2.206], p < 0.001) and ICU (B [95% CI] 2.077 [1.811-2.382], p < 0.001) and total costs (B [95% CI] 1.442 [1.301-1.597], p < 0.001). However, delirium was not independently associated with in-hospital mortality (OR [95% CI] 2.263 [0.925-5.537], p = 0.074).Conclusions: In ICU patients with malignancy, delirium was a frequent complication independently associated with high resource utilizations, however, it was not independently associated with in-hospital mortality.

AIMS OF THE STUDY Invasive streptococcal infections affect more than half a million patients worldwide every year and have a high lethality. Little is known about the epidemiology and microbiological characteristics of streptococcal infections in Switzerland. This case series study aims to describe the demographics, known risk factors for streptococcal skin and soft tissue infections, clinical presentations, treatment and outcomes of patients admitted to the University Hospital Zurich between 2000 and 2014 with invasive streptococcal infections caused by Streptococcus pyogenes (group A Streptococcus), Streptococcus dysgalactiae ssp. equisimilis or the Streptococcus anginosus group, as well as the microbiological characteristics of the clinical isolates. METHODS Data collected retrospectively from patients hospitalised between 2000 and 2014 with invasive streptococcal infections were analysed. M protein gene (emm) typing of the bacterial clinical isolates was carried out according to the Centers for Disease Control and Prevention guidelines. RESULTS A total of 86 patients with invasive beta-haemolytic streptococcal infections were included in this study, of which 49% presented with necrotising fasciitis. The median age was 44 years and half were female. The most common risk factor was acute skin lesions. C-reactive protein levels were significantly higher in patients with necrotising fasciitis, as were acute renal failure and distributive shock. Beta-lactam antibiotics were given to most patients, and intravenous immunoglobulins were given to 18% of patients within the first 24 hours. All patients suffering from necrotising fasciitis underwent surgery. The overall case fatality rate was 8.1% at 30 days post admission. All Group A Streptococcus strains were susceptible to penicillin and clindamycin, and we found resistance to tetracycline in 11.9% of strains. The most common emm-type isolated was emm1 (44.4%). CONCLUSIONS Invasive beta-haemolytic streptococcal infections, the most severe presentation of which is necrotising fasciitis, remain a serious clinical issue and require rapid diagnosis and treatment. This is the first representative analysis monitoring clinical and microbiological characteristics of patients with a severe invasive beta-haemolytic streptococcal infection and treated in Zurich, Switzerland. In addition to the detailed reporting of various clinical and microbiological characteristics, we show that C-reactive protein levels, acute renal failure and distributive shock were higher in the patients with necrotising fasciitis. We also found a low case fatality rate compared to other reports. The detailed clinical data and microbiological characteristics depicted in this study will lead to a better understanding of regional differences in severe invasive streptococcal infections.

BackgroundWhile the pathogenesis of coronavirus disease 2019 (COVID-19) is becoming increasingly clear, there is little data on IgA response, the first line of bronchial immune defense.ObjectiveTo determine, whether COVID-19 is associated with a vigorous total IgA response and whether IgA autoantibodies are associated with complications of severe illness. Since thrombotic events are frequent in severe COVID-19 and resemble hypercoagulation of antiphospholipid syndrome (APS), our approach focused on antiphospholipid antibodies (aPL).Materials and methodsIn this retrospective cohort study we compared clinical data and aPL from 64 patients with COVID-19 from three independent centers (two in Switzerland, one in Liechtenstein). Samples were collected from April 9, 2020 to May 1, 2020. Total IgA and aPL were measured with FDA-approved commercially available clinical diagnostic kits.ResultsClinical records of the 64 patients with COVID-19 were reviewed and divided into a cohort with mild illness (mCOVID, n=26 [41%]), a discovery cohort with severe illness (sdCOVD, n=14 [22%]) and a confirmation cohort with severe illness (scCOVID, n=24 [38%]). Severe illness was significantly associated with increased total IgA (sdCOVID, P=0.01; scCOVID, PPP=0.003; scCOVID, PPConclusionsHigher total IgA and IgA-aPL were consistently associated with severe illness. These novel data strongly suggest that a vigorous antiviral IgA-response triggered in the bronchial mucosa induces systemic autoimmunity.

Background Venous thromboembolism (VTE) is a recognized complication in patients with traumatic brain injury (TBI) and is associated with increased morbidity and mortality. Currently, no standard exists for optimal timing or a pharmacological agent for VTE prophylaxis (pharmacological thromboprophylaxis - PTP) in patients with TBI. PTP is often delayed out of fear of causing extension of intracranial hemorrhage (ICH). The purpose of this study was to report the frequency of VTE and ICH progression after initiation of PTP with a continuous infusion of unfractionated heparin in patients with moderate to severe TBI, and to identify risk factors associated with development of VTE. Methods In this single-center retrospective study, patients with moderate to severe TBI admitted to the ICU of a Swiss Level I Trauma Center over a three-year period were analyzed. Results In 23 (13%) of the 177 patients included in the study a VTE episode occurred during the hospital stay. ICH progression after initiation of PTP occurred in 7 (4%) patients. In a multivariable logistic regression model, only the timing of initiation of PTP was identified as an independent predictor of VTE. Conclusions In this study population, the risk of developing VTE increased with the delay of initiation of a pharmacological VTE prophylaxis, while ICH progression after initiation of PTP was a rare event.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) frequently entails complications that bear similarities to autoimmune diseases. To date, there are little data on possible immunoglobulin (Ig) A-mediated autoimmune responses. Here, we aim to determine whether COVID-19 is associated with a vigorous total IgA response and whether IgA antibodies are associated with complications of severe illness. Since thrombotic events are frequent in severe COVID-19 and resemble hypercoagulation of antiphospholipid syndrome, our approach focused on antiphospholipid antibodies (aPL). METHODS: In this retrospective cohort study, clinical data and aPL from 64 patients with COVID-19 were compared from 3 independent tertiary hospitals (1 in Liechtenstein, 2 in Switzerland). Samples were collected from 9 April to 1 May 2020. RESULTS: Clinical records of 64 patients with COVID-19 were reviewed and divided into a cohort with mild illness (mCOVID; 41%), a discovery cohort with severe illness (sdCOVID; 22%) and a confirmation cohort with severe illness (scCOVID; 38%). Total IgA, IgG, and aPL were measured with clinical diagnostic kits. Severe illness was significantly associated with increased total IgA (sdCOVID, P = .01; scCOVID, P < .001), but not total IgG. Among aPL, both cohorts with severe illness significantly correlated with elevated anticardiolipin IgA (sdCOVID and scCOVID, P < .001), anticardiolipin IgM (sdCOVID, P = .003; scCOVID, P< .001), and anti-beta 2 glycoprotein-1 IgA (sdCOVID and scCOVID, P< .001). Systemic lupus erythematosus was excluded from all patients as a potential confounder. CONCLUSIONS: Higher total IgA and IgA-aPL were consistently associated with severe illness. These novel data strongly suggest that a vigorous antiviral IgA response, possibly triggered in the bronchial mucosa, induces systemic autoimmunity.

Aims of the study An extracorporeal membrane oxygenation system (ECMO), as a bridge to either recovery, a ventricular assist device (VAD), or heart or lung transplantation, may be the only lifesaving option for critically ill patients suffering from refractory cardiac, respiratory or combined cardiopulmonary failure. As peripheral hospitals may not offer ECMO treatment, tertiary care centres provide specialised ECMO teams for on-site implantation and subsequent patient transfer on ECMO to the tertiary hospital. This study reports the results of the largest ECMO transportation programme in Switzerland and describes its feasibility and safety. Methods Patients transported on ECMO by our mobile ECMO team to our tertiary centre between 1 September 2009 and 31 December, 2016 underwent retrospective analysis. Implantation was performed by our specialised ECMO team (primary transport) or by the medical staff of the referring hospital (secondary transport) with subsequent transfer to our institution. Type of ECMO, transport data, patient baseline characteristics, operative variables and postoperative outcomes including complications and mortality were collected from medical records. Results Fifty-eight patients were included (three patients excluded: one repatriation, two with incomplete medical records). Thirty-five patients (60%) received veno-venous, 22 (38%) veno-arterial and one patient (2%) veno-venoarterial ECMO. Forty-nine (84%) patients underwent primary and nine (16%) secondary transport. Thirty-five (60%) patients were transferred by helicopter and 23 (40%) by ambulance, with median distances of 38.1 (13n225) km and 21 (3-71) km respectively. No clinical or technical complications occurred during transportation. During hospitalisation, three patients had ECMO-associated complications (two compartment syndrome of lower limb, one haemothorax after central ECMO upgrade). Median days on ECMO was 8 (l1n49) and median days in hospital was 17 (l1n122). ECMO weaning was successful in 41 patients (71%), on-transport survival was 100%, 40 patients survived to discharge (69%), and overall survival was 67% (39 patients) at a median follow-up of 58 days (l1n1441). Cumulative survival was significantly affected by cardiogenic shock vs. ARDS (p = 0.001), veno-arterial and veno-venoarterial vs. veno-venous ECMO (p = 0.001) and after secondary vs. primary transport (p l0.001). The ECMO weaning rate was significantly lower after secondary transfer (22%, two patients, both vaECMO) vs. primary transfer (80%, p = 0.002, 39 patients of which 35 (71%) had vvECMO). Conclusions The first results of our ECMO transportation programme show its feasibility, safety and efficacy without on-site implant or on-transport complications or mortality. The favourable early survival may justify the large effort with respect to logistics, costs and manpower. With rising awareness, referring centres may increasingly consider this lifesaving option at an early stage, which may further improve outcomes.

Objectives Streptococcus pyogenes causes life-threatening invasive infections including necrotizing fasciitis (NF). Current treatment guidelines recommend the use of a cell-wall–active antibiotic combined with a protein synthesis inhibitor and surgical debridement in NF patients. Adjunctive therapy with intravenous immunoglobulin (IVIG) has been proposed for superantigen-associated streptococcal toxic shock syndrome. So far, benefits of IVIG treatment remain unclear and prospective clinical studies are scarce. Thus, we aimed to assess the effects of IVIG on virulence factor activity in vitro, ex vivo in patients and in vivo in a NF mouse model. Methods We investigated the effect of IVIG on the activity of the virulence factors streptolysin O (SLO), streptodornase 1 (Sda1), S. pyogenes cell envelope protease and streptococcal pyrogenic exotoxin B in vitro and ex vivo in patient sera. Additionally, we assessed the influence of IVIG on the clinical outcome in a murine NF model. Results In vitro, IVIG inhibited various streptococcal virulence factors. Further, IVIG treatment of group A Streptococcus–infected mice led to a reduced skin lesion size (median (interquartile range) day 3 intraperitoneal administration: 12 mm2 (9–14.5) vs. 4 mm2 (0.8–10.5), subcutaneous: 10.3 mm2 (6.9–18.6) vs. 0.5 mm2 (0.1–6.8)) and lower SLO activity. After treatment with IVIG, patient sera showed an elevated titre of specific SLO (7/9) and Sda1 (5/9) antibodies, reducing SLO and Sda1 activity. Conclusions The clear reduction in disease severity in IVIG-treated mice and inhibition of virulence factor activity in mouse and human sera suggest that IVIG may be beneficial in invasive group A Streptococcus infections such as NF in addition to streptococcal toxic shock syndrome.

Purpose Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating disease, for which the underlying pathophysiological mechanisms have yet to be fully elucidated. In recent years, microRNAs have emerged as important players in regulation of physiological processes, and dysregulation of microRNA expression has been linked to various diseases. So far, only a limited number of studies has investigated microRNAs in CTEPH. Therefore, the aim of this study was to investigate whether microRNAs are also detectable in tissue specimens obtained from patients undergoing pulmonary endarterectomy (PEA), since differential expression in the tissues could suggest a role of these microRNAs in disease development. Methods Tissue specimens were obtained from patients 16 patients undergoing PEA at the University Hospital Zurich, between 2016 and September 2018. RNA was extracted from FFPE blocks, and expression levels of three microRNAs identified as potential players in CTEPH development through a study of circular RNAs (Miao et al, Medicine 2017), miR-939, miR-942 and miR-92a-2-5p, were measured by microRNA-specific RT-qPCR. In addition, miR-210, the most important microRNA in regulation of hypoxia was measured. Expression of microRNAs was correlated to various clinical factors. Results Of the three miR-candidates measured in plasma before, miR-939 and miR-942 were detectable in PEA tissue specimens. In addition, the hypoxamiR miR-210 was also detectable and represented the microRNA with the highest expression levels. Expression of miR-939 showed a significant negative correlation with peripheral oxygen saturation (p=0.03; Spearman's R=-0.548) and pulmonary vascular resistance (p=0.05, R=-0.502), while miR-942 expression negatively correlated with Jamieson Classification (p=0.04, R=-0.623). Conclusion This pilot study has shown for the first time that microRNAs are readily detectable in material extracted during PEA. Our data shows that microRNAs are differentially expressed between different patients, and that microRNA expression is correlated with various factors of clinical presentation. Thus, our data highlight that microRNA expression warrants further investigation as their dysregulation might be involved in the development of CTEPH.

BACKGROUND The purpose of the present study was to analyze clinical features of patients with traumatic brain injury (TBI), their age-related outcomes and determinants of long-term outcome. METHODS This retrospective cohort study was conducted in a level I University Swiss trauma center. Consecutive patients with moderate to severe TBI admitted for more than 48 hours to the Intensive Care Unit (ICU) were included. Patients' and trauma characteristics, management during ICU stay, prognostic scores and long-term outcomes were analyzed. RESULTS Hundred-seventy-four patients (72% males, mean age 49 years) were divided in three age groups: young (≤39 years, N.=69, 39.7%), middle aged (40-64 years, N.=55, 31.6%), and elderly (≥65 years, N.=50, 28.7%). In elderly patients, falls (62%) were the most common cause of TBI. Overall ICU mortality was 15% with no difference among age groups. Within six-months after TBI, 80% of elderly patients presented unfavorable outcomes. Age, pre-existing cardiovascular disease, use of anticoagulants and/or antiplatelet agents, abnormal pupillary reactivity, a high score in Marshall CT classification, and a higher glucose level were associated with unfavorable outcomes in a univariable logistic regression. In a multivariable logistic regression, age and abnormal pupillary reactivity were identified as independent risk factors for unfavorable outcomes, while presence of epidural hematoma and higher hemoglobin levels were predictors for favorable outcomes. CONCLUSIONS Older patients are at higher risk for long-term unfavorable outcomes than younger patients. Use of anticoagulants and/or antiplatelet agents and lower hemoglobin levels during rescue phase are associated with unfavorable long-term outcomes. Fall prevention in the elderly should be a key target of intervention programs.

OBJECTIVES: Brain death (BD) is associated with various systemic responses and a cascade of inflammatory reactions. It is still unknown how the time interval from BD to cold preservation (CP) affects outcome after lung transplantation (LTx). This report investigates the impact of the time interval from BD to CP on long-term outcome in LTx. METHODS: We reviewed 250 consecutive recipients who underwent LTx at our institution between January 2000 and December 2011. In Group I (n = 212), the time interval from BD to CP was 24 h. Cox proportional hazard regression analysis was performed to determine the risk factors affecting survival. RESULTS: The median time from BD to CP was 18.6 h (range 9-65). The rate of postoperative complications was comparable (P = 0.8). The 30-day mortality rate was 7.5% in Group I and 0% in Group II. The 5-year survival rate was better in Group II [70% (95% CI: 48.5-83.8%)] than in Group I [66% (95% CI: 58.3-72.5%)] without statistical significance (P = 0.3). Intraoperative extracorporeal membrane oxygenation (ECMO) use was identified as a significant risk factor for survival [HR = 1.7, (95% CI: 1.1-2.6), P = 0.01]. CONCLUSION: In our cohort, the time interval from BD to CP had no impact on long-term outcome after LTx.

ECP is an established "second-line" treatment for CLAD/BOS. Recently, ECP was used for the first time in an adolescent CF patient as a "second-line" treatment therapy in life-threatening primary graft dysfunction following lung transplantation who deteriorated despite extensive treatment including ECMO and ATG. Within 10 days after initiation of ECP twice weekly, allograft function and clinical status improved significantly and the patient was weaned from mechanical ventilation support. ECP has been continued every 2 weeks since. Two hundred days after lung transplantation, the patient has an acceptable allograft function (FEV1 67%) and no signs of allograft rejection. We advocate that use of ECP and its immunomodulatory effects should be evaluated in the early period following lung transplantation. KEYWORDS: extracorporeal photopheresis; lung transplantation; primary graft dysfunction

Wir berichten über einen 52-jährigen Schweizer mit Halsschmerzen und progredienter Heiserkeit. Histologisch fand sich eine granulomatöse Entzündung der Epiglottis. Mikrobiologisch erfolgte der Nachweis von dimorphen Pilzen im Sputum, die als Histoplasma sp. identifiziert wurden. Das Histoplasma-Antigen war positiv im Urin und Serum. Unter der Therapie mit Itroconazol zeigte sich eine weitere Verschlechterung der Klinik, weshalb die antimykotische Therapie auf Amphotericin B umgestellt wurde. An die Nebenniereninsuffizienz muss gedacht werden, da diese durch die Histoplasmose per se aber auch durch die Itraconazol-Therapie verursacht werden kann. Als alternative Therapie der disseminierten Histoplasmose kommt eine Therapie mit Voriconazol infrage. Die Erhebung einer Reiseanamnese ist wichtig.

Recognition of multifocal vasculopathy due to varicella-zoster virus (VZV) is often problematic. We describe a human immunodeficiency virus-infected patient who had progressive central nervous system disease for >3 months. Both VZV DNA and antibody were detected in cerebrospinal fluid (CSF) specimens; serial polymerase chain reaction analyses confirmed the diagnosis and guided the duration of therapy. Reduced ratios of VZV antibody in serum to that in CSF were also demonstrated.