A prolonged intensive care unit stay defines a worse long-term prognosis - Insights from the critically ill mortality by age (Cimba) study.

BACKGROUND: Patients with critical illness often survive the intensive care unit (ICU) at a cost of prolonged length of stay (LOS) and slow recovery. This chronic critically ill disease may lead to long-term poor outcomes, especially in older or frail patients. OBJECTIVES: The main goal of this study was to address the characteristics and outcomes of patients with prolonged ICU LOS. Mainly, short- and long-term admissions were compared to identify risk factors for persistent critical illness and to characterise the impact on ICU, hospital, and long-term mortality. METHODS: Subanalysis of a retrospective, multicentric, observational study addressing the 2-year outcome of patients admitted to Portuguese ICUs (the Cimba study). Patients were segregated according to an ICU LOS of ≥14 days. RESULTS: Data from 37 118 patients were analysed, featuring a median ICU LOS of 4 days (percentile: 25-75 2-9), and a mortality of 16.1% in the ICU, 24.0% in the hospital, and 38.7% after 2 years. A total of 5334 patients (14.4%) had an ICU LOS of ≥14 days (corresponding to 48.9% of all ICU patients/days). Patients with prolonged LOS were more often younger (52.8% vs 46.4%, were ≤65 years of age , p < 0.001), although more severe (Simplified Acute Physiology Score II: 49.1 ± 16.9 vs 41.8 ± 19.5, p < 0.001), and had higher ICU and hospital mortality (18.3% vs 15.7%, and 31.2 vs 22.8%, respectively). Prolonged ICU LOS was linked to an increased risk of dying during the 2-year follow-up (adjusted Cox proportional hazard: 1.65, p < 0.001). CONCLUSION: Prolonged LOS is associated with a long-term impact on patient prognosis. More careful planning of care should incorporate these data.

Clinical characteristics, risk factors and outcomes in patients with severe COVID-19 registered in the International Severe Acute Respiratory and Emerging Infection Consortium WHO clinical characterisation protocol: a prospective, multinational, multicentre, observational study.

Due to the large number of patients with severe coronavirus disease 2019 (COVID-19), many were treated outside the traditional walls of the intensive care unit (ICU), and in many cases, by personnel who were not trained in critical care. The clinical characteristics and the relative impact of caring for severe COVID-19 patients outside the ICU is unknown. This was a multinational, multicentre, prospective cohort study embedded in the International Severe Acute Respiratory and Emerging Infection Consortium World Health Organization COVID-19 platform. Severe COVID-19 patients were identified as those admitted to an ICU and/or those treated with one of the following treatments: invasive or noninvasive mechanical ventilation, high-flow nasal cannula, inotropes or vasopressors. A logistic generalised additive model was used to compare clinical outcomes among patients admitted or not to the ICU. A total of 40 440 patients from 43 countries and six continents were included in this analysis. Severe COVID-19 patients were frequently male (62.9%), older adults (median (interquartile range (IQR), 67 (55-78) years), and with at least one comorbidity (63.2%). The overall median (IQR) length of hospital stay was 10 (5-19) days and was longer in patients admitted to an ICU than in those who were cared for outside the ICU (12 (6-23) days versus 8 (4-15) days, p<0.0001). The 28-day fatality ratio was lower in ICU-admitted patients (30.7% (5797 out of 18 831) versus 39.0% (7532 out of 19 295), p<0.0001). Patients admitted to an ICU had a significantly lower probability of death than those who were not (adjusted OR 0.70, 95% CI 0.65-0.75; p<0.0001). Patients with severe COVID-19 admitted to an ICU had significantly lower 28-day fatality ratio than those cared for outside an ICU.

Monitoring of the Forgotten Immune System during Critical Illness-A Narrative Review.

Immune organ failure is frequent in critical illness independent of its cause and has been acknowledged for a long time. Most patients admitted to the ICU, whether featuring infection, trauma, or other tissue injury, have high levels of alarmins expression in tissues or systemically which then activate innate and adaptive responses. Although necessary, this response is frequently maladaptive and leads to organ dysfunction. In addition, the counter-response aiming to restore homeostasis and repair injury can also be detrimental and contribute to persistent chronic illness. Despite intensive research on this topic in the last 40 years, the immune system is not routinely monitored in critical care units. In this narrative review we will first discuss the inflammatory response after acute illness and the players of maladaptive response, focusing on neutrophils, monocytes, and T cells. We will then go through commonly used biomarkers, like C-reactive protein, procalcitonin and pancreatic stone protein (PSP) and what they monitor. Next, we will discuss the strengths and limitations of flow cytometry and related techniques as an essential tool for more in-depth immune monitoring and end with a presentation of the most promising cell associated markers, namely HLA-DR expression on monocytes, neutrophil expression of CD64 and PD-1 expression on T cells. In sum, immune monitoring critically ill patients is a forgotten and missing piece in the monitoring capacity of intensive care units. New technology, including bed-side equipment and in deep cell phenotyping using emerging multiplexing techniques will likely allow the definition of endotypes and a more personalized care in the future.

SARS-CoV2 pneumonia recovery is linked to expansion of innate lymphoid cells type 2 expressing CCR10.

Accelerate lung repair in SARS-CoV-2 pneumonia is essential for pandemic handling. Innate lymphoid cells (ILCs) are likely players, given their role in mucosal protection and tissue homeostasis. We studied ILC subpopulations at two time points in a cohort of patients admitted in the hospital due to SARS-CoV-2 infection. COVID-19 patients with moderate/severe respiratory failure featured profound depletion of circulating ILCs at hospital admission, in agreement with overall lymphocyte depletion. However, ILCs recovered in direct correlation with lung function improvement as measured by oxygenation index and in negative association with inflammatory and lung/endothelial damage markers like RAGE. While both ILC1 and ILC2 expanded, ILC2 showed the most striking phenotype changes, with CCR10 upregulation in strong correlation with these parameters. Overall, CCR10+ ILC2 emerge as relevant contributors to SARS-CoV-2 pneumonia recovery.

Acute HIV-1 and SARS-CoV-2 Infections Share Slan+ Monocyte Depletion-Evidence from an Hyperacute HIV-1 Case Report.

Monocytes are key modulators in acute viral infections, determining both inflammation and development of specific B- and T-cell responses. Recently, these cells were shown to be associated to different SARS-CoV-2 infection outcome. However, their role in acute HIV-1 infection remains unclear. We had the opportunity to evaluate the mononuclear cell compartment in an early hyper-acute HIV-1 patient in comparison with an untreated chronic HIV-1 and a cohort of SARS-CoV-2 infected patients, by high dimensional flow cytometry using an unsupervised approach. A distinct polarization of the monocyte phenotype was observed in the two viral infections, with maintenance of pro-inflammatory M1-like profile in HIV-1, in contrast to the M2-like immunosuppressive shift in SARS-CoV-2. Noticeably, both acute infections had reduced CD14low/-CD16+ non-classical monocytes, with depletion of the population expressing Slan (6-sulfo LacNac), which is thought to contribute to immune surveillance through pro-inflammatory properties. This depletion indicates a potential role of these cells in acute viral infection, which has not previously been explored. The inflammatory state accompanied by the depletion of Slan+ monocytes may provide new insights on the critical events that determine the rate of viral set-point in acute HIV-1 infection and subsequent impact on transmission and reservoir establishment.

Severe COVID-19 Recovery Is Associated with Timely Acquisition of a Myeloid Cell Immune-Regulatory Phenotype.

After more than one year since the COVID-19 outbreak, patients with severe disease still constitute the bottleneck of the pandemic management. Aberrant inflammatory responses, ranging from cytokine storm to immune-suppression, were described in COVID-19 and no treatment was demonstrated to change the prognosis significantly. Therefore, there is an urgent need for understanding the underlying pathogenic mechanisms to guide therapeutic interventions. This study was designed to assess myeloid cell activation and phenotype leading to recovery in patients surviving severe COVID-19. We evaluated longitudinally patients with COVID-19 related respiratory insufficiency, stratified according to the need of intensive care unit admission (ICU, n = 11, and No-ICU, n = 9), and age and sex matched healthy controls (HCs, n = 11), by flow cytometry and a wide array of serum inflammatory/immune-regulatory mediators. All patients featured systemic immune-regulatory myeloid cell phenotype as assessed by both unsupervised and supervised analysis of circulating monocyte and dendritic cell subsets. Specifically, we observed a reduction of CD14lowCD16+ monocytes, and reduced expression of CD80, CD86, and Slan. Moreover, mDCs, pDCs, and basophils were significantly reduced, in comparison to healthy subjects. Contemporaneously, both monocytes and DCs showed increased expression of CD163, CD204, CD206, and PD-L1 immune-regulatory markers. The expansion of M2-like monocytes was significantly higher at admission in patients featuring detectable SARS-CoV-2 plasma viral load and it was positively correlated with the levels of specific antibodies. In No-ICU patients, we observed a peak of the alterations at admission and a progressive regression to a phenotype similar to HCs at discharge. Interestingly, in ICU patients, the expression of immuno-suppressive markers progressively increased until discharge. Notably, an increase of M2-like HLA-DRhighPD-L1+ cells in CD14++CD16- monocytes and in dendritic cell subsets was observed at ICU discharge. Furthermore, IFN-γ and IL-12p40 showed a decline over time in ICU patients, while high values of IL1RA and IL-10 were maintained. In conclusion, these results support that timely acquisition of a myeloid cell immune-regulatory phenotype might contribute to recovery in severe systemic SARS-CoV-2 infection and suggest that therapeutic agents favoring an innate immune system regulatory shift may represent the best strategy to be implemented at this stage.

Austrian Syndrome: a report of an exceptionally rare and deadly syndrome / Síndrome de Austrian: descrição de uma entidade excepcionalmente rara e mortal

ABSTRACT: Austrian Syndrome is the rare combination of a triad of endocarditis, meningitis, and pneumonia in the context of pneumococcal infection. Due to the involvement of several anatomical sites, the Austrian syndrome has a high mortality. Importantly, endocarditis is usually not considered during pneumococcal infection. We present a case of Austrian syndrome in a previously healthy 67-year-old woman. She featured with mental state alteration, respiratory failure, and shock, and was diagnosed with ceftriaxone-sensitive pneumococcal bacteremia, meningitis, and pneumonia. A transesophageal echocardiogram revealed vegetation of the mitral valve. Despite an improvement in her medical condition, she remained in a coma and died due to neurological complications. Even though the major cause of mortality in Austrian syndrome is cardiac involvement, meningitis is also linked with high morbidity and eventually death. We emphasize the relevance of an early diagnosis of the triad in order to decrease the very high mortality associated with this syndrome

RESUMO: A síndrome de Austrian é uma entidade extremamente rara, pautada por meningite, endocardite e pneumonia secundárias a doença pneumocócica invasiva. Devido à expressão multissistêmica, a mortalidade associada é elevada. Particularmente, a manifestação como endocardite é muitas vezes clinicamente insuspeita, carecendo de elevado índice de suspeita. Apresenta-se um caso de síndrome de Austrian numa doente do sexo feminino, 67 anos, previamente saudável. Clinicamente, apresentava coma, insuficiência respiratória e choque, tendo sido diagnosticada pneumonia e meningite, e com bacteremia a Streptococcus pneumoniae. Ecocardiograma transesofágico evidenciou uma vegetação na válvula mitral. Apesar da regressão do quadro respiratório, persistiu um quadro de coma, acabando a doente por morrer. Apesar da principal causa de morte descrita na síndrome de Austrian estar relacionada com complicações de endocardite, apresenta-se um caso único de apresentação e morte por meningite. Com poucos casos descritos mundialmente, sublinha-se a necessidade de um diagnóstico precoce desta tríade, motivo pelo qual relatamos o caso descrito

Major CD4 T-Cell Depletion and Immune Senescence in a Patient with Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) results from primary defects in phagocytic reactive oxygen species (ROS) production. T-cell evaluation is usually neglected during patients' follow-up, although T-cell depletion has been reported in CGD through unknown mechanisms. We describe here a 36-year-old patient with X-linked CGD with severe CD4 T-cell depletion <200 CD4 T-cells/µl, providing insights into the mechanisms that underlie T-cell loss in the context of oxidative burst defects. In addition to the typical infections, the patient featured a progressive T-cell loss associated with persistent lymphocyte activation, expansion of interleukin (IL)-17-producing CD4 T-cells, and impaired thymic activity, leading to a reduced replenishment of the T-cell pool. A relative CD4 depletion was also found at the gut mucosal level, although no bias to IL-17-production was documented. This immunological pattern of exhaustion of immune resources favors prompt, potentially curative, therapeutic interventions in CGD patients, namely, stem-cell transplantation or gene therapy. Moreover, this clinical case raises new research questions on the interplay of ROS production and T-cell homeostasis and immune senescence.

Human naïve regulatory T-cells feature high steady-state turnover and are maintained by IL-7.

Naïve FoxP3-expressing regulatory T-cells (Tregs) are essential to control immune responses via continuous replenishment of the activated-Treg pool with thymus-committed suppressor cells. The mechanisms underlying naïve-Treg maintenance throughout life in face of the age-associated thymic involution remain unclear. We found that in adults thymectomized early in infancy the naïve-Treg pool is remarkably well preserved, in contrast to conventional naïve CD4 T-cells. Naïve-Tregs featured high levels of cycling and pro-survival markers, even in healthy individuals, and contrasted with other circulating naïve/memory CD4 T-cell subsets in terms of their strong γc-cytokine-dependent signaling, particularly in response to IL-7. Accordingly, ex-vivo stimulation of naïve-Tregs with IL-7 induced robust cytokine-dependent signaling, Bcl-2 expression, and phosphatidylinositol 3-kinase (PI3K)-dependent proliferation, whilst preserving naïve phenotype and suppressive capacity. Altogether, our data strongly implicate IL-7 in the thymus-independent long-term survival of functional naïve-Tregs, and highlight the potential of targeting the IL-7 pathway to modulate Tregs in different clinical settings.

Enteric mucosa integrity in the presence of a preserved innate interleukin 22 compartment in HIV type 1-treated individuals.

BACKGROUND: Interleukin 22 (IL-22) is emerging as a key cytokine for gut epithelial homeostasis and mucosal repair. Gut disruption is a hallmark of human immunodeficiency virus (HIV) infection. Here, we investigated IL-22 production and gut mucosal integrity in HIV type 1 (HIV-1)-infected individuals receiving long-term antiretroviral therapy (ART). METHODS: Biopsy specimens from 37 individuals who underwent colonoscopy primarily for cancer screening and from 17 HIV-1-infected and 20 healthy age-matched controls were assessed. RESULTS: We found significant depletion of sigmoid IL-22-producing CD4(+) T cells (T-helper type 22 [Th22] cells) even after prolonged ART, contrasting with the apparently normal compartments of regulatory and interleukin 17 (IL-17)-producing CD4(+) T cells, as well as total mucosal CD4(+) T cells. Despite the preferential Th22 cell depletion, IL-22 production by innate lymphoid cells (ILCs) was similar to that observed in HIV-1-seronegative subjects, and transcription of genes encoding molecules relevant for IL-22 production (ie, AHR, IL23, IL23R, IL1B, IL6, and TGFB1) was preserved. Remarkably, levels of transcripts of IL-22-target genes (ie, REG3G, DEFB4A, S100A9, MUC1, and MUC13) were unaltered, suggesting an adequate production of antimicrobial peptides and mucins. In agreement, enteric epithelial architecture was fully preserved. CONCLUSIONS: Despite the reduced Th22 cell subset, innate IL-22-mediated mechanisms, essential for sigmoid mucosa integrity, were fully operational in long-term-treated HIV-1-infected individuals. Our data highlight IL-22 production by ILCs as an important target for therapies aimed at facilitating human mucosal reconstitution.

Types of clinical studies. II. Cohort studies.

Cohort studies include groups of patients that are followed over time to determine the incidence or natural history of a disease, together with the risk factors for specific outcomes. These studies can be used to determine disease characteristics as well as the causal relationship between exposure and disease. They are, however, very expensive, because they need large patient samples. Cohort studies can be classified as prospective (the investigator defines the sample and measures predictive variables before outcomes arise) or retrospective (the investigator defines the sample and measures predictive variables after outcomes arise). Cohort studies are susceptible to various types of bias (systematic errors) that must be eliminated in order to ensure the validity of the results. To increase the validity of cohort studies the investigator has to consider exposure, outcome, sample selection and the statistical analysis (risk ratios and/or differences, absolute and relative risks, etc.).

Studies of harm. Clinical applications.

When a clinician institutes a therapy, he/she has to consider, besides its efficacy, the harm a substance that is foreign to the body may cause. Nowadays, with the number of drugs available, more and more iatrogenic events are occurring, to the extent that the term 'iatroepidemic' has been coined to describe the phenomenon. Harm can be assessed by experimental studies, but this design raises ethical as well as financial issues, so the best evidence is gathered from observational data, mainly case-control and cohort studies. In previous articles we discussed the methodology to evaluate therapeutic benefit. In this article we aim to review designs for determining harm.