Translocated microbiome composition determines immunological outcome in treated HIV infection.

The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.

CXCR5(+) follicular cytotoxic T cells control viral infection in B cell follicles.

During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell-derived malignancies.

Safety and Virologic Impact of Haploidentical NK Cells Plus Interleukin 2 or N-803 in HIV Infection.

BACKGROUND: Natural killer (NK) cells are dysfunctional in chronic human immunodeficiency virus (HIV) infection as they are not able to clear virus. We hypothesized that an infusion of NK cells, supported by interleukin 2 (IL-2) or IL-15, could decrease virus-producing cells in the lymphatic tissues. METHODS: We conducted a phase 1 pilot study in 6 persons with HIV (PWH), where a single infusion of haploidentical related donor NK cells was given plus either IL-2 or N-803 (an IL-15 superagonist). RESULTS: The approach was well tolerated with no unexpected adverse events. We did not pretreat recipients with cyclophosphamide or fludarabine to "make immunologic space," reasoning that PWH on stable antiretroviral treatment remain T-cell depleted in lymphatic tissues. We found donor cells remained detectable in blood for up to 8 days (similar to what is seen in cancer pretreatment with lymphodepleting chemotherapy) and in the lymph nodes and rectum up to 28 days. There was a moderate decrease in the frequency of viral RNA-positive cells in lymph nodes. CONCLUSIONS: There was a moderate decrease in HIV-producing cells in lymph nodes. Further studies are warranted to determine the impact of healthy NK cells on HIV reservoirs and if restoring NK-cell function could be part of an HIV cure strategy. Clinical Trials Registration. NCT03346499 and NCT03899480.

Understanding the renin-angiotensin-aldosterone-SARS-CoV axis: a comprehensive review.

IMPORTANCE: Coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic with significant morbidity and mortality since first appearing in Wuhan, China, in late 2019. As many countries are grappling with the onset of their epidemics, pharmacotherapeutics remain lacking. The window of opportunity to mitigate downstream morbidity and mortality is narrow but remains open. The renin-angiotensin-aldosterone system (RAAS) is crucial to the homeostasis of both the cardiovascular and respiratory systems. Importantly, SARS-CoV-2 utilises and interrupts this pathway directly, which could be described as the renin-angiotensin-aldosterone-SARS-CoV (RAAS-SCoV) axis. There exists significant controversy and confusion surrounding how anti-hypertensive agents might function along this pathway. This review explores the current state of knowledge regarding the RAAS-SCoV axis (informed by prior studies of SARS-CoV), how this relates to our currently evolving pandemic, and how these insights might guide our next steps in an evidence-based manner. OBSERVATIONS: This review discusses the role of the RAAS-SCoV axis in acute lung injury and the effects, risks and benefits of pharmacological modification of this axis. There may be an opportunity to leverage the different aspects of RAAS inhibitors to mitigate indirect viral-induced lung injury. Concerns have been raised that such modulation might exacerbate the disease. While relevant preclinical, experimental models to date favour a protective effect of RAAS-SCoV axis inhibition on both lung injury and survival, clinical data related to the role of RAAS modulation in the setting of SARS-CoV-2 remain limited. CONCLUSION: Proposed interventions for SARS-CoV-2 predominantly focus on viral microbiology and aim to inhibit viral cellular injury. While these therapies are promising, immediate use may not be feasible, and the time window of their efficacy remains a major unanswered question. An alternative approach is the modulation of the specific downstream pathophysiological effects caused by the virus that lead to morbidity and mortality. We propose a preponderance of evidence that supports clinical equipoise regarding the efficacy of RAAS-based interventions, and the imminent need for a multisite randomised controlled clinical trial to evaluate the inhibition of the RAAS-SCoV axis on acute lung injury in COVID-19.

National Trends and Variation of Functional Status Deterioration in the Medically Critically Ill.

OBJECTIVES: Physical and psychologic deficits after an ICU admission are associated with lower quality of life, higher mortality, and resource utilization. This study aimed to examine the prevalence and secular changes of functional status deterioration during hospitalization among nonsurgical critical illness survivors over the past decade. DESIGN: We performed a retrospective longitudinal cohort analysis. SETTING: Analysis performed using the Cerner Acute Physiology and Chronic Health Evaluation outcomes database which included manually abstracted data from 236 U.S. hospitals from 2008 to 2016. PATIENTS: We included nonsurgical adult ICU patients who survived their hospitalization and had a functional status documented at ICU admission and hospital discharge. Physical functional status was categorized as fully independent, partially dependent, or fully dependent. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Functional status deterioration occurred in 38,116 patients (29.3%). During the past decade, functional status deterioration increased in each disease category, as well as overall (prevalence rate ratio, 1.15; 95% CI, 1.13-1.17; p < 0.001). Magnitude of functional status deterioration also increased over time (odds ratio, 1.03; 95% CI, 1.03-1.03; p < 0.001) with hematological, sepsis, neurologic, and pulmonary disease categories having the highest odds of severe functional status deterioration. CONCLUSIONS: Following nonsurgical critical illness, the prevalence of functional status deterioration and magnitude increased in a nationally representative cohort, despite efforts to reduce ICU dysfunction over the past decade. Identifying the prevalence of functional status deterioration and primary etiologies associated with functional status deterioration will elucidate vital areas for further research and targeted interventions. Reducing ICU debilitation for key disease processes may improve ICU survivor mortality, enhance quality of life, and decrease healthcare utilization.

Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption.

Antiretroviral therapy (ART) suppresses HIV replication in most individuals but cannot eradicate latently infected cells established before ART was initiated. Thus, infection rebounds when treatment is interrupted by reactivation of virus production from this reservoir. Currently, one or a few latently infected resting memory CD4 T cells are thought be the principal source of recrudescent infection, but this estimate is based on peripheral blood rather than lymphoid tissues (LTs), the principal sites of virus production and persistence before initiating ART. We, therefore, examined lymph node (LN) and gut-associated lymphoid tissue (GALT) biopsies from fully suppressed subjects, interrupted therapy, monitored plasma viral load (pVL), and repeated biopsies on 12 individuals as soon as pVL became detectable. Isolated HIV RNA-positive (vRNA+) cells were detected by in situ hybridization in LTs obtained before interruption in several patients. After interruption, multiple foci of vRNA+ cells were detected in 6 of 12 individuals as soon as pVL was measureable and in some subjects, in more than one anatomic site. Minimal estimates of the number of rebounding/founder (R/F) variants were determined by single-gene amplification and sequencing of viral RNA or DNA from peripheral blood mononuclear cells and plasma obtained at or just before viral recrudescence. Sequence analysis revealed a large number of R/F viruses representing recrudescent viremia from multiple sources. Together, these findings are consistent with the origins of recrudescent infection by reactivation from many latently infected cells at multiple sites. The inferred large pool of cells and sites to rekindle recrudescent infection highlights the challenges in eradicating HIV.

Burden of Surgical Conditions in Uganda: A Cross-sectional Nationwide Household Survey.

OBJECTIVE: To quantify the burden of surgical conditions in Uganda. BACKGROUND: Data on the burden of disease have long served as a cornerstone to health policymaking, planning, and resource allocation. Population-based data are the gold standard, but no data on surgical burden at a national scale exist; therefore, we adapted the Surgeons OverSeas Assessment of Surgical Need survey and conducted a nation-wide, cross-sectional survey of Uganda to quantify the burden of surgically treatable conditions. METHODS: The 2-stage cluster sample included 105 enumeration areas, representing 74 districts and Kampala Capital City Authority. Enumeration occurred from August 20 to September 12, 2014. In each enumeration area, 24 households were randomly selected; the head of the household provided details regarding any household deaths within the previous 12 months. Two household members were randomly selected for a head-to-toe verbal interview to determine existing untreated and treated surgical conditions. RESULTS: In 2315 households, we surveyed 4248 individuals: 461 (10.6%) reported 1 or more conditions requiring at least surgical consultation [95% confidence interval (CI) 8.9%-12.4%]. The most frequent barrier to surgical care was the lack of financial resources for the direct cost of care. Of the 153 household deaths recalled, 53 deaths (34.2%; 95% CI 22.1%-46.3%) were associated with surgically treatable signs/symptoms. Shortage of time was the most frequently cited reason (25.8%) among the 11.6% household deaths that should have, but did not, receive surgical care (95% CI 6.4%-16.8%). CONCLUSIONS: Unmet surgical need is prevalent in Uganda. There is an urgent need to expand the surgical care delivery system starting with the district-level hospitals. Routine surgical data collection at both the health facility and household level should be implemented.

Readiness of US General Surgery Residents for Independent Practice.

OBJECTIVE: This study evaluates the current state of the General Surgery (GS) residency training model by investigating resident operative performance and autonomy. BACKGROUND: The American Board of Surgery has designated 132 procedures as being "Core" to the practice of GS. GS residents are expected to be able to safely and independently perform those procedures by the time they graduate. There is growing concern that not all residents achieve that standard. Lack of operative autonomy may play a role. METHODS: Attendings in 14 General Surgery programs were trained to use a) the 5-level System for Improving and Measuring Procedural Learning (SIMPL) Performance scale to assess resident readiness for independent practice and b) the 4-level Zwisch scale to assess the level of guidance (ie, autonomy) they provided to residents during specific procedures. Ratings were collected immediately after cases that involved a categorical GS resident. Data were analyzed using descriptive statistics and supplemented with Bayesian ordinal model-based estimation. RESULTS: A total of 444 attending surgeons rated 536 categorical residents after 10,130 procedures. Performance: from the first to the last year of training, the proportion of Performance ratings for Core procedures (n = 6931) at "Practice Ready" or above increased from 12.3% to 77.1%. The predicted probability that a typical trainee would be rated as Competent after performing an average Core procedure on an average complexity patient during the last week of residency training is 90.5% (95% CI: 85.7%-94%). This falls to 84.6% for more complex patients and to less than 80% for more difficult Core procedures. Autonomy: for all procedures, the proportion of Zwisch ratings indicating meaningful autonomy ("Passive Help" or "Supervision Only") increased from 15.1% to 65.7% from the first to the last year of training. For the Core procedures performed by residents in their final 6 months of training (cholecystectomy, inguinal/femoral hernia repair, appendectomy, ventral hernia repair, and partial colectomy), the proportion of Zwisch ratings (n = 357) indicating near-independence ("Supervision Only") was 33.3%. CONCLUSIONS: US General Surgery residents are not universally ready to independently perform Core procedures by the time they complete residency training. Progressive resident autonomy is also limited. It is unknown if the amount of autonomy residents do achieve is sufficient to ensure readiness for the entire spectrum of independent practice.

Geospatial Analysis of Unmet Surgical Need in Uganda: An Analysis of SOSAS Survey Data.

BACKGROUND: Globally, a staggering five billion people lack access to adequate surgical care. Sub-Saharan Africa represents one of the regions of greatest need. We sought to understand how geographic factors related to unmet surgical need (USN) in Uganda. METHODS: We performed a geographic information system analysis of a nationwide survey on surgical conditions performed in 105 enumeration areas (EAs) representing the national population. At the district level, we determined the spatial autocorrelation of the following study variables: prevalence of USN, hub distance (distance from EA to the nearest surgical center), area of coverage (geographic catchment area of each center), tertiary facility transport time (average respondent-reported travel time), and care availability (rate of hospital beds by population and by district). We then used local indicators of spatial association (LISA) and spatial regression to identify any significant clustering of these study variables among the districts. RESULTS: The survey enumerated 4248 individuals. The prevalence of USN varied from 2.0-45 %. The USN prevalence was highest in the Northern and Western Regions. Moran's I bivariate analysis indicated a positive correlation between USN and hub distance (p = 0.03), area of coverage (p = 0.02), and facility transport time (p = 0.03). These associations were consistent nationally. The LISA analysis showed a high degree of clustering among sets of districts in the Northern Sub-Region. CONCLUSIONS: This study demonstrates a statistically significant association between USN and the geographic variables examined. We have identified the Northern Sub-Region as the highest priority areas for financial investment to reduce this unmet surgical disease burden.

Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues.

Antiretroviral therapy can reduce HIV-1 to undetectable levels in peripheral blood, but the effectiveness of treatment in suppressing replication in lymphoid tissue reservoirs has not been determined. Here we show in lymph node samples obtained before and during 6 mo of treatment that the tissue concentrations of five of the most frequently used antiretroviral drugs are much lower than in peripheral blood. These lower concentrations correlated with continued virus replication measured by the slower decay or increases in the follicular dendritic cell network pool of virions and with detection of viral RNA in productively infected cells. The evidence of persistent replication associated with apparently suboptimal drug concentrations argues for development and evaluation of novel therapeutic strategies that will fully suppress viral replication in lymphatic tissues. These strategies could avert the long-term clinical consequences of chronic immune activation driven directly or indirectly by low-level viral replication to thereby improve immune reconstitution.

Quantifying the pediatric surgical need in Uganda: results of a nationwide cross-sectional, household survey.

PURPOSE: Little is known about the prevalence of pediatric surgical conditions in low- and middle-income countries. Many children never seek medical care, thus the true prevalence of surgical conditions in children in Uganda is unknown. The objective of this study was to determine the prevalence of surgical conditions in children in Uganda. METHODS: Using the Surgeons OverSeas Assessment of Surgical Need (SOSAS) survey, we enumerated 4248 individuals in 2315 households in 105 randomly selected clusters throughout Uganda. Children aged 0-18 were included if randomly selected from the household; for those who could not answer for themselves, parents served as surrogates. RESULTS: Of 2176 children surveyed, 160 (7.4 %) reported a currently untreated surgical condition. Lifetime prevalence of surgical conditions was 14.0 % (305/2176). The predominant cause of surgical conditions was trauma (48.4 %), followed by wounds (19.7 %), acquired deformities (16.2 %), and burns (12.5 %). Of 90 pediatric household deaths, 31.1 % were associated with a surgically treatable proximate cause of death (28/90 deaths). CONCLUSION: Although some trauma-related surgical burden among children can be adequately addressed at district hospitals, the need for diagnostics, human resources, and curative services for more severe trauma cases, congenital deformities, and masses outweighs the current capacity of hospitals and trained pediatric surgeons in Uganda.

Surgeons OverSeas Assessment of Surgical Need (SOSAS) Uganda: Update for Household Survey.

INTRODUCTION: The first step in improving surgical care delivery in low- and middle-income countries (LMICs) is quantifying surgical need. The Surgeons OverSeas Assessment of Surgical Need (SOSAS) is a validated household survey that has been previously implemented in three LMICs with great success. We implemented the SOSAS survey in Uganda, a medium-sized country with comparatively more language and ethnic group diversity. METHODS: The investigators partnered with the Performance Monitoring and Accountability 2020 (PMA2020) Uganda to access a data collection platform sampling 2520 households in 105 randomly selected enumeration areas. Due to geographic size consideration and language diversity, SOSAS's methodology was updated in three significant dimensions (1) technology, (2) staff management, and (3) questionnaire adaptations. RESULTS: The SOSAS survey was successfully implemented with non-medically trained but field proven research assistants. We sampled 2315 of 2402 eligible households (response rate 96.4 %) and 4248 of 4374 eligible individual respondents (response rate 97.1 %). The female-to-male ratio was 51.1-48.9 %. Total survey cost was USD 73,145 and data collection occurred in 14 days. DISCUSSION: SOSAS Uganda has demonstrated that non-medically trained, but university-educated, experienced researchers supervised by academic surgeons can successfully perform accurate data collection of SOSAS. SOSAS can be successfully implemented within larger and more diverse LMICs using existing national survey platforms, and SOSAS Uganda provides insights on how SOSAS can be executed specifically within other PMA2020 program countries.

Lymphoid tissue damage in HIV-1 infection depletes naïve T cells and limits T cell reconstitution after antiretroviral therapy.

Highly active antiretroviral therapy (HAART) can suppress HIV-1 replication and normalize the chronic immune activation associated with infection, but restoration of naïve CD4+ T cell populations is slow and usually incomplete for reasons that have yet to be determined. We tested the hypothesis that damage to the lymphoid tissue (LT) fibroblastic reticular cell (FRC) network contributes to naïve T cell loss in HIV-1 infection by restricting access to critical factors required for T cell survival. We show that collagen deposition and progressive loss of the FRC network in LTs prior to treatment restrict both access to and a major source of the survival factor interleukin-7 (IL-7). As a consequence, apoptosis within naïve T cell populations increases significantly, resulting in progressive depletion of both naïve CD4+ and CD8+ T cell populations. We further show that the extent of loss of the FRC network and collagen deposition predict the extent of restoration of the naïve T cell population after 6 month of HAART, and that restoration of FRC networks correlates with the stage of disease at which the therapy is initiated. Because restoration of the FRC network and reconstitution of naïve T cell populations are only optimal when therapy is initiated in the early/acute stage of infection, our findings strongly suggest that HAART should be initiated as soon as possible. Moreover, our findings also point to the potential use of adjunctive anti-fibrotic therapies to avert or moderate the pathological consequences of LT fibrosis, thereby improving immune reconstitution.

Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution.

Loss of the fibroblastic reticular cell (FRC) network in lymphoid tissues during HIV-1 infection has been shown to impair the survival of naive T cells and limit immune reconstitution after antiretroviral therapy. What causes this FRC loss is unknown. Because FRC loss correlates with loss of both naive CD4 and CD8 T-cell subsets and decreased lymphotoxin-ß, a key factor for maintenance of FRC network, we hypothesized that loss of naive T cells is responsible for loss of the FRC network. To test this hypothesis, we assessed the consequences of antibody-mediated depletion of CD4 and CD8 T cells in rhesus macaques and sooty mangabeys. We found that only CD4 T-cell depletion resulted in FRC loss in both species and that this loss was caused by decreased lymphotoxin-ß mainly produced by the CD4 T cells. We further found the same dependence of the FRC network on CD4 T cells in HIV-1-infected patients before and after antiretroviral therapy and in other immunodeficiency conditions, such as CD4 depletion in cancer patients induced by chemotherapy and irradiation. CD4 T cells thus play a central role in the maintenance of lymphoid tissue structure necessary for their own homeostasis and reconstitution.

The association between ASA status and other risk stratification models on postoperative intensive care unit outcomes.

BACKGROUND: There is limited medical literature investigating the association between perioperative risk stratification methods and surgical intensive care unit (SICU) outcomes. Our hypothesis contends that routine assessments such as higher ASA physical status classification, surgical risk as defined by American College of Cardiology/American Heart Association guidelines, and simplified Revised Cardiac Index (SRCI) can reliably be associated with SICU outcomes. METHODS: We performed a chart review of all patients 18 years or older admitted to the SICU between October 1, 2010, and March 1, 2011. We collected demographic and preoperative clinical data: age, sex, ASA physical status class, surgical risk, and SRCI. Outcome data included our primary end point, SICU length of stay, and secondary end points: mechanical ventilation and vasopressor treatment duration, number of acquired organ dysfunctions (NOD), readmission to the intensive care unit (ICU) within 7 days, SICU mortality, and 30-day mortality. Regression analysis and nonparametric tests were used, and P < 0.05 was considered significant. RESULTS: We screened 239 patients and included 220 patients in the study. The patients' mean age was 58 ± 16 years. There were 32% emergent surgery and 5% readmissions to the SICU within 7 days. The SICU mortality and the 30-day mortality were 3.2%. There was a significant difference between SICU length of stay (2.9 ± 2.1 vs 5.9 ± 7.4, P = 0.007), mechanical ventilation (0.9 ± 2.0 vs 3.4 ± 6.8, P = 0.01), and NOD (0 [0-2] vs 1 [0-5], P < 0.001) based on ASA physical status class (≤ 2 vs ≥ 3). Outcomes significantly associated with ASA physical status class after adjusting for confounders were: SICU length of stay (incidence rate ratio [IRR] = 1.79, 95% confidence interval [CI], 1.35-2.39, P < 0.001), mechanical ventilation (IRR = 2.57, 95% CI, 1.69-3.92, P < 0.001), vasopressor treatment (IRR = 3.57, 95% CI, 1.84-6. 94, P < 0.001), NOD (IRR = 1.71, 95% CI, 1.46-1.99, P < 0.001), and readmission to ICU (odds ratio = 3.39, 95% CI, 1.04-11.09, P = 0.04). We found significant association between surgery risk and NOD (IRR = 1.56, 95% CI, 1.29-1.89, P < 0.001, and adjusted IRR = 1.31, 95% CI, 1.05-1.64, P = 0.02). SRCI was not significantly associated with SICU outcomes. CONCLUSIONS: Our study revealed that ASA physical status class is associated with increased SICU length of stay, mechanical ventilation, vasopressor treatment duration, NOD, readmission to ICU, and surgery risk is associated with NOD.

Acute Appendicitis Treatment Strategies and Mortality Based on Critical Illness on Admission: An Observational Study.

Background: Trials have shown non-inferiority of non-operative management (NOM) for appendicitis, although critically ill patients have been often excluded. The purpose of this study is to evaluate surgical versus NOM outcomes in critically ill patients with appendicitis by measuring mortality and hospital length of stay (LOS). Patients and Methods: The Healthcare Cost and Utilization Project's (HCUP) Database was utilized to analyze data from 10 states between 2008 and 2015. All patients with acute appendicitis by International Classification of Diseases, Ninth Revision (ICD-9) codes over the age of 18 were included. Negative binomial and logistic regression were used to determine the association of acute renal failure (ARF), cardiovascular failure (CVF), pulmonary failure (PF), and sepsis by treatment strategy (laparoscopic, open, both, or no surgery) on mortality and hospital LOS. Results: Among 464,123 patients, 67.5%, 23.3%, 8.2%, and 0.8% underwent laparoscopic, open, NOM, or both laparoscopic and open surgery, respectively. Patients who underwent surgery had 58% lower odds of mortality and 34% shorter hospital LOS compared with NOM patients. Patients with ARF, CVF, PF, and sepsis had 102%, 383%, 475%, and 666% higher odds of mortality and a 47%, 46%, 71%, and 163% longer hospital LOS, respectively, compared with patients without these diagnoses on admission. Conclusions: Critical illness on admission increases mortality and hospital LOS. Patients who underwent laparoscopic, and to a lesser extent, open appendectomy had improved mortality compared with those who did not undergo surgery regardless of critical illness status.

Comparison of Outcomes and Process of Care for Patients Treated at Hospitals Dedicated for COVID-19 Care vs Other Hospitals.

Importance: Early in the SARS-CoV-2 pandemic, the M Health Fairview Hospital System established dedicated hospitals for establishing cohorts and caring for patients with COVID-19, yet the association between treatment at COVID-19-dedicated hospitals and mortality and complications is not known. Objective: To analyze the mortality rate and complications associated with treatment at the COVID-19-dedicated hospitals. Design, Setting, and Participants: This retrospective cohort study evaluated data prospectively collected from March 1, 2020, through June 30, 2021, from 11 hospitals in Minnesota, including 2 hospitals created solely to care for patients with COVID-19. Data obtained included demographic characteristics, treatments, and outcomes of interest for all patients with a confirmed COVID-19 infection admitted to this hospital system during the study period. Exposures: Patients were grouped based on whether they received treatment from 1 of the 2 COVID-19-dedicated hospitals compared with the remainder of the hospitals within the hospital system. Main Outcomes and Measures: Multivariate analyses, including risk-adjusted logistic regression and propensity score matching, were performed to evaluate the primary outcome of in-hospital mortality and secondary outcomes, including complications and use of COVID-specific therapeutics. Results: There were 5504 patients with COVID-19 admitted during the study period (median age, 62.5 [IQR, 45.0-75.6] years; 2854 women [51.9%]). Of these, 2077 patients (37.7%) (median age, 63.4 [IQR, 50.7-76.1] years; 1080 men [52.0%]) were treated at 1 of the 2 COVID-19-dedicated hospitals compared with 3427 (62.3%; median age, 62.0 [40.0-75.1] years; 1857 women (54.2%) treated at other hospitals. The mortality rate was 11.6% (n = 241) at the dedicated hospitals compared with 8.0% (n = 274) at the other hospitals (P < .001). However, risk-adjusted in-hospital mortality was significantly lower for patients in the COVID-19-dedicated hospitals in both the unmatched group (n = 2077; odds ratio [OR], 0.75; 95% CI, 0.59-0.95) and the propensity score-matched group (n = 1317; OR, 0.78; 95% CI, 0.58-0.99). The rate of overall complications in the propensity score-matched group was significantly lower (OR, 0.81; 95% CI, 0.66-0.99) and the use of COVID-19-specific therapeutics including deep vein thrombosis prophylaxis (83.9% vs 56.9%; P < .001), high-dose corticosteroids (56.1% vs 22.2%; P < .001), remdesivir (61.5% vs 44.5%; P < .001), and tocilizumab (7.9% vs 2.0; P < .001) was significantly higher. Conclusions and Relevance: In this cohort study, COVID-19-dedicated hospitals had multiple benefits, including providing high-volume repetitive treatment and isolating patients with the infection. This experience suggests improved in-hospital mortality for patients treated at dedicated hospitals owing to improved processes of care and supports the use of establishing cohorts for future pandemics.

Factors Associated with Mortality in Patients with COVID-19 Receiving Prolonged Ventilatory Support.

Background: Since its emergence in early 2020, coronavirus disease 2019 (COVID-19)-associated pneumonia has caused a global strain on intensive care unit (ICU) resources with many intubated patients requiring prolonged ventilatory support. Outcomes for patients with COVID-19 who receive prolonged intubation (>21 days) and possible predictors of mortality in this group are not well established. Patients and Methods: Data were prospectively collected from adult patients with COVID-19 requiring mechanical ventilation from March 2020 through December 2021 across a system of 11 hospitals. The primary end point was in-hospital mortality. Factors associated with mortality were evaluated using univariable and multivariable logistic regression analyses. Results: Six hundred six patients were placed on mechanical ventilation for COVID-19 pneumonia during the study period, with in-hospital mortality of 40.3% (n = 244). Increased age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.03-1.09), increased creatinine (OR, 1.40; 95% CI, 1.08-1.82), and receiving corticosteroids (OR, 2.68; 95% CI, 1.20-5.98) were associated with mortality. Intubations lasting longer than 21 days (n = 140) had a lower in-hospital mortality of 25.7% (n = 36; p < 0.001). Increasing Elixhauser comorbidity index (OR, 1.12; 95% CI, 1.04-1.19) and receiving corticosteroids (OR, 1.92; 95% CI, 1.06-3.47) were associated with need for prolonged ventilation. In this group, increased age (OR, 1.06; 95% CI, 1.01-1.08) and non-English speaking (OR, 3.74; 95% CI, 1.13-12.3) were associated with mortality. Conclusions: In-hospital mortality in mechanically ventilated patients with COVID-19 pneumonia occurs primarily in the first 21 days after intubation, possibly related to the early active inflammatory process. In patients on prolonged mechanical ventilation, increased age and being non-English speaking were associated with mortality.