Organ-specific immunity: A tissue analysis framework for investigating local immune responses to SARS-CoV-2.

Local immune activation at mucosal surfaces, mediated by mucosal lymphoid tissues, is vital for effective immune responses against pathogens. While pathogens like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can spread to multiple organs, patients with coronavirus disease 2019 (COVID-19) primarily experience inflammation and damage in their lungs. To investigate this apparent organ-specific immune response, we develop an analytical framework that recognizes the significance of mucosal lymphoid tissues. This framework combines histology, immunofluorescence, spatial transcript profiling, and mathematical modeling to identify cellular and gene expression differences between the lymphoid tissues of the lung and the gut and predict the determinants of those differences. Our findings indicate that mucosal lymphoid tissues are pivotal in organ-specific immune response to SARS-CoV-2, mediating local inflammation and tissue damage and contributing to immune dysfunction. The framework developed here has potential utility in the study of long COVID and may streamline biomarker discovery and treatment design for diseases with differential pathologies at the organ level.

Standard Venipuncture vs a Capillary Blood Collection Device for the Prospective Determination of Abnormal Liver Chemistry.

BACKGROUND: Abnormal liver function is a common manifestation of human disease and may also occur in approved and investigational medications as drug-induced liver injury (DILI). Capillary blood collection devices may allow for more frequent and convenient measurement outside of the clinic. Validation of such approaches is lacking. METHODS: This prospective, biospecimens collection study evaluated the Tasso+ in patients with abnormal liver tests (NCT05259618). The primary objective was to define the concordance of alanine aminotransferase (ALT) obtained via Tasso+ compared to standard venipuncture. Secondary objectives included measurement of 14 other analytes and patient surveys. At the time of venipuncture, 2 Tasso+ samples were collected: one was centrifuged and shipped, and the other was refrigerated and shipped as whole blood. RESULTS: Thirty-six patients with elevated ALT values were enrolled. In total, 100 venipuncture, 50 Tasso+ centrifuged, and 48 Tasso+ whole blood samples were obtained. Tasso+ centrifuged samples demonstrated concordance correlation coefficients (CCC) of >0.99 for ALT, alkaline phosphatase (ALP), aspartate aminotransferase (AST), and total bilirubin and CCC >0.95 for albumin, chloride, enzymatic creatinine, serum glucose, magnesium, and phosphorus. Tasso+ whole blood showed CCC of >0.99 for AST, bilirubin total, and enzymatic creatinine and CCC >0.95 for ALT, ALP, albumin, magnesium, and phosphorus. Hemolysis was comparable across the 3 sample types, but its impact was reflected in the Tasso+ potassium data. Patient feedback indicated a very favorable patient experience. CONCLUSIONS: The capillary blood collection device, Tasso+, showed substantial to almost perfect concordance to standard venipuncture for measurement of abnormal liver function. Studies are ongoing to validate longitudinal sampling outside of the clinic. Clinicaltrials.gov Registration Number: NCT05259618.

Temporal Improvements in COVID-19 Outcomes for Hospitalized Adults: A Post Hoc Observational Study of Remdesivir Group Participants in the Adaptive COVID-19 Treatment Trial.

BACKGROUND: The COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear. OBJECTIVE: To evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial). DESIGN: ACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4]). SETTING: 94 hospitals in 10 countries (86% U.S. participants). PARTICIPANTS: Adults hospitalized with COVID-19. INTERVENTION: SOC. MEASUREMENTS: 28-day mortality and recovery. RESULTS: Although outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages. LIMITATION: Unmeasured confounding. CONCLUSION: Changes in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.

Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. METHODS: We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 µg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475. FINDINGS: Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. INTERPRETATION: Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. FUNDING: The National Institute of Allergy and Infectious Diseases (USA).

Remdesivir for the Treatment of Covid-19 - Final Report.

BACKGROUND: Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. RESULTS: A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%). CONCLUSIONS: Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.).

The forest for the trees: tuberculosis control efforts in west Kalimantan.

Alam Sehat Lestari (ASRI), an Indonesian-American, non-profit organization located on the border of Gunung Palung National Park in west Kalimantan on the island of Borneo, is linking the delivery of health care to the conservation of natural resources. The clinic's experience shows that an unconventional 'forests-for-health care' incentive programme can provide a powerful way to break the cycle that links poverty, poor health and environmental destruction around the park. However, the challenges of preventing, diagnosing and treating tuberculosis in this setting remain considerable and success will still depend upon a multilateral collaborative approach.

Predictors of CD4+ cell count response and of adverse outcome among HIV-infected patients receiving highly active antiretroviral therapy in a public hospital in Peru.

OBJECTIVES: Our aim was to investigate CD4+ cell recovery and adverse outcome after highly active antiretroviral therapy (HAART) under the Peruvian National Program for HIV. METHODS: A prospective, observational study was conducted between May 2004 and September 2005. Data were collected from records of patients receiving HAART at a public hospital under the Peruvian National Program for HIV. Predictors of CD4+ cell count recovery and adverse outcome were analyzed by multiple regression. RESULTS: Three hundred and twenty-six patients were included in the study. The mean increase in CD4+ cell count at six months was 114 cells/microl (95% confidence interval: 103-126). Patients with a lower CD4+ cell count at baseline and those starting HAART with a didanosine-based regimen had a higher increase in CD4+ cell count at six months. Patients starting HAART with a stavudine-based regimen had a lower increase in CD4+ cell count at six months. World Health Organization clinical stage IV at diagnosis of HIV infection, a low body weight at baseline, and starting HAART with a stavudine-based regimen were independently associated with an adverse outcome. CONCLUSIONS: The CD4+ cell response to HAART under Peruvian National Program for HIV was comparable with reports from other countries. However, the fact that advanced clinical disease predicted adverse outcome emphasizes the need for earlier access to HAART.

Foxp3+ regulatory T cells in antiretroviral-naive HIV patients.

We characterized regulatory T cells from antiretroviral-naive HIV patients by flow cytometry. The proportion of CD4 cells positive for CD25 and Foxp3 was increased, mainly in those with CD4 cell counts less than 200 cells/microl. The total number of Foxp3-positive cells correlated with the CD4 cell count. Further studies are needed on whether Foxp3-positive cell numbers or function explain the susceptibility to autoimmune and inflammatory diseases seen in some patients with advanced HIV.

[Intestinal parasitosis in patients with HIV-AIDS]. / Parasitosis intestinal en el paciente con infección VIH-SIDA.

INTRODUCTION: Diarrhea, a common complication and one of the most important causes of malabsorption and malnutrition in AIDS patients. Our objective was to determine the parasitic causes of diarrhea in patients with HIV-AIDS at the Cayetano Heredia National Hospital (Lima, Peru). METHODS: We included 217 HIV-AIDS patients who reported diarrhea between May 2002 and September 2005. We analyzed 1-3 stool samples per patient using six methods to detect oocysts, cysts, eggs and larvae of parasites. RESULTS: The average patients age was 34.5 years (range 15-68); 75.12% were males. Patients with diarrhea during two weeks or more were 149/217 (68.66%). A total of 123 parasites were detected in 103/217 patients (47.5%) 18/217 (8.3%) had mixed parasitic infections. Cryptosporidium spp. was the most frequent parasite detected. It was more prevalent in the group of patients who had diarrhea for two or more weeks than those who had diarrhea for less than two weeks (22.82% vs. 10.29%, p=0.029). Other frequent parasitosis cases were isosporidiasis (10.6%), giardiasis (8.3%) and strongyloidiasis (6.9%). CONCLUSION: Intestinal parasitosis is frequent in HIV-AIDS patients at the Cayetano Heredia National Hospital. The most common opportunistic pathogens were Criptosporidium spp. and Isospora belli and the most frequent non-opportunistic pathogens were Giardia lamblia and Strongyloidiasis stercoralis.

Parasitosis intestinal en el paciente con infección VIH-SIDA / Intestinal diseases parasitic in patients with HIV-AIDS

Introducción: La diarrea es una complicación común y una de las principales causas de malabsorción y desnutrición entre los paciente con SIDA. Nuestro objetivo es determinar las causas parasitarias de diarrea en pacientes con VIH-SIDA del Hospital Nacional Cayetano Heredia (Lima, Perú). MÉTODOS: Fueron incluidos 217 pacientes con VIH-SIDA que reportaron diarrea entre Mayo-2002 y Septiembre-2005. Fueron analizadas 1-3 muestras de heces mediante seis métodos para la detección de ooquistes, quistes, huevos y larvas de parásitos. RESULTADOS: La edad promedio fue 34.5 años (rango 15-68 años), 75.12 por ciento eran hombres. De ellos, 149/217 (68.66 por ciento) presentaron diarrea durante dos o más semanas. Se detectaron 123 parásitos en 103/217 pacientes (47.5 por ciento), presentando 18 de ellos(8.3 por ciento) infecciones parasitarias mixtas. Cryptosporidium spp. fue detectado con más frecuencia, sin embargo fue más prevalente en el grupo que presentaba dos o más semanas de diarrea, siendo esta diferencia estadísticamente significativa (22.82 por ciento vs. 10.29 por ciento, p=0.029). Otras parasitosis frecuentes fueron isosporidiasis (10.6 por ciento), giardiasis (8.3 por ciento) y strongyloidiasis (6.9 por ciento. CONCLUSIÓN: La enteroparasitosis es una condición frecuente entre los pacientes con VIH SIDA que acuden al Hospital Nacional Cayetano Heredia, siendo frecuente la presencia de agentes oportunistas (Cryptosporidium spp. e Isospora belli) y no oportunistas (Giardia lamblia y Strongyloides stercoralis).

Introduction: Diarrhea,a common complication and one of the most important causes of malabsorption and malnutrition in AIDS patients. Our objective was to determine the parasitic causes of diarrhea in patients with HIV-AIDSat the Cayetano Heredia National Hospital (Lima, Perú). METHODS:We included 217 HIV-AIDS patients who reported diarrhea between May 2002 and September 2005. We analyzed 1-3 stool samples per patient using six methods to detect oocysts, cysts, eggs and larvae of parasites. RESULTS: The average patients' age was 34.5 years (range 15-68); 75.12 percent were males. Patients with diarrhea during two weeks or more were149/217(68.66 percent).A total of 123 parasites were detected in 103/217 patients (47.5 percent) 18/217 (8.3 percent) had mixed parasitic infections. Cryptosporidium spp. was the most frequent parasite detected. It was more prevalent in the group of patients who had diarrhea for two or more weeksthan those who had diarrhea for less than two weeks (22.82 percent vs. 10.29 percent, p=0.029). Other frequent parasitosis cases were isosporidiasis (10.6 percent), giardiasis (8.3 percent) and strongyloidiasis (6.9 percent). CONCLUSION:Intestinal parasitosis is frequent in HIV-AIDS patients at the Cayetano Heredia National Hospital. The most common opportunistic pathogens were Criptosporidium spp. and Isospora belli and the most frequent non-opportunisticpathogens were Giardia lamblia and Strongyloidiasis stercoralis.