Microbiome in the nasopharynx: Insights into the impact of COVID-19 severity.

Background: The respiratory tract harbors a variety of microbiota, whose composition and abundance depend on specific site factors, interaction with external factors, and disease. The aim of this study was to investigate the relationship between COVID-19 severity and the nasopharyngeal microbiome. Methods: We conducted a prospective cohort study in Mexico City, collecting nasopharyngeal swabs from 30 COVID-19 patients and 14 healthy volunteers. Microbiome profiling was performed using 16S rRNA gene analysis. Taxonomic assignment, classification, diversity analysis, core microbiome analysis, and statistical analysis were conducted using R packages. Results: The microbiome data analysis revealed taxonomic shifts within the nasopharyngeal microbiome in severe COVID-19. Particularly, we observed a significant reduction in the relative abundance of Lawsonella and Cutibacterium genera in critically ill COVID-19 patients (p < 0.001). In contrast, these patients exhibited a marked enrichment of Streptococcus, Actinomyces, Peptostreptococcus, Atopobium, Granulicatella, Mogibacterium, Veillonella, Prevotella_7, Rothia, Gemella, Alloprevotella, and Solobacterium genera (p < 0.01). Analysis of the core microbiome across all samples consistently identified the presence of Staphylococcus, Corynebacterium, and Streptococcus. Conclusions: Our study suggests that the disruption of physicochemical conditions and barriers resulting from inflammatory processes and the intubation procedure in critically ill COVID-19 patients may facilitate the colonization and invasion of the nasopharynx by oral microorganisms.

Changes in pulmonary mechanics from supine to prone position measured through esophageal manometry in critically ill patients with COVID-19 severe acute respiratory distress syndrome.

OBJECTIVE: To describe changes in pulmonary mechanics when changing from supine position (SP) to prone position (PP) in mechanically ventilated (MV) patients with Acute Respiratory Distress Syndrome (ARDS) due to severe COVID-19. DESIGN: Retrospective cohort. SETTING: Intensive Care Unit of the National Institute of Respiratory Diseases (Mexico City). PATIENTS: COVID-19 patients on MV due to ARDS, with criteria for PP. INTERVENTION: Measurement of pulmonary mechanics in patients on SP to PP, using esophageal manometry. MAIN VARIABLES OF INTEREST: Changes in lung and thoracic wall mechanics in SP and PP RESULTS: Nineteen patients were included. Changes during first prone positioning were reported. Reductions in lung stress (10.6 vs 7.7, p=0.02), lung strain (0.74 vs 0.57, p=0.02), lung elastance (p=0.01), chest wall elastance (p=0.003) and relation of respiratory system elastances (p=0.001) were observed between patients when changing from SP to PP. No differences were observed in driving pressure (p=0.19) and transpulmonary pressure during inspiration (p=0.70). CONCLUSIONS: Changes in pulmonary mechanics were observed when patients were comparing values of supine position with measurements obtained 24h after prone positioning. Esophageal pressure monitoring may facilitate ventilator management despite patient positioning.

Feeding intolerance during prolonged prone position in overweight and obese patients with severe COVID-19 / Intolerancia a la alimentación durante el prono prolongado en pacientes con COVID-19 y sobrepeso y obesidad

Objective: the aim of this study was to compare the incidence rate of feeding intolerance (FI) during supine (SP) or prone positioning (PP) in critically ill COVID-19 patients. Methods: this was a retrospective cohort study of critically ill patients with overweight or obesity who received enteral nutrition (EN) in prone or supine positioning continuously during the first five days of mechanical ventilation. Nutritional risk, anthropometric measurements and body composition were assessed at the first 24 hours upon Intensive Care Unit (ICU) admission. Biochemical and clinical variables (Sequential Organ Failure Assessment [SOFA], Acute Physiology and Chronic Health Evaluation II [APACHE II], Acute Kidney Injury [AKI] or comorbidities diagnosis) were collected. Pharmacotherapy (prokinetics, sedatives or neuromuscular blocking agents) and FI incidence (gastric residual volume [GRV] ≥ 200 ml or ≥ 500 ml, vomiting or diarrhea) were daily recorded. Constipation was defined as the absence of evacuation for five consecutive days. Results: eighty-two patients were included. Higher rate of prophylactic prokinetic prescription was observed in PP (42.8 vs 12.5 %, p = 0.002). GRV ≥ 200 in supine position was not different when compared to PP (p = 0.47). Vomiting episodes in supine compared to PP showed no difference between groups (15 % vs 24 %, p = 0.31). No differences in diarrhea events were detected (10 % vs 4.7 %, p = 0.36). Constipation was common in both groups (95 % vs 82 %, p = 0.06). Conclusion: FI during prone position was not different in comparison to supine position. Routinely use of prokinetics in continuous prone position may help to prevent FI incidence. Algorithm development is necessary for FI prevention and treatment so to avoid EN interruptions and adverse clinical outcomes. (AU)

Objetivo: comparar la incidencia de intolerancia a la alimentación entre pacientes críticos en posición supino (PS) o prono (PP). Métodos: cohorte retrospectiva de pacientes bajo ventilación mecánica por distrés respiratorio por COVID-19 y sobrepeso y obesidad, quienes recibieron nutrición enteral (NE) en PP o PS. Se evaluaron riesgo nutricional, mediciones antropométricas y composición corporal en las primeras 24 horas de ingreso a la Unidad de Cuidados Intensivos (UCI). Se recolectaron variables bioquímicas y clínicas (Sequential Organ Failure Assessment [SOFA], Acute Physiology and Chronic Health Evaluation II [APACHE II], lesión renal aguda y otras comorbilidades). Se registró el esquema de farmacoterapia prescrita durante los primeros cinco días (procinéticos, sedantes y bloqueadores neuromusculares). Se evaluó la incidencia de intolerancia a la alimentación, definida como la presencia de residuo gástrico (RG) ≥ 200 o ≥ 500 ml, vómito, diarrea o estreñimiento. Resultados: fueron incluidos 82 pacientes. Se observó una mayor prescripción de procinéticos como terapia profiláctica en PP (42,8 vs. 12,5 %, p = 0,002). No se observaron diferencias en RG ≥ 200 ml (p = 0,47) ni vómito (p = 0,31) entre ambos grupos. No se observaron diferencias en episodios de diarrea (10 % en PS vs. 4,7 % en PP, p = 0,36). El estreñimiento fue común en ambos grupos de estudio (95 vs. 82 %, p = 0,06). Conclusiones: la PP no se relaciona con una mayor incidencia de intolerancias a la alimentación. El uso rutinario de procinéticos durante la PP continua puede ayudar a prevenir la incidencia de dichas intolerancias. Es necesario el desarrollo de algoritmos para la prevención y tratamiento de las intolerancias a la alimentación para evitar interrupciones en la NE y desenlaces no deseables. (AU)

Feeding intolerance during prolonged prone position in overweight and obese patients with severe COVID-19.

Introduction: Objective: the aim of this study was to compare the incidence rate of feeding intolerance (FI) during supine (SP) or prone positioning (PP) in critically ill COVID-19 patients. Methods: this was a retrospective cohort study of critically ill patients with overweight or obesity who received enteral nutrition (EN) in prone or supine positioning continuously during the first five days of mechanical ventilation. Nutritional risk, anthropometric measurements and body composition were assessed at the first 24 hours upon Intensive Care Unit (ICU) admission. Biochemical and clinical variables (Sequential Organ Failure Assessment [SOFA], Acute Physiology and Chronic Health Evaluation II [APACHE II], Acute Kidney Injury [AKI] or comorbidities diagnosis) were collected. Pharmacotherapy (prokinetics, sedatives or neuromuscular blocking agents) and FI incidence (gastric residual volume [GRV] ≥ 200 ml or ≥ 500 ml, vomiting or diarrhea) were daily recorded. Constipation was defined as the absence of evacuation for five consecutive days. Results: eighty-two patients were included. Higher rate of prophylactic prokinetic prescription was observed in PP (42.8 vs 12.5 %, p = 0.002). GRV ≥ 200 in supine position was not different when compared to PP (p = 0.47). Vomiting episodes in supine compared to PP showed no difference between groups (15 % vs 24 %, p = 0.31). No differences in diarrhea events were detected (10 % vs 4.7 %, p = 0.36). Constipation was common in both groups (95 % vs 82 %, p = 0.06). Conclusion: FI during prone position was not different in comparison to supine position. Routinely use of prokinetics in continuous prone position may help to prevent FI incidence. Algorithm development is necessary for FI prevention and treatment so to avoid EN interruptions and adverse clinical outcomes.

Introducción: Objetivo: comparar la incidencia de intolerancia a la alimentación entre pacientes críticos en posición supino (PS) o prono (PP). Métodos: cohorte retrospectiva de pacientes bajo ventilación mecánica por distrés respiratorio por COVID-19 y sobrepeso y obesidad, quienes recibieron nutrición enteral (NE) en PP o PS. Se evaluaron riesgo nutricional, mediciones antropométricas y composición corporal en las primeras 24 horas de ingreso a la Unidad de Cuidados Intensivos (UCI). Se recolectaron variables bioquímicas y clínicas (Sequential Organ Failure Assessment [SOFA], Acute Physiology and Chronic Health Evaluation II [APACHE II], lesión renal aguda y otras comorbilidades). Se registró el esquema de farmacoterapia prescrita durante los primeros cinco días (procinéticos, sedantes y bloqueadores neuromusculares). Se evaluó la incidencia de intolerancia a la alimentación, definida como la presencia de residuo gástrico (RG) ≥ 200 o ≥ 500 ml, vómito, diarrea o estreñimiento. Resultados: fueron incluidos 82 pacientes. Se observó una mayor prescripción de procinéticos como terapia profiláctica en PP (42,8 vs. 12,5 %, p = 0,002). No se observaron diferencias en RG ≥ 200 ml (p = 0,47) ni vómito (p = 0,31) entre ambos grupos. No se observaron diferencias en episodios de diarrea (10 % en PS vs. 4,7 % en PP, p = 0,36). El estreñimiento fue común en ambos grupos de estudio (95 vs. 82 %, p = 0,06). Conclusiones: la PP no se relaciona con una mayor incidencia de intolerancias a la alimentación. El uso rutinario de procinéticos durante la PP continua puede ayudar a prevenir la incidencia de dichas intolerancias. Es necesario el desarrollo de algoritmos para la prevención y tratamiento de las intolerancias a la alimentación para evitar interrupciones en la NE y desenlaces no deseables.

Differential Leukocyte Expression of IFITM1 and IFITM3 in Patients with Severe Pandemic Influenza A(H1N1) and COVID-19.

Interferon-induced transmembrane (IFITM) proteins mediate protection against enveloped viruses by blocking membrane fusion at endosomes. IFITM1 and IFITM3 are crucial for protection against influenza, and various single nucleotide polymorphisms altering their function have been linked to disease susceptibility. However, bulk IFITM1 and IFITM3 mRNA expression dynamics and their correlation with clinical outcomes have not been extensively addressed in patients with respiratory infections. In this study, we evaluated the expression of IFITM1 and IFITM3 in peripheral leukocytes from healthy controls and individuals with severe pandemic influenza A(H1N1) or coronavirus disease 2019 (COVID-19). Comparisons between participants grouped according to their clinical characteristics, underlying disease, and outcomes showed that the downregulation of IFITM1 was a distinctive characteristic of severe pandemic influenza A(H1N1) that correlated with outcomes, including mortality. Conversely, increased IFITM3 expression was a common feature of severe pandemic influenza A(H1N1) and COVID-19. Using a high-dose murine model of infection, we confirmed not only the downregulation of IFITM1 but also of IFITM3 in the lungs of mice with severe influenza, as opposed to humans. Analyses in the comparative cohort also indicate the possible participation of IFITM3 in COVID-19. Our results add to the evidence supporting a protective function of IFITM proteins against viral respiratory infections in humans.

Efectividad de las vacunas contra SARS-CoV-2 en hospitalizados con fallas vacunales en 10 hospitales de la CCINSHAE.

OBJETIVO: Evaluar la efectividad de las vacunas contra SARS-CoV-2 para evitar muerte e intubación en pacientes hospitalizados con Covid-19. Material y métodos. Se presentó un análisis de 3 565 hospitalizaciones por SARS-CoV-2 de personas mayores de 20 años de edad, reportadas con fines de salud pública por 10 hospitales de especialidad. Se comparó a los egresados por mejoría (2 094) con los fallecidos (1 471) en modelos mixtos de regresión logística ajustados por edad, sexo, número de comorbilidades y el hospital como variable aleatoria. RESULTADOS: Un esquema completo de vacunación, con cinco tipos de vacunas disponi-bles, tuvo un efecto protector para muerte o intubación (RM: 0.67, IC95%: 0.54,0.83, 33% de protección); y para muerte (RM: 0.80, IC95%: 0.64,0.99, 20% de protección) estos datos se compararon con los que no habían sido vacunados. Todas las vacunas aplicadas mostraron un efecto protector con un RM<0.8, con intervalos de confianza variables. Conclusio-nes. El antecedente de vacunación reduce los riesgos de ser intubado y morir, aun en pacientes previamente vacunados y hospitalizados con Covid-19 grave.

Efectividad de las vacunas contra SARS-CoV-2 en hospitalizados con fallas vacunales en 10 hospitales de la CCINSHAE / Effectiveness of SARS-CoV-2 vaccines in hospitalized patients with vaccine failures in 10 CCINSHAE hospitals

Resumen: Objetivo: Evaluar la efectividad de las vacunas contra SARS-CoV-2 para evitar muerte e intubación en pacientes hospitalizados con Covid-19. Material y métodos: Se presentó un análisis de 3 565 hospitalizaciones por SARS-CoV-2 de personas mayores de 20 años de edad, reportadas con fines de salud pública por 10 hospitales de especialidad. Se comparó a los egresados por mejoría (2 094) con los fallecidos (1 471) en modelos mixtos de regresión logística ajustados por edad, sexo, número de comorbilidades y el hospital como variable aleatoria. Resultados: Un esquema completo de vacunación, con cinco tipos de vacunas disponibles, tuvo un efecto protector para muerte o intubación (RM: 0.67, IC95%: 0.54,0.83, 33% de protección); y para muerte (RM: 0.80, IC95%: 0.64,0.99, 20% de protección) estos datos se compararon con los que no habían sido vacunados. Todas las vacunas aplicadas mostraron un efecto protector con un RM<0.8, con intervalos de confianza variables. Conclusiones: El antecedente de vacunación reduce los riesgos de ser intubado y morir, aun en pacientes previamente vacunados y hospitalizados con Covid-19 grave.

Abstract: Objective: To evaluate the effectiveness of SARS-CoV-2 vaccines to avoid death and intubation in hospitalized patients with Covid-19. Materials and methods: We present an analysis of 3 565 hospitalizations for SARS-CoV-2 in people over 20 years of age, reported for public health purposes by 10 specialty hospitals, comparing those discharged for improvement (2 094) with those who died (1 471) in mixed models of logistic regression adjusted for age, sex, number of comorbidities and the reporting hospital as a random variable. Results: A complete vaccination schedule, with five types of vaccine available, had a protective effect for death or intubation (OR: 0.67, CI95%: 0.54,0.83, 33% protection) and for death (OR: 0.80, CI95%: 0.64,0.99, 20% protection) compared to those who had not been vaccinated. All the applied vaccines in the Mexican program showed a protective effect with an OR<0.8, with variable confidence intervals. Conclusions: Even in patients previously vaccinated and hospitalized with severe Covid-19, a history of vaccination reduces the risks of being intubated and dying.

Phase angle and overhydration are associated with post-extubating dysphagia in patients with COVID-19 discharged from the ICU.

BACKGROUND: Few studies have evaluated the prevalence of post-extubation dysphagia and associated factors in patients with coronavirus disease 2019 (COVID-19) . Our study assessed the prevalence of post-extubation dysphagia and body composition in patients with COVID-19 discharged from an intensive care unit (ICU). METHODS: A prospective cohort study was performed in post-ICU extubated patients with acute respiratory distress syndrome related to COVID-19 in two referral hospitals. A total of 112 patients were evaluated and included; swallowing assessment and bioelectrical impedance analysis (BIA) were performed after extubation and discharge from the ICU. To identify associations between dysphagia, lower phase angle (PhA) (<4.8°) and hydration (extracellular water/total body water < 0.390) logistic and linear regression analyses were conducted. RESULTS: The incidence of post-extubation dysphagia was 41% (n = 46). From these, 65% (n = 30) had severe swallowing impairment. Overhydration and PhA were significantly different in patients with dysphagia, and segmental hydration in the trunk and legs was higher than in arms. PhA <4.8° (odds ratio [OR], 12.2; 95% CI, 4.3-34.1; P < .05) and overhydration measured by BIA (OR, 9.1; 95% CI, 3.4-24.5; P < .05) were associated with post-extubation dysphagia in multivariate analysis. PhA (<4.8°) was associated with a lower rate of swallowing recovery at hospital discharge (log-rank test = 0.007). CONCLUSIONS: A high incidence of post-extubation dysphagia was found in patients with COVID-19. Low PhA and overhydration were associated with the presence of dysphagia. Lower PhA was an independent factor for swallowing recovery at discharge.

Low phase angle is associated with 60-day mortality in critically ill patients with COVID-19.

BACKGROUND: Malnutrition status, body composition indicators, and bioelectrical impedance analysis (BIA) parameters have been associated with increased risk of death in several pathologies. The aim of this study was to describe the associations between phase angle (PhA) indicators obtained by BIA with length of hospital stay, days on mechanical ventilation, and 60-day mortality in critically ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: This is a prospective cohort of mechanically ventilated patients with coronavirus disease 2019 (COVID-19). We assessed nutrition risk and body composition with BIA within 48 h from intensive care unit admission. Logistic and linear regression models were used to analyze the association between variables and clinical outcomes. Survival analysis by PhA value was performed using Kaplan-Meier curves. RESULTS: Sixty-seven patients were included. PhA (odds ratio [OR], 0.36; P = .002), standardized PhA (SPA) (OR, 0.45; P = .001), and extracellular water/total body water ratio (OR, 3.25; P = .002) were significant predictors of 60-day mortality. PhA <3.85° in females and <5.25° in males showed good and fair discrimination, respectively, for mortality prediction. Using cutoff values, low PhA was associated with a significantly increased risk of 60-day mortality (hazard ratio, 3.08; 95% CI, 1.12-8.41; P = .02). No association was detected for SPA. CONCLUSION: Low PhA values could be a predictor of 60-day mortality in critically ill patients with COVID-19. This biological marker could be incorporated as part of nutrition and mortality risk assessment in this population.

Hydroxychloroquine for the treatment of severe respiratory infection by COVID-19: A randomized controlled trial.

INTRODUCTION: The novel coronavirus pandemic (COVID-19) represents a major public health problem and it is key to find a treatment that reduces mortality. Our objective was to estimate whether treatment with 400 mg/day of Hydroxychloroquine for 10 days reduces in-hospital mortality in subjects with severe respiratory disease due to COVID-19 compared with placebo. MATERIAL AND METHODS: A double-blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of Hydroxychloroquine for the treatment of severe disease by COVID-19 through an intention-to-treat analysis. Eligible for the study were adults aged more than 18 years with COVID-19 confirmed by RT-PCR and lung injury requiring hospitalization with or without mechanical ventilation. Primary outcome was 30-day mortality. Secondary outcomes: days of mechanical ventilation, days of hospitalization and cumulative incidence of serious adverse events. RESULTS: A total of 214 patients with COVID-19 were recruited, randomized and analyzed. They were hypoxemic with a mean SpO2 of 65% ± 20, tachycardic (pulse rate 108±17 min-1) and tachypneic (32 ±10 min-1); 162 were under mechanical ventilation at randomization. Thirty-day mortality was similar in both groups (38% in Hydroxychloroquine vs. 41% in placebo, hazard ratio [HR] 0.88, 95% Confidence Interval [95%CI] 0.51-1.53). In the surviving participants, no significant difference was found in secondary outcomes. CONCLUSION: No beneficial effect or significant harm could be demonstrated in our randomized controlled trial including 214 patients, using relatively low doses of Hydroxychloroquine compared with placebo in hospitalized patients with severe COVID-19.

Clinical Risk Factors for Mortality Among Critically Ill Mexican Patients With COVID-19.

Little literature exists about critically ill patients with coronavirus disease 2019 (COVID-19) from Latin America. Here, we aimed to describe the clinical characteristics and mortality risk factors in mechanically ventilated COVID-19 patients from Mexico. For this purpose, we recruited 67 consecutive mechanically ventilated COVID-19 patients which were grouped according to their clinical outcome (survival vs. death). Clinical risk factors for mortality were identified by machine-learning and logistic regression models. The median age of participants was 42 years and 65% were men. The most common comorbidity observed was obesity (49.2%). Fever was the most frequent symptom of illness (88%), followed by dyspnea (84%). Multilobe ground-glass opacities were observed in 76% of patients by thoracic computed tomography (CT) scan. Fifty-two percent of study participants were ventilated in prone position, and 59% required cardiovascular support with norepinephrine. Furthermore, 49% of participants were coinfected with a second pathogen. Two-thirds of COVID-19 patients developed acute kidney injury (AKIN). The mortality of our cohort was 44.7%. AKIN, uric acid, lactate dehydrogenase (LDH), and a longitudinal increase in the ventilatory ratio were associated with mortality. Baseline PaO2/FiO2 values and a longitudinal recovery of lymphocytes were protective factors against mortality. Our study provides reference data about the clinical phenotype and risk factors for mortality in mechanically ventilated Mexican patients with COVID-19.

Corrigendum: CXCL17 Is a Specific Diagnostic Biomarker for Severe Pandemic Influenza A(H1N1) That Predicts Poor Clinical Outcome.

[This corrects the article DOI: 10.3389/fimmu.2021.633297.].

Clinical and Immunological Factors That Distinguish COVID-19 From Pandemic Influenza A(H1N1).

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a global health threat with the potential to cause severe disease manifestations in the lungs. Although COVID-19 has been extensively characterized clinically, the factors distinguishing SARS-CoV-2 from other respiratory viruses are unknown. Here, we compared the clinical, histopathological, and immunological characteristics of patients with COVID-19 and pandemic influenza A(H1N1). We observed a higher frequency of respiratory symptoms, increased tissue injury markers, and a histological pattern of alveolar pneumonia in pandemic influenza A(H1N1) patients. Conversely, dry cough, gastrointestinal symptoms and interstitial lung pathology were observed in COVID-19 cases. Pandemic influenza A(H1N1) was characterized by higher levels of IL-1RA, TNF-α, CCL3, G-CSF, APRIL, sTNF-R1, sTNF-R2, sCD30, and sCD163. Meanwhile, COVID-19 displayed an immune profile distinguished by increased Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-5, IL-10, IL-13) cytokine levels, along with IL-1ß, IL-6, CCL11, VEGF, TWEAK, TSLP, MMP-1, and MMP-3. Our data suggest that SARS-CoV-2 induces a dysbalanced polyfunctional inflammatory response that is different from the immune response against pandemic influenza A(H1N1). Furthermore, we demonstrated the diagnostic potential of some clinical and immune factors to differentiate both diseases. These findings might be relevant for the ongoing and future influenza seasons in the Northern Hemisphere, which are historically unique due to their convergence with the COVID-19 pandemic.

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

CXCL17 Is a Specific Diagnostic Biomarker for Severe Pandemic Influenza A(H1N1) That Predicts Poor Clinical Outcome.

The C-X-C motif chemokine ligand 17 (CXCL17) is chemotactic for myeloid cells, exhibits bactericidal activity, and exerts anti-viral functions. This chemokine is constitutively expressed in the respiratory tract, suggesting a role in lung defenses. However, little is known about the participation of CXCL17 against relevant respiratory pathogens in humans. Here, we evaluated the serum levels and lung tissue expression pattern of CXCL17 in a cohort of patients with severe pandemic influenza A(H1N1) from Mexico City. Peripheral blood samples obtained on admission and seven days after hospitalization were processed for determinations of serum CXCL17 levels by enzyme-linked immunosorbent assay (ELISA). The expression of CXCL17 was assessed by immunohistochemistry (IHQ) in lung autopsy specimens from patients that succumbed to the disease. Serum CXCL17 levels were also analyzed in two additional comparative cohorts of coronavirus disease 2019 (COVID-19) and pulmonary tuberculosis (TB) patients. Additionally, the expression of CXCL17 was tested in lung autopsy specimens from COVID-19 patients. A total of 122 patients were enrolled in the study, from which 68 had pandemic influenza A(H1N1), 24 had COVID-19, and 30 with PTB. CXCL17 was detected in post-mortem lung specimens from patients that died of pandemic influenza A(H1N1) and COVID-19. Interestingly, serum levels of CXCL17 were increased only in patients with pandemic influenza A(H1N1), but not COVID-19 and PTB. CXCL17 not only differentiated pandemic influenza A(H1N1) from other respiratory infections but showed prognostic value for influenza-associated mortality and renal failure in machine-learning algorithms and regression analyses. Using cell culture assays, we also identified that human alveolar A549 cells and peripheral blood monocyte-derived macrophages increase their CXCL17 production capacity after influenza A(H1N1) pdm09 virus infection. Our results for the first time demonstrate an induction of CXCL17 specifically during pandemic influenza A(H1N1), but not COVID-19 and PTB in humans. These findings could be of great utility to differentiate influenza and COVID-19 and to predict poor prognosis specially at settings of high incidence of pandemic A(H1N1). Future studies on the role of CXCL17 not only in severe pandemic influenza, but also in seasonal influenza, COVID-19, and PTB are required to validate our results.

Expression of Surfactant Protein D Distinguishes Severe Pandemic Influenza A(H1N1) from Coronavirus Disease 2019.

The differentiation between influenza and coronavirus disease 2019 (COVID-19) could constitute a diagnostic challenge during the ongoing winter owing to their clinical similitude. Thus, novel biomarkers are required to enable making this distinction. Here, we evaluated whether the surfactant protein D (SP-D), a collectin produced at the alveolar epithelium with known immune properties, was useful to differentiate pandemic influenza A(H1N1) from COVID-19 in critically ill patients. Our results revealed high serum SP-D levels in patients with severe pandemic influenza but not those with COVID-19. This finding was validated in a separate cohort of mechanically ventilated patients with COVID-19 who also showed low plasma SP-D levels. However, plasma SP-D levels did not distinguish seasonal influenza from COVID-19 in mild-to-moderate disease. Finally, we found that high serum SP-D levels were associated with death and renal failure among severe pandemic influenza cases. Thus, our studies have identified SP-D as a unique biomarker expressed during severe pandemic influenza but not COVID-19.