External validation of unsupervised COVID-19 clinical phenotypes and their prognostic impact.

BACKGROUND: Hospitalized patients with coronavirus disease 2019 (COVID-19) can be classified into different clinical phenotypes based on their demographic, clinical, radiology, and laboratory features. We aimed to validate in an external cohort of hospitalized COVID-19 patients the prognostic value of a previously described phenotyping system (FEN-COVID-19) and to assess the reproducibility of phenotypes development as a secondary analysis. METHODS: Patients were classified in phenotypes A, B or C according to the severity of oxygenation impairment, inflammatory response, hemodynamic and laboratory tests according to the FEN-COVID-19 method. RESULTS: Overall, 992 patients were included in the study, and 181 (18%), 757 (76%) and 54 (6%) of them were assigned to the FEN-COVID-19 phenotypes A, B, and C, respectively. An association with mortality was observed for phenotype C vs. A (hazard ratio [HR] 3.10, 95% confidence interval [CI] 1.81-5.30, p < 0.001) and for phenotype C vs. B (HR 2.20, 95% CI 1.50-3.23, p < 0.001). A non-statistically significant trend towards higher mortality was also observed for phenotype B vs. A (HR 1.41; 95% CI 0.92-2.15, p = 0.115). By means of cluster analysis, three different phenotypes were also identified in our cohort, with an overall similar gradient in terms of prognostic impact to that observed when patients were assigned to FEN-COVID-19 phenotypes. CONCLUSIONS: The prognostic impact of FEN-COVID-19 phenotypes was confirmed in our external cohort, although with less difference in mortality between phenotypes A and B than in the original study.

Hospitalized patients with COVID-19 can be classified into different clinical phenotypes based on their demographic, clinical, radiology, and laboratory featuresIn this study, we externally confirmed the prognostic impact of clinical phenotypes previously identified by Gutierrez-Gutierrez and colleagues in a Spanish cohort of hospitalized patients with COVID-19, and the usefulness of their simplified probabilistic model for phenotypes assignmentThis could indirectly support the validity of both phenotype's development and their extrapolation to other hospitals and countries for management decisions during other possible future viral pandemics.

Neurological manifestations of COVID-19 in adults and children.

Different neurological manifestations of COVID-19 in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicenter observational study using the International Severe Acute Respiratory and emerging Infection Consortium cohort across 1507 sites worldwide from January/30th/2020 to May/25th/2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models. Overall, 161,239 patients (158,267 adults; 2,972 children) hospitalized with COVID-19 and assessed for neurological manifestations and complications were included. In adults and children, the most frequent neurological manifestations at admission were fatigue (adults: 37.4%; children: 20.4%), altered consciousness (20.9%; 6.8%), myalgia (16.9%; 7.6%), dysgeusia (7.4%; 1.9%), anosmia (6.0%; 2.2%), and seizure (1.1%; 5.2%). In adults, the most frequent in-hospital neurological complications were stroke (1.5%), seizure (1%), and central nervous system (CNS) infection (0.2%). Each occurred more frequently in ICU than in non-ICU patients. In children, seizure was the only neurological complication to occur more frequently in ICU vs. non-ICU (7.1% vs. 2.3%, P < .001). Stroke prevalence increased with increasing age, while CNS infection and seizure steadily decreased with age. There was a dramatic decrease in stroke over time during the pandemic. Hypertension, chronic neurological disease, and the use of extracorporeal membrane oxygenation were associated with increased risk of stroke. Altered consciousness was associated with CNS infection, seizure, and stroke. All in-hospital neurological complications were associated with increased odds of death. The likelihood of death rose with increasing age, especially after 25 years of age. In conclusion, adults and children have different neurological manifestations and in-hospital complications associated with COVID-19. Stroke risk increased with increasing age, while CNS infection and seizure risk decreased with age.

Systemic and Cerebral Effects of Physiotherapy in Mechanically Ventilated Subjects.

BACKGROUND: Physiotherapy may result in better functional outcomes, shorter duration of delirium, and more ventilator-free days. The effects of physiotherapy on different subpopulations of mechanically ventilated patients on respiratory and cerebral function are still unclear. We evaluated the effect of physiotherapy on systemic gas exchange and hemodynamics as well as on cerebral oxygenation and hemodynamics in mechanically ventilated subjects with and without COVID-19 pneumonia. METHODS: This was an observational study in critically ill subjects with and without COVID-19 who underwent protocolized physiotherapy (including respiratory and rehabilitation physiotherapy) and neuromonitoring of cerebral oxygenation and hemodynamics. PaO2 /FIO2 , PaCO2 , hemodynamics (mean arterial pressure [MAP], mm Hg; heart rate, beats/min), and cerebral physiologic parameters (noninvasive intracranial pressure, cerebral perfusion pressure using transcranial Doppler, and cerebral oxygenation using near-infrared spectroscopy) were assessed before (T0) and immediately after physiotherapy (T1). RESULTS: Thirty-one subjects were included (16 with COVID-19 and 15 without COVID-19). Physiotherapy improved PaO2 /FIO2 in the overall population (T1 = 185 [108-259] mm Hg vs T0 = 160 [97-231] mm Hg, P = .02) and in the subjects with COVID-19 (T1 = 119 [89-161] mm Hg vs T0 = 110 [81-154] mm Hg, P = .02) and decreased the PaCO2 in the COVID-19 group only (T1 = 40 [38-44] mm Hg vs T0 = 43 [38-47] mm Hg, P = .03). Physiotherapy did not affect cerebral hemodynamics, whereas increased the arterial oxygen part of hemoglobin both in the overall population (T1 = 3.1% [-1.3 to 4.9] vs T0 = 1.1% [-1.8 to 2.6], P = .007) and in the non-COVID-19 group (T1 = 3.7% [0.5-6.3] vs T0 = 0% [-2.2 to 2.8], P = .02). Heart rate was higher after physiotherapy in the overall population (T1 = 87 [75-96] beats/min vs T0 = 78 [72-92] beats/min, P = .044) and in the COVID-19 group (T1 = 87 [81-98] beats/min vs T0 = 77 [72-91] beats/min, P = .01), whereas MAP increased in the COVID-19 group only (T1 = 87 [82-83] vs T0 = 83 [76-89], P = .030). CONCLUSIONS: Protocolized physiotherapy improved gas exchange in subjects with COVID-19, whereas it improved cerebral oxygenation in non-COVID-19 subjects.

Biomarkers as predictors of mortality in critically ill obese patients with COVID-19 at high altitude.

BACKGROUND: Obesity is a common chronic comorbidity of patients with COVID-19, that has been associated with disease severity and mortality. COVID-19 at high altitude seems to be associated with increased rate of ICU discharge and hospital survival than at sea-level, despite higher immune levels and inflammation. The primary aim of this study was to investigate the survival rate of critically ill obese patients with COVID-19 at altitude in comparison with overweight and normal patients. Secondary aims were to assess the predictive factors for mortality, characteristics of mechanical ventilation setting, extubation rates, and analytical parameters. METHODS: This is a retrospective cohort study in critically ill patients with COVID-19 admitted to a hospital in Quito-Ecuador (2,850 m) from Apr 1, 2020, to Nov 1, 2021. Patients were cathegorized as normal weight, overweight, and obese, according to body mass index [BMI]). RESULTS: In the final analysis 340 patients were included, of whom 154 (45%) were obese, of these 35 (22.7%) were hypertensive and 25 (16.2%) were diabetic. Mortality in obese patients (31%) was lower than in the normal weight (48%) and overweight (40%) groups, but not statistically significant (p = 0.076). At multivariable analysis, in the overall population, older age (> 50 years) was independent risk factor for mortality (B = 0.93, Wald = 14.94, OR = 2.54 95%CI = 1.58-4.07, p < 0.001). Ferritin and the neutrophil/lymphocyte ratio were independent predictors of mortality in obese patients. Overweight and obese patients required more positive and-expiratory pressure compared to normal-weight patients. In obese patients, plateau pressure and mechanical power were significantly higher, whereas extubation failure was lower as compared to overweight and normal weight. CONCLUSIONS: This preliminary study suggests that BMI was not associated with mortality in critically ill patients at high altitude. Age was associated with an increase in mortality independent of the BMI. Biomarkers such as ferritin and neutrophils/lymphocytes ratio were independent predictors of mortality in obese patients with COVID-19 at high altitude.

Morphological and functional findings in COVID-19 lung disease as compared to Pneumonia, ARDS, and High-Altitude Pulmonary Edema.

Coronavirus disease-2019 (COVID-19) may severely affect respiratory function and evolve to life-threatening hypoxia. The clinical experience led to the implementation of standardized protocols assuming similarity to severe acute respiratory syndrome (SARS-CoV-2). Understanding the histopathological and functional patterns is essential to better understand the pathophysiology of COVID-19 and then develop new therapeutic strategies. Epithelial and endothelial cell damage can result from the virus attack, thus leading to immune-mediated response. Pulmonary histopathological findings show the presence of Mallory bodies, alveolar coating cells with nuclear atypia, reactive pneumocytes, reparative fibrosis, intra-alveolar hemorrhage, moderate inflammatory infiltrates, micro-abscesses, microthrombus, hyaline membrane fragments, and emphysema-like lung areas. COVID-19 patients may present different respiratory stages from silent to critical hypoxemia, are associated with the degree of pulmonary parenchymal involvement, thus yielding alteration of ventilation and perfusion relationships. This review aims to: discuss the morphological (histopathological and radiological) and functional findings of COVID-19 compared to acute interstitial pneumonia, acute respiratory distress syndrome (ARDS), and high-altitude pulmonary edema (HAPE), four entities that share common clinical traits, but have peculiar pathophysiological features with potential implications to their clinical management.

High flow nasal oxygen and awake prone positioning - Two allies against COVID-19: A systematic review.

INTRODUCTION: Severe acute respiratory distress syndrome coronavirus disease-2 (SARS-CoV-2) can lead to acute hypoxemic respiratory failure (AHRF) with possible multisystemic involvement. Ventilation/perfusion mismatch and shunt increase are critical determinants of hypoxemia. Understanding hypoxemia and the mechanisms involved in its genesis is essential to determine the optimal therapeutic strategy. High flow nasal oxygen (HFNO) and awake prone positioning (APP) in patients with COVID-19 AHRF showed promising benefits. The aim of this systematic review was to depict current situation around the combined use of HFNO and APP in patients with COVID-19 AHRF. Particularly, to investigate and report the pathophysiological rationale for adopting this strategy and to evaluate the (1) criteria for initiation, (2) timing, monitoring and discontinuation, and to assess the (3) impact of HFNO/ APP on outcome. METHODS: We performed a systematic search collecting the articles present in PubMed, Scopus, EMBASE, and Cochrane databases with the following keywords: COVID-19 pneumonia, high flow nasal oxygen, awake prone position ventilation. RESULTS: Thirteen studies displayed inclusion criteria and were included, accounting for 1242 patients who received HFNO/ APP. The combination of HFNO/ APP has an encouraging pathophysiological rationale for implementing this technique. The recognition of patients who can benefit from HFNO/ APP is difficult and there are no validated protocols to start, monitoring, and discontinue HFNO/ APP therapy. The most used method to monitor the efficacy and failure of this combined technique are oxygenation indexes, but discontinuation techniques are inconsistently and poorly described limiting possible generatability. Finally, this technique provided no clear benefits on outcome. CONCLUSIONS: Our systematic search provided positive feedbacks for improving the utilization of this combination technique, although we still need further investigation about methods to guide timing, management, and discontinuation, and to assess the intervention effect on outcome.

Biological Markers to Predict Outcome in Mechanically Ventilated Patients with Severe COVID-19 Living at High Altitude.

BACKGROUND: There is not much evidence on the prognostic utility of different biological markers in patients with severe COVID-19 living at high altitude. The objective of this study was to determine the predictive value of inflammatory and hematological markers for the risk of mortality at 28 days in patients with severe COVID-19 under invasive mechanical ventilation, living at high altitude and in a low-resource setting. METHODS: We performed a retrospective observational study including patients with severe COVID-19, under mechanical ventilation and admitted to the intensive care unit (ICU) located at 2850 m above sea level, between 1 April 2020 and 1 August 2021. Inflammatory (interleukin-6 (IL-6), ferritin, D-dimer, lactate dehydrogenase (LDH)) and hematologic (mean platelet volume (MPV), neutrophil/lymphocyte ratio (NLR), MPV/platelet ratio) markers were evaluated at 24 h and in subsequent controls, and when available at 48 h and 72 h after admission to the ICU. The primary outcome was the association of inflammatory and hematological markers with the risk of mortality at 28 days. RESULTS: We analyzed 223 patients (median age (1st quartile [Q1]-3rd quartile [Q3]) 51 (26-75) years and 70.4% male). Patients with severe COVID-19 and with IL-6 values at 24 h ≥ 11, NLR values at 24 h ≥ 22, and NLR values at 72 h ≥ 14 were 8.3, 3.8, and 3.8 times more likely to die at 28 days, respectively. The SOFA and APACHE-II scores were not able to independently predict mortality. CONCLUSIONS: In mechanically ventilated patients with severe COVID-19 and living at high altitude, low-cost and immediately available blood markers such as IL-6 and NLR may predict the severity of the disease in low-resource settings.

The Use of Noninvasive Multimodal Neuromonitoring in Adult Critically Ill Patients With COVID-19 Infection.

INTRODUCTION: Noninvasive neuromonitoring could be a valuable option for bedside assessment of cerebral dysfunction in patients with coronavirus disease-2019 (COVID-19) admitted to intensive care units (ICUs). This systematic review aims to investigate the use of noninvasive multimodal neuromonitoring in critically ill adult patients with COVID-19 infection. METHODS: MEDLINE/PubMed, Scopus, Cochrane, and EMBASE databases were searched for studies investigating noninvasive neuromonitoring in patients with COVID-19 admitted to ICUs. The monitoring included transcranial Doppler ultrasonography (TCD), the Brain4care Corp. cerebral compliance monitor (B4C), optic nerve sheath diameter (ONSD), near infrared spectroscopy, automated pupillometry, and electroencephalography (EEG). RESULTS: Thirty-two studies that investigated noninvasive neuromonitoring techniques in patients with COVID-19 in the ICU were identified from a systematic search of 7001 articles: 1 study investigating TCD, ONSD and pupillometry; 2 studies investigating the B4C device and TCD; 3 studies investigating near infrared spectroscopy and TCD; 4 studies investigating TCD; 1 case series investigating pupillometry, and 21 studies investigating EEG. One hundred and nineteen patients underwent TCD monitoring, 47 pupillometry, 49 ONSD assessment, 50 compliance monitoring with the B4C device, and 900 EEG monitoring. Alterations in cerebral hemodynamics, brain compliance, brain oxygenation, pupillary response, and brain electrophysiological activity were common in patients with COVID-19 admitted to the ICU; these abnormalities were not clearly associated with worse outcome or the development of new neurological complications. CONCLUSIONS: The use of noninvasive multimodal neuromonitoring in critically ill COVID-19 patients could be considered to facilitate the detection of neurological derangements. Determining whether such findings allow earlier detection of neurological complications or guide appropriate therapy requires additional studies.

Personalized medicine using omics approaches in acute respiratory distress syndrome to identify biological phenotypes.

In the last decade, research on acute respiratory distress syndrome (ARDS) has made considerable progress. However, ARDS remains a leading cause of mortality in the intensive care unit. ARDS presents distinct subphenotypes with different clinical and biological features. The pathophysiologic mechanisms of ARDS may contribute to the biological variability and partially explain why some pharmacologic therapies for ARDS have failed to improve patient outcomes. Therefore, identifying ARDS variability and heterogeneity might be a key strategy for finding effective treatments. Research involving studies on biomarkers and genomic, metabolomic, and proteomic technologies is increasing. These new approaches, which are dedicated to the identification and quantitative analysis of components from biological matrixes, may help differentiate between different types of damage and predict clinical outcome and risk. Omics technologies offer a new opportunity for the development of diagnostic tools and personalized therapy in ARDS. This narrative review assesses recent evidence regarding genomics, proteomics, and metabolomics in ARDS research.

Post-COVID-19 syndrome symptoms after mild and moderate SARS-CoV-2 infection.

Background: Post-COVID-19 Syndrome (PCS) is characterized by residual symptoms following the initial recovery from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The prevalence of PCS is known to be the highest among severe and critical forms of the disease. However, the occurrence and risk factors for PCS after mild or moderate SARS-CoV-2 infection has not been extensively investigated. Methods: Online and offline via both paper or mailed questionnaires distributed among Jordan collected between 1st and 21st August 2021, including a total number of 800 respondents, of whom 495 had previous mild to moderate COVID-19 infection. The Newcastle post-COVID syndrome Follow-up Screening Questionnaire was modified, translated, and used as a standard instrument for data collection regarding psychological, medical, and socio-economic symptoms post-infection. The primary outcome was the prevalence of PCS after mild to moderate COVID-19 in Jordan. Secondary outcome was the identification of PCS risk factors. Results: The most common PCS symptom was mood disturbance followed by fatigue, anxiety, and myalgia. Female gender significantly increased the risk for multiple PCS symptoms. Age < 30 years was found to be an independent risk factor for myalgia (p = 0.001). Conclusion: PCS is highly prevalent among COVID-19 survivors in Jordan, especially in females and patients with comorbidities. Planning physical and mental rehabilitation services is recommended for those patients with PCS symptoms after mild to moderate COVID-19 infection.

Association of ventilator-free days with respiratory physiotherapy in critically ill patients with Coronavirus Disease 2019 (COVID-19) during the first pandemic wave. A propensity score-weighted analysis.

Background: Respiratory physiotherapy is reported as safe and feasible in mechanically ventilated patients with severe Coronavirus Disease (COVID-19) admitted to Intensive Care Unit (ICU), but the short-term benefits remain unclear. Methods: We performed a retrospective observational study in four ICUs in Northern Italy. All patients with COVID-19 admitted to ICU and under invasive mechanical ventilation (MV) between March 1st and May 30th, 2020, were enrolled into the study. Overlap weighting based on the propensity score was used to adjust for confounding in the comparison of patients who had or had not been treated by physiotherapists. The primary outcome was the number of days alive and ventilator-free (VFDs). The secondary outcomes were arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio (P/F) at ICU discharge, ICU length of stay, ICU and hospital mortality, and survival at 90 days. The trial protocol was registered on clinicaltrials.gov (NCT05067907). Results: A total of 317 patients were included in the analysis. The median VFDs was 18 days [interquartile range (IQR) 10; 24] in patients performing physiotherapy and 21 days (IQR 0; 26) in the group without physiotherapy [incidence rate ratio (IRR) 0.86, 95% confidence interval (CI): 0.78; 0.95]. The chance of 0 VFDs was lower for patients treated by physiotherapists compared to those who were not [odds ratio (OR) = 0.36, 95% CI: 0.18-0.71]. Survival at 90 days was 96.0% in the physiotherapy group and 70.6% in patients not performing physiotherapy [hazard ratio (HR) = 0.14, 95% CI: 0.03-0.71]. Number of VFDs was not associated with body mass index (BMI), sex, or P/F at ICU admission for individuals with at least 1 day off the ventilator. Conclusion: In patients with COVID-19 admitted to ICU during the first pandemic wave and treated by physiotherapists, the number of days alive and free from MV was lower compared to patients who did not perform respiratory physiotherapy. Survival at 90 days in the physiotherapy group was greater compared to no physiotherapy. These findings may be the starting point for further investigation in this setting.

The value of EEG attenuation in the prediction of outcome in COVID-19 patients.

INTRODUCTION: During the COVID-19 pandemic, electroencephalography (EEG) proved to be a useful tool to demonstrate brain involvement. Many studies reported non-reactive generalized slowing as the most frequent pattern and epileptiform activity in a minority of patients. OBJECTIVE: To investigate the prevalence of diffuse unreactive background attenuation or suppression and its correlation with outcome in a cohort of COVID-19 patients. METHODS: The EEGs recorded during the first year of the COVID-19 pandemic were retrospectively evaluated to identify the main pattern and focus on the occurrence of a low-voltage background, either attenuated (10-20 µV) or suppressed (< 10 µV). We sought a correlation between in-hospital mortality and low-voltage EEG. In a subsample of patients, biomarkers of inflammation, hypoxemia and organ failure were collected. Brain imaging was also evaluated. RESULTS: Among 98 EEG performed in 50 consecutive patients, diffuse unreactive slowing was the most prevalent pattern (54%), followed by unreactive attenuation or suppression pattern (26%), being the latter significantly correlated with an unfavourable outcome (p = 0.0004). Survivors showed significantly lower interleukine-6 values compared to non-survivors. Patients with attenuated EEG and non-survivors also showed lower PaO2/FiO2 values. Neuroradiological findings were very heterogeneous with a prevalence of lesions suggestive of a microangiopathic substrate. CONCLUSIONS: EEG attenuation or suppression may be more frequent than previously reported and significantly associated with a poor outcome. SARS-CoV-2 infection may result in encephalopathy and reduced EEG voltage through mechanisms that are still unknown but deserve attention given its negative impact on prognosis.

Failed clinical trials on COVID-19 acute respiratory distress syndrome in hospitalized patients: common oversights and streamlining the development of clinically effective therapeutics.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has put a strain on global healthcare systems. Despite admirable efforts to develop rapidly new pharmacotherapies, supportive treatments remain the standard of care. Multiple clinical trials have failed due to design issues, biased patient enrollment, small sample sizes, inadequate control groups, and lack of long-term outcomes monitoring. AREAS COVERED: This narrative review depicts the current situation around failed and success COVID-19 clinical trials and recommendations in hospitalized patients with COVID-19, oversights and streamlining of clinically effective therapeutics. PubMed, EBSCO, Cochrane Library, and WHO and NIH guidelines were searched for relevant literature up to 5 August 2022. EXPERT OPINION: The WHO, NIH, and IDSA have issued recommendations to better clarify which drugs should be used during the different phases of the disease. Given the biases and high heterogeneity of published studies, interpretation of the current literature is difficult. Future clinical trials should be designed to standardize clinical approaches, with appropriate organization, patient selection, addition of control groups, and careful identification of disease phase to reduce heterogeneity and bias and should rely on the integration of scientific societies to promote a consensus on interpretation of the data and recommendations for optimal COVID-19 therapies.

Physical and psychological impairment in survivors of acute respiratory distress syndrome: a systematic review and meta-analysis.

BACKGROUND: Survivors of acute respiratory distress syndrome (ARDS) are at risk of long-term comorbidities. This systematic review and meta-analysis evaluated health-related quality of life (HRQoL), and physical and psychological impairments in ARDS survivors from 3 months to 5 yr follow-up after ICU discharge. METHODS: Systematic search of PubMed, AMED, BNI, and CINAHL databases from January 2000 to date. The primary outcome was HRQoL. Secondary outcomes included physical, pulmonary, and cognitive function, mental health, and return to work. A secondary analysis compared classical ARDS with severe acute respiratory syndrome coronavirus disease-2 (SARS-CoV-2) ARDS. RESULTS: Forty-eight papers met inclusion criteria including 11 693 patients; of those 85% (n=9992) had classical ARDS and 14% (n=1632) had SARS-CoV-2 ARDS. The 36-Item Short Form Health Survey (SF-36) physical component summary score mean (95% confidence interval [CI]) was 46 (41-50) at 3 months, 39 (36-41) at 6 months, and 40 (38-43) at 12 months. The SF-36 mental component summary mean score was 53 (48-57) at 3 months, 45 (40-50) at 6 months, and 44 (42-47) at 12 months. SF-36 values were lower than those found in the normal population up to 5 yr. The predictive distance walked in 6 min was 57% (45-69), 63% (56-69), and 66% (62-70) at 3, 6, and 12 months, respectively. Classical ARDS and SARS-CoV-2 ARDS showed no difference in HRQoL and physical function; however, patients with classical ARDS had higher incidence of anxiety and depression (P<0.001). CONCLUSION: ARDS survivors can experience reduced HRQoL and physical and mental health impairment. These symptoms might not recover completely up to 5 yr after ICU discharge. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42021296506.

Neurological Manifestations of SARS-CoV-2 Infection: Protocol for a Sub-analysis of the COVID-19 Critical Care Consortium Observational Study.

Introduction: Neurological manifestations and complications in coronavirus disease-2019 (COVID-19) patients are frequent. Prior studies suggested a possible association between neurological complications and fatal outcome, as well as the existence of potential modifiable risk factors associated to their occurrence. Therefore, more information is needed regarding the incidence and type of neurological complications, risk factors, and associated outcomes in COVID-19. Methods: This is a pre-planned secondary analysis of the international multicenter observational study of the COVID-19 Critical Care Consortium (which collected data both retrospectively and prospectively from the beginning of COVID-19 pandemic) with the aim to describe neurological complications in critically ill COVID-19 patients and to assess the associated risk factors, and outcomes. Adult patients with confirmed COVID-19, admitted to Intensive Care Unit (ICU) will be considered for this analysis. Data collected in the COVID-19 Critical Care Consortium study includes patients' pre-admission characteristics, comorbidities, severity status, and type and severity of neurological complications. In-hospital mortality and neurological outcome were collected at discharge from ICU, and at 28-days. Ethics and Dissemination: The COVID-19 Critical Care Consortium main study and its amendments have been approved by the Regional Ethics Committee of participating sites. No further approval is required for this secondary analysis. Trial Registration Number: ACTRN12620000421932.

Treatment for acute respiratory distress syndrome in adults: a narrative review of phase 2 and 3 trials.

INTRODUCTION: Ventilatory management and general supportive care of acute respiratory distress syndrome (ARDS) in the adult population have led to significant clinical improvements, but morbidity and mortality remain high. Pharmacologic strategies acting on the coagulation cascade, inflammation, oxidative stress, and endothelial cell injury have been targeted in the last decade for patients with ARDS, but only a few of these have shown potential benefits with a meaningful clinical response and improved patient outcomes. The lack of availability of specific pharmacologic treatments for ARDS can be attributed to its complex pathophysiology, different risk factors, huge heterogeneity, and difficult classification into specific biological phenotypes and genotypes. AREAS COVERED: In this narrative review, we briefly discuss the relevance and current advances in pharmacologic treatments for ARDS in adults and the need for the development of new pharmacological strategies. EXPERT OPINION: Identification of ARDS phenotypes, risk factors, heterogeneity, and pathophysiology may help to design clinical trials personalized according to ARDS-specific features, thus hopefully decreasing the rate of failed clinical pharmacologic trials. This concept is still under clinical investigation and needs further development.

Tracheostomy outcomes in critically ill patients with COVID-19: a systematic review, meta-analysis, and meta-regression.

BACKGROUND: We performed a systematic review of mechanically ventilated patients with COVID-19, which analysed the effect of tracheostomy timing and technique (surgical vs percutaneous) on mortality. Secondary outcomes included intensive care unit (ICU) and hospital length of stay (LOS), decannulation from tracheostomy, duration of mechanical ventilation, and complications. METHODS: Four databases were screened between January 1, 2020 and January 10, 2022 (PubMed, Embase, Scopus, and Cochrane). Papers were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Population or Problem, Intervention or exposure, Comparison, and Outcome (PICO) guidelines. Meta-analysis and meta-regression for main outcomes were performed. RESULTS: The search yielded 9024 potentially relevant studies, of which 47 (n=5268 patients) were included. High levels of between-study heterogeneity were observed across study outcomes. The pooled mean tracheostomy timing was 16.5 days (95% confidence interval [CI]: 14.7-18.4; I2=99.6%). Pooled mortality was 22.1% (95% CI: 18.7-25.5; I2=89.0%). Meta-regression did not show significant associations between mortality and tracheostomy timing, mechanical ventilation duration, time to decannulation, and tracheostomy technique. Pooled mean estimates for ICU and hospital LOS were 29.6 (95% CI: 24.0-35.2; I2=98.6%) and 38.8 (95% CI: 32.1-45.6; I2=95.7%) days, both associated with mechanical ventilation duration (coefficient 0.8 [95% CI: 0.2-1.4], P=0.02 and 0.9 [95% CI: 0.4-1.4], P=0.01, respectively) but not tracheostomy timing. Data were insufficient to assess tracheostomy technique on LOS. Duration of mechanical ventilation was 23.4 days (95% CI: 19.2-27.7; I2=99.3%), not associated with tracheostomy timing. Data were insufficient to assess the effect of tracheostomy technique on mechanical ventilation duration. Time to decannulation was 23.8 days (95% CI: 19.7-27.8; I2=98.7%), not influenced by tracheostomy timing or technique. The most common complications were stoma infection, ulcers or necrosis, and bleeding. CONCLUSIONS: In patients with COVID-19 requiring tracheostomy, the timing and technique of tracheostomy did not clearly impact on patient outcomes. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42021272220.

Laboratory Biomarkers for Diagnosis and Prognosis in COVID-19.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) causes a wide spectrum of clinical manifestations, with progression to multiorgan failure in the most severe cases. Several biomarkers can be altered in coronavirus disease 2019 (COVID-19), and they can be associated with diagnosis, prognosis, and outcomes. The most used biomarkers in COVID-19 include several proinflammatory cytokines, neuron-specific enolase (NSE), lactate dehydrogenase (LDH), aspartate transaminase (AST), neutrophil count, neutrophils-to-lymphocytes ratio, troponins, creatine kinase (MB), myoglobin, D-dimer, brain natriuretic peptide (BNP), and its N-terminal pro-hormone (NT-proBNP). Some of these biomarkers can be readily used to predict disease severity, hospitalization, intensive care unit (ICU) admission, and mortality, while others, such as metabolomic and proteomic analysis, have not yet translated to clinical practice. This narrative review aims to identify laboratory biomarkers that have shown significant diagnostic and prognostic value for risk stratification in COVID-19 and discuss the possible clinical application of novel analytic strategies, like metabolomics and proteomics. Future research should focus on identifying a limited but essential number of laboratory biomarkers to easily predict prognosis and outcome in severe COVID-19.

Neurological long-COVID in the outpatient clinic: Two subtypes, two courses.

INTRODUCTION: Symptoms referable to central and peripheral nervous system involvement are often evident both during the acute phase of COVID-19 infection and during long-COVID. In this study, we evaluated a population of patients with prior COVID-19 infection who showed signs and symptoms consistent with neurological long-COVID. METHODS: We prospectively collected demographic and acute phase course data from patients with prior COVID-19 infection who showed symptoms related to neurological involvement in the long-COVID phase. Firstly, we performed a multivariate logistic linear regression analysis to investigate the impact of demographic and clinical data, the severity of the acute COVID-19 infection and hospitalization course, on the post-COVID neurological symptoms at three months follow-up. Secondly, we performed an unsupervised clustering analysis to investigate whether there was evidence of different subtypes of neurological long COVID-19. RESULTS: One hundred and nine patients referred to the neurological post-COVID outpatient clinic. Clustering analysis on the most common neurological symptoms returned two well-separated and well-balanced clusters: long-COVID type 1 contains the subjects with memory disturbances, psychological impairment, headache, anosmia and ageusia, while long-COVID type 2 contains all the subjects with reported symptoms related to PNS involvement. The analysis of potential risk-factors among the demographic, clinical presentation, COVID 19 severity and hospitalization course variables showed that the number of comorbidities at onset, the BMI, the number of COVID-19 symptoms, the number of non-neurological complications and a more severe course of the acute infection were all, on average, higher for the cluster of subjects with reported symptoms related to PNS involvement. CONCLUSION: We analyzed the characteristics of neurological long-COVID and presented a method to identify well-defined patient groups with distinct symptoms and risk factors. The proposed method could potentially enable treatment deployment by identifying the optimal interventions and services for well-defined patient groups, so alleviating long-COVID and easing recovery.