Luo H, Liu D, Liu W, et al. Germline variants in UNC13D and AP3B1 are enriched in COVID-19 patients experiencing severe cytokine storms. Eur J Hum Genet Apr 19, 2021. https://www.nature.com/articles/s41431-021-00886-x
Whole-exome sequencing in 233 hospitalized COVID-19 patients identified four primary immunodeficiency gene variants significantly enriched in patients experiencing severe cytokine storms. The percentage of COVID-19 patients with variants in UNC13D or AP3B1, two typical hemophagocytic lymphohistiocytosis genes, was dramatically higher in the high level cytokine group than in the low level group (33.3% vs 5.7%, p < 0.001).
de la Morena-Barrio ME, Bravo-Pérez C, Miñano A. et al. Prognostic value of thrombin generation parameters in hospitalized COVID-19 patients. Sci Rep 08 April 2021, 11, 7792 (2021). https://www.nature.com/articles/s41598-021-85906-y
More on the pathogenesis of severe COVID-19. The severe “storm” of pro-inflammatory cytokines, combined with cell lysis, particularly at the endothelium, constitute insults leading to a significant hypercoagulable state that, despite antithrombotic prophylaxis, cause a consumptive and diffuse coagulopathy reflected by the increase of D-dimer, independent of the hypofibrinolysis that is also present in these patients. Patients with lower capacity of thrombin generation and higher D-dimer levels have poor prognosis.
Järhult JD, Hultström M, Bergqvist A. et al. The impact of viremia on organ failure, biomarkers and mortality in a Swedish cohort of critically ill COVID-19 patients. Sci Rep March 31, 11, 7163 (2021). https://www.nature.com/articles/s41598-021-86500-y
In this cohort from Sweden, RNAemia was found in 31/92 patients (34%). Extra-pulmonary organ failure biomarkers and the extent of organ failure were similar in patients with and without RNAemia. RNAemia was not an independent predictor of death at 30 days after adjustment for age.
INSPIRATION Investigators. Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit. JAMA March 18, 2021. doi:10.1001/jama.2021.4152. https://jamanetwork.com/journals/jama/fullarticle/2777829?resultClick=1
No need to increase the dose of prophylactic anticoagulation: a large RCT indicates no clinical benefit of intermediate dose compared with standard dose prophylactic anticoagulation in 452 patients with COVID-19 admitted to the intensive care unit (ICU).
Lin X, Fu B, Yin S, et al. ORF8 contributes to cytokine storm during SARS-CoV-2 infection by activating IL-17 pathway. iScience March 09, 2021. https://www.cell.com/iscience/fulltext/S2589-0042(21)00261-3
SARS-CoV-2 coding protein open reading frame 8 (ORF8) acts as a contributing factor to the cytokine storm during COVID-19 infection. ORF8 activated the IL-17 signaling pathway and promoted the expression of pro-inflammatory factors. Treatment of IL17RA antibody protects mice from ORF8-induced inflammation.
Yang P, Zhao Y, Li J. et al. Downregulated miR-451a as a feature of the plasma cfRNA landscape reveals regulatory networks of IL-6/IL-6R-associated cytokine storms in COVID-19 patients. Cell Mol Immunol (2021). https://doi.org/10.1038/s41423-021-00652-5
Cell-free circulating RNAs (cfRNAs) in plasma carry information from pathologic sites, and they have been reported to play important roles in disease development. Compared with healthy donors, significantly higher mRNA expression of IL-6R was observed; miR-451a, a known negative regulator of IL-6R translation, was down-regulated, which may promote IL-6R expression at the protein level.
Deinhardt-Emmer S, Böttcher S, Häring C, et al. SARS-CoV-2 causes severe epithelial inflammation and barrier dysfunction. J Virol 2021 Feb 26:JVI.00110-21. PubMed: https://pubmed.gov/33637603. Full-text: https://doi.org/10.1128/JVI.00110-21
To elucidate the viral effects on the barrier integrity and immune reactions, Stefanie Deinhardt-Emmer and colleagues from Jena, Germany used mono-cell culture systems and a complex human chip model composed of epithelial, endothelial, and mononuclear cells. SARS-CoV-2 efficiently infected epithelial cells with high viral loads and inflammatory response, including interferon expression. By contrast, the adjacent endothelial layer was not infected nor did it show productive viral replication or release of interferon. With prolonged infection, both cell types were damaged, and the barrier function was deteriorated, allowing the viral particles to have to carry too much.
Althaus K, Marini I, Zlamal J, et al. Antibody-induced procoagulant platelets in severe COVID-19 infection. Blood February 25, 2021, 137 (8): 1061–1071. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791311/
Severe COVID-19 is associated with antibody-mediated up-regulation of platelet apoptosis. In addition, Karina Althaus and colleagues from Tübingen, Germany found a correlation between platelet apoptosis markers and SOFA score, plasma levels of D-dimer, and the incidence of thromboembolic complications in severe COVID-19 patients. These data indicate that platelet apoptosis may contribute to sustained inflammation and increased thromboembolic risk in COVID-19 patients and could potentially present a potential therapeutic target.
Yao Y, Ye F, Li K, et al. Genome and epigenome editing identify CCR9 and SLC6A20 as target genes at the 3p21.31 locus associated with severe COVID-19. Sig Transduct Target Ther February 22, 2021, 6, 85. https://www.nature.com/articles/s41392-021-00519-1
Recently, genome-wide association studies (GWASs) have identified chromosome 3p21.31 (sentinel variant: rs11385942) to be associated with severe COVID-19. By utilizing CRISPR/Cas9-mediated genomic deletion, the authors identified CCR9 and SLC6A20 as potential target genes of the 3p21.31 locus.
Feldstein LR, Tenforde MW, Friedman KW, et al. Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19. JAMA Network February 24, 2021. JAMA February 24, 2021. https://jamanetwork.com/journals/jama/fullarticle/2777026
Incredibly large case series of 1116 patients aged less than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Comparing children and adolescents with MIS-C vs those with severe COVID-19, MIS-C was distinguished by certain demographic features and clinical presentations including being aged 6 to 12 years, being of non-Hispanic Black race, having severe cardiovascular or mucocutaneous involvement, and having more extreme inflammation.
Shah P, Smith H, Olarewaju A, et al. Is Cardiopulmonary Resuscitation Futile in Coronavirus Disease 2019 Patients Experiencing In-Hospital Cardiac Arrest? Critical Care Medicine: February 2021 – Volume 49 – Issue 2 – p 201-208. Full-text: https://doi.org/10.1097/CCM.0000000000004736
Well, probably yes. Out of 1094 COVID-19 patients who were admitted to three hospitals in Georgia, 63 patients suffered from in-hospital cardiac arrest with attempted resuscitation and were included in this study. Although return of spontaneous circulation was achieved in 29% of patients, it was brief in all of them. The in-hospital mortality was 100%.
Zeberg H, Pääbo S. A genomic region associated with protection against severe COVID-19 is inherited from Neandertals. PNAS 2021, published 2 March. Full-text: https://www.pnas.org/content/118/9/e2026309118
Svante Pääbo and Hugo Zeberg show that a haplotype on chromosome 12, which is associated with a ∼22% reduction in relative risk of becoming severely ill with COVID-19 when infected by SARS-CoV-2, is inherited from the Neanderthals. A great thanks to them!
Schwab P, Mehrjou A, Parbhoo S, et al. Real-time prediction of COVID-19 related mortality using electronic health records. Nat Commun 12, 1058 (2021). Full-text: https://www.nature.com/articles/s41467-020-20816-7
Patrick Schwab et al. present the COVID-19 early warning system (CovEWS), a real-time early warning system for predicting mortality of COVID-19 positive patients, using routinely collected clinical measurements and laboratory results from electronic health records (EHRs). CovEWS predicted mortality from 78,8% (95% CI: 76,0, 84,7%) to 69,4% (95% CI: 57,6, 75,2%) specificity at sensitivities greater than 95% between, respectively, 1 and 192 h prior to mortality events.
Chamberlain SR, Grant JE, Trender W. Post-traumatic stress disorder symptoms in COVID-19 survivors: online population survey. BJPsych Open 2021, published 9 February. Full-text: https://www.cambridge.org/core/journals/bjpsych-open/article/posttraumatic-stress-disorder-symptoms-in-covid19-survivors-online-population-survey/66F00143472B15757736AE5E3E42E52C
Samuel R. Chamberlain et al. examined post-traumatic stress disorder (PTSD) symptoms in 13.049 survivors of suspected or confirmed COVID-19, from the UK general population. Up to a third of COVID-19 patients who required ventilator support experienced extensive PTSD symptoms. Intrusive images were the most prominent elevated symptom.
Huang Z, Ning B, Yang HS, et al. Sensitive tracking of circulating viral RNA through all stages of SARS-CoV-2 infection. J Clin Invest 2021, published 9 February. Full-text: https://www.jci.org/articles/view/146031
Sensitive detection of SARS-CoV-2 RNA in blood by CRISPR-augmented RT-PCR permits accurate COVID-19 diagnosis, and can detect COVID-19 cases with transient or negative nasal swab RT-qPCR results. Tony Hu, Zhen Huang and colleagues suggest that this approach could improve COVID-19 diagnosis and the evaluation of SARS-CoV-2 infection clearance, and predict severity of infection.
Sablerolles RSG, Lafeber M, van Kempen JAL, et al. Association between Clinical Frailty Scale score and hospital mortality in adult patients with COVID-19 (COMET): an international, multicentre, retrospective, observational cohort study. Lancet Healthy Longevity 2021, published 9 February. Full-text: https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(21)00006-4/fulltext
In some places, the scarcity of resources has necessitated triage of critical care for COVID-19 patients. In patients aged 65 years and older, triage decisions are regularly based on degree of frailty, measured by the Clinical Frailty Scale (CFS). Here, Roos Sablerolles et al. show that among patients younger than 65 years, frail patients had an increased incidence of admission to intensive care, whereas mildly frail patients had no significant difference in incidence compared to fit patients. Likewise, an increased hospital mortality risk was only observed in frail patients. However, the authors caution that treatment decisions based on the CFS in patients younger than 65 years should be made with caution.
Liu L, Xie J, Wu W, et al. A simple nomogram for predicting failure of non-invasive respiratory strategies in adults with COVID-19: a retrospective multicentre study. Lancet Digital Health 2021, published 8 February. Full-text: https://www.thelancet.com/journals/landig/article/PIIS2589-7500(20)30316-2/fulltext
The authors developed and validated a nomogram and online calculator for the early prediction of non-invasive respiratory strategies (NIRS) failure in patients with COVID-19. These patients might benefit from early triage and more intensive monitoring. The nomogram, based on age, number of co-morbidities, ROX index, Glasgow coma scale score, and use of vasopressors on day 1 of NIRS, had a discriminatory ability (C-statistic) of 0,84 (95% CI: 0,81–0,87) in predicting NIRS failure. Patients in whom NIRS fails have a high risk of death.
Silva J, Lucas C, Sundaram M, et al. Saliva viral load is a dynamic unifying correlate of COVID-19 severity and mortality. medRxiv. 2021 Jan 10:2021.01.04.21249236. PubMed: https://pubmed.gov/33442706. Full-text: https://doi.org/10.1101/2021.01.04.21249236
Saliva viral load was significantly higher in those with COVID-19 risk factors and correlated with increasing levels of disease severity and showed a superior ability over nasopharyngeal viral load as a predictor of mortality over time. This is the message by Akiko Iwasaki, Julio Silva and colleagues who studied 154 patients admitted to Yale-New Haven hospital between March and June of 2020. Saliva viral load was positively associated with many known COVID-19 inflammatory markers such as IL-6, IL-18, IL-10, and CXCL10, as well as type 1 immune response cytokines. The authors conclude that viral load measured by saliva is a dynamic unifying correlate of disease presentation, severity, and mortality over time.
Downar J, Kekewich M. Improving family access to dying patients during the COVID-19 pandemic. Lancet Respir Med 2021, published 12 January. Full-text: https://doi.org/10.1016/S2213-2600(21)00025-4
James Downar and Mike Kekewich propose elements of an end-of-life visitor policy: 1) Visitors (up to 4, according to the size of the room) should be allowed during normal visiting hours, 2) preferably 1 h at a time, and 3) when physical circumstances allow, one family member can remain with the patient outside of these hours. 4) Avoid cycling of visitors and 5) make visitors comply with proper infection prevention and control procedures to limit the risks to patients, staff, and to themselves.
Supady A, Curtis JR, Abrams D, et al. Allocating scarce intensive care resources during the COVID-19 pandemic: practical challenges to theoretical frameworks. Lancet Respir Med 2021, published 12 January. Full-text: https://doi.org/10.1016/S2213-2600(20)30580-4
In the coming weeks, available medical resources will not always meet the increased demand for life-saving intensive care. Alexander Supady, Randall Curtis and colleagues propose that triage committees could be involved in providing policies and guidance for clinicians to help ensure equity in the application of rationing under crisis standards of care.
Gupta RK, Harrison WM, Ho A, et al. Development and validation of the ISARIC 4C Deterioration model for adults hospitalised with COVID-19: a prospective cohort study. Lancet Respir Med 2021, published 11 January. Full-text: DOI:https://doi.org/10.1016/S2213-2600(20)30559-2
How would you predict the risk of clinical deterioration in acute COVID-19 cases? Mahdad Noursadeghi, Rishi K Gupta and colleagues developed and validated a prognostic model for in-hospital clinical deterioration which integrated 11 routinely available predictors: age, sex, nosocomial infection, Glasgow coma scale score, peripheral oxygen saturation (SpO2) at admission, breathing room air or oxygen therapy (contemporaneous with SpO2 measurement), respiratory rate, urea concentration, C-reactive protein concentration, lymphocyte count, and presence of radiographic chest infiltrates.
Contou D, Fraissé M, Pajot O, Tirolien JA, Mentec H, Plantefève G. Comparison between first and second wave among critically ill COVID-19 patients admitted to a French ICU: no prognostic improvement during the second wave? Crit Care. 2021 Jan 4;25(1):3. PubMed: https://pubmed.gov/33397421. Full-text: https://doi.org/10.1186/s13054-020-03449-6
During the first wave of the SARS-CoV-2 pandemic in Spring 2020, intensive care physicians discovered specificities of severe COVID-19 including the need for deep sedation and neuromuscular blockade, the increased risk of thrombotic and hemorrhagic events, the prolonged duration of mechanical ventilation with high rate of delirium, and the beneficial effects of early administration of glucocorticoids. Here, Damien Contou et al. report their experience during the second SARS-CoV-2 wave in Autumn 2020. Their sobering discovery: compared to the first wave, less patients required invasive mechanical ventilation, thrombotic events were less frequent and the delay between ICU admission and tracheal intubation was longer. However, ICU mortality (50% vs. 52%, p = 0.96) and duration of ICU stay did not differ between the two waves. The Kaplan–Meier survival analysis did not show a significant difference between the two waves (p = 0.90, log-rank test).
Le Breton C, Besset S, Freita-Ramos S, et al. Extracorporeal membrane oxygenation for refractory COVID-19 acute respiratory distress syndrome. J Crit Care. 2020 Dec;60:10-12. PubMed: https://pubmed.gov/32731100. Full-text: https://doi.org/10.1016/j.jcrc.2020.07.013
Extra-corporeal membrane oxygenation (ECMO) in patients with severe COVID-1 has been associated with high mortality rates. Here, Jean-Damien Ricard, D. Roux, C. Le Breton and colleagues report on 13 patients who required VV-ECMO (femoro-jugular cannulation). All 13 patients were weaned from ECMO after a median of 13 days (range 3 to 34). Two patients died while still on mechanical ventilation. As of June 28th, 2020 all surviving patients were weaned from the ventilator after a median duration of 29 days (range 20 to 51) and were discharged alive from the ICU after a mean stay of 34 days (range 23 to 55). The authors conclude that ECMO should be an integral part of intensive care for properly selected COVID-19 patients without life-threatening co-morbidities.
Maltezou HC, Raftopoulos V, Vorou R, et al. Association between upper respiratory tract viral load, comorbidities, disease severity and outcome of patients with SARS-CoV-2 infection. J Infect Dis 2021, published 3 January. Full-text: https://doi.org/10.1093/infdis/jiaa804
Upper respiratory tract (URT) viral load could be used to identify patients at higher risk for morbidity or severe outcome. This is the result of a study that included 1122 patients (mean age: 46 years), both asymptomatic and symptomatic patients, either hospitalized or cared for in the community. Helena Maltezou et al. categorized URT as high, moderate or low. A high URT viral load was more often detected in patients with COVID-19 than in asymptomatic patients. Patients with the following co-morbidities more often had high URT viral load than moderate or low URT viral load: chronic cardiovascular disease, hypertension, chronic pulmonary disease, immunosuppression, obesity, and chronic neurological disease (p values < 0.05 for all comparisons). A high SARS-CoV-2 URT viral load was significantly associated with an increased risk for intubation or a fatal outcome in the course of COVID-19, as well as with prolonged disease severity.
Park J, Kim H, Kim SY, et al. In-depth blood proteome profiling analysis revealed distinct functional characteristics of plasma proteins between severe and non-severe COVID-19 patients. Sci Rep. 2020 Dec 29;10(1):22418. PubMed: https://pubmed.gov/33376242. Full-text: https://doi.org/10.1038/s41598-020-80120-8
The authors found 76 previously unreported proteins which could be novel prognostic biomarker candidates. Their plasma proteome signatures highlighted the role of neutrophil activation, complement activation, platelet function, and T cell suppression as well as pro-inflammatory factors upstream and downstream of interleukin-6, interleukin-1B, and tumor necrosis factor.
Lee MH, Perl DP, Nair G, et al. Microvascular Injury in the Brains of Patients with Covid-19. N Engl J Med 2020, published 30 December. Full-text: https://doi.org/10.1056/NEJMc2033369
Avindra Nath, Myoung-Hwa Lee and colleagues from the US National Institute of Neurological Disorders and Stroke in Bethesda observed multifocal microvascular injury in the brain and olfactory bulbs in the brains of 13 patients. They found no evidence of viral infection after PCR with multiple primer sets, RNA sequencing of several areas of the brain, and RNA in situ hybridization and immunostaining.
Maximous S, Brotherton BJ, Achilleos A, et al. Pragmatic Recommendations for the Management of COVID-19 Patients with Shock in Low- and Middle-Income Countries. Am J Trop Med Hyg. 2020 Dec 21. PubMed: https://pubmed.gov/33350378. Full-text: https://doi.org/10.4269/ajtmh.20-1105
The authors suggest using Sequential Organ Failure Assessment (qSOFA) and point-of-care ultrasound (POCUS) for evaluation purposes to use fluid therapy, norepinephrine and low-dose corticosteroids depending on etiology. The authors also recommend avoiding the routine use of central venous or arterial catheters and using simple bedside measures such as capillary refill time to address targets of resuscitation.
Shashikumar SP, Wardi G, Paul P, et al. Development and Prospective Validation of a Deep Learning Algorithm for Predicting Need for Mechanical Ventilation. Chest. 2020 Dec 17:S0012-3692(20)35454-4. PubMed: https://pubmed.gov/33345948. Full-text: https://doi.org/10.1016/j.chest.2020.12.009
Can a transparent deep learning (DL) model predict the need for MV in hospitalized patients and those with COVID-19 up to 24 hours in advance? The authors used commonly available data in electronic health records as well as commonly used clinical criteria (heart rate, oxygen saturation, respiratory rate, FiO2 and pH) to feed their deep learning algorithm. The model provided significant improvement over traditional clinical criteria (p < 0.001).
Feng Z, Zhao H, Kang W, et al. Association of Paraspinal Muscle Measurements on Chest Computed Tomography with Clinical Outcomes in Patients with Severe Coronavirus Disease 2019. J Gerontol A Biol Sci Med Sci. 2020 Dec 23:glaa317. PubMed: https://pubmed.gov/33355656. Full-text: https://doi.org/10.1093/gerona/glaa317
For elderly patients in intensive care units or with critical illness, skeletal muscle loss adversely affects clinical outcomes. Here, Pengfei Rong, Zhishao Feng and colleagues from Third Xiangya Hospital, Central South University, Changsha, report that higher paraspinal muscle radiodensity (PMD), a proxy measure of lower muscle fat deposition, may be associated with a reduced risk of disease deterioration and decreased likelihood of prolonged viral shedding among female patients with severe COVID-19.
Asch DA, Sheils NE, Islam N, et al. Variation in US Hospital Mortality Rates for Patients Admitted With COVID-19 During the First 6 Months of the Pandemic. JAMA Intern Med. Published online December 22, 2020. Full-text: https://doi.org/10.1001/jamainternmed.2020.8193
COVID-19 mortality in hospitals seems to be lower when the prevalence of SARS-CoV-2 infection in their surrounding communities is lower; and hospital outcomes for patients with COVID-19 have been improving throughout the year 2020. These are the key messages of a cohort study of 38.517 adult patients by David Asch and colleagues from the University of Pennsylvania. See also the comment by Boudourakis L. Decreased COVID-19 Mortality—A Cause for Optimism. JAMA Intern Med. Published online December 22, 2020. Full-text: https://doi.org/10.1001/jamainternmed.2020.8438.
Jorge A, D’Silva KM, Cohen A, et al. Temporal trends in severe COVID-19 outcomes in patients with rheumatic disease: a cohort study. Lancet Rheumatology 2020, published 23 December. Full-text: https://doi.org/10.1016/S2665-9913(20)30422-7
In this cohort study of patients with rheumatic and musculoskeletal diseases, Hyon Choi, April Jorge and colleagues from Massachusetts General Hospital compared 2811 patients who were diagnosed with COVID-19 during the first 90 days of the pandemic (early cohort) with 5729 patients diagnosed during the second 90 days of the pandemic (late cohort). The late cohort fared better: the risk of hospitalization, intensive care unit admission, mechanical ventilation, acute kidney injury, renal replacement therapy, and death was lower in the late cohort than in the early cohort. This finding is probably multifactorial, due to increased testing capacity allowing for detection of milder cases, improved supportive care, and improved treatments. The lesson for the future: use historical comparators cautiously in observational studies of new therapies for COVID-19!
Jiang Y, Abudurexiti S, An MM, et al. Risk factors associated with 28-day all-cause mortality in older severe COVID-19 patients in Wuhan, China: a retrospective observational study. Sci Rep 10, 22369 (2020). https://doi.org/10.1038/s41598-020-79508-3
Studies about risk factors for increased COVID-19 mortality abound. In this retrospective study from Wuhan including 281 older patients with severe COVID-19 categorized into two age groups (60–79 years and ≥ 80 years), LDH had the highest predictive value for 28-day all-cause mortality.
Working group for the surveillance and control of COVID-19 in Spain; Members of the Working group for the surveillance and control of COVID-19 in Spain. The first wave of the COVID-19 pandemic in Spain: characterisation of cases and risk factors for severe outcomes, as at 27 April 2020. Euro Surveill. 2020 Dec;25(50). PubMed: https://pubmed.gov/33334400. Full-text: https://doi.org/10.2807/1560-7917.ES.2020.25.50.2001431
During the first pandemic wave in Spain in spring 2020, males had higher odds ratio (OR) of severe outcomes than females with regard to hospitalization, ICU admission and death. Pneumonia was associated with a 27-fold higher odds of hospitalization. Patients who presented with cardiovascular disease were more likely to have a severe outcome. Older age predicted mortality, with highest odds of death among patients ≥ 80 years (OR: 28.45; 95% CI: 19.85–40.78), compared with patients < 40 years. Looking at predisposing conditions, chronic kidney disease had the highest OR of death.
Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med 2020, published 17 December. Full-text: https://doi.org/10.1056/NEJMcp2009575
David Berlin, Roy Gulick and Fernando Martinez describe the case of a 50-year-old, previously healthy man who presented to the emergency department with 2 days of worsening dyspnea. He had fever, cough, and fatigue during the week before presentation. The authors discuss various strategies, review some guidelines for severe COVID-19 (American Thoracic Society, Infectious Diseases Society of America, National Institutes of Health, and Surviving Sepsis Campaign) and conclude with recommendations.
Kwak PE, Connors JR, Benedict PA. Early Outcomes From Early Tracheostomy for Patients With COVID-19. JAMA Otolaryngol Head Neck Surg December 17, 2020. Full-text: https://doi.org/10.1001/jamaoto.2020.4837
Retrospective medical record review of 148 patients requiring mechanical ventilation at a single tertiary-care medical center in New York City. Median length of stay was 40 days in those who underwent early tracheostomy (within 10 days of endotracheal intubation) and 49 days in those who underwent late tracheostomy. In a competing risks model with death as the competing risk, the late tracheostomy group was 16% less likely to discontinue mechanical ventilation (hazard ratio, 0.84; 95% CI, 0.55 to 1.28). According to the authors, their data provide an opportunity to reconsider guidelines for tracheostomy for patients with COVID-19, demonstrating non-inferiority of early tracheostomy.
Bharat A, Querrey M, Markov NS, et al. Lung transplantation for patients with severe COVID-19. Sci Transl Med. 2020 Dec 16;12(574):eabe4282. PubMed: https://pubmed.gov/33257409. Full-text: https://doi.org/10.1126/scitranslmed.abe4282
Ankit Bharat and colleagues from Chicago report the results of lung transplantation in three patients with non-resolving COVID-19–associated respiratory failure: a 28-year-old Latina female with neuromyelitis optica (who was treated with rituximab, patient A), a 62-year-old male with hypertension (B), and a 43-year-old man with medically controlled type 2 diabetes mellitus (C). About 4-5 months after transplantation, patients A and B reported independence in activities of daily living while patient C received care in an in-patient rehabilitation facility at month 3. SARS-CoV-2 RNA could not be detected in the explanted lungs of these patients, but fibrotic pathology and transcriptional changes resembling those of lungs from patients with pulmonary fibrosis were observed.
Koehler P, Bassetti M, Chakrabarti A, et al. Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. Lancet Infect Dis 2020, published 14 December. Full-text: 2020. Full-text: https://doi.org/10.1016/S1473-3099(20)30847-1
SARS-CoV-2 causes direct damage to the airway epithelium, enabling aspergillus invasion, and azole-resistant aspergillus have been reported. Philipp Koehler et al. present a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, endorsed by medical mycology societies. Among the key messages: a) Three different grades are proposed (possible, probable, and proven COVID-19-associated invasive pulmonary aspergillosis [CAPA]) to enable researchers to homogeneously classify patients in registries and interventional clinical trials; b) voriconazole or isavuconazole are recommended as first-line treatment for possible, probable, and proven CAPA.
Kaeuffer C, Le Hyaric C, Fabacher T, et al. Clinical characteristics and risk factors associated with severe COVID-19: prospective analysis of 1,045 hospitalised cases in North-Eastern France, March 2020. Eurosurveill 2020, published 3 December. Full-text: https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.48.2000895
This non-interventional prospective study (1045 adult COVID-19 patients hospitalized in two different hospitals in Alsace, France: Strasbourg University Hospital and Mulhouse Hospital in March 2020) presents a wealth of data. Advanced age, being male, inflammation parameters and dyspnea were associated with the development of severe disease and death. Being overweight or obese was associated with severe disease only, whereas co-morbidities such as chronic kidney disease, diabetes and immunosuppression increased the risk of death.
Bramante CT, Ingraham NE, Murray TA, et al. Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis. Lancet Healthy Longevity 2020, published 3 December. Full-text: https://doi.org/10.1016/S2666-7568(20)30033-7
Metformin for women with obesity or type 2 diabetes who are hospitalized for COVID-19? This is the suggestion of a retrospective cohort analysis by Carolyn Bramante from the University of Minnesota. Metformin was associated with decreased mortality in women by Cox proportional hazards (HR 0·785, 95% CI 0·650–0·951) and propensity matching (OR 0·759, 95% CI 0·601–0·960, p = 0·021). If these findings are reproduced in prospective studies, the safe and inexpensive drug might be used for prevention of COVID-19 mortality. There was no significant reduction in mortality among men.
See also the comment by Dardano A, Del Prato S. Metformin: an inexpensive and effective treatment in people with diabetes and COVID-19? Lancet Healthy Longevity 2020, published 3 December. Full-text: https://doi.org/10.1016/S2666-7568(20)30047-7
Ceulemans LJ, Van Slambrouck J, De Leyn, P, et al. Successful double-lung transplantation from a donor previously infected with SARS-CoV-2. Lancet Respir Med 2020 published 1 December. Full-text: https://doi.org/10.1016/S2213-2600(20)30524-5
Laurens Ceulemans from the University Hospitals Leuven, Belgium, report a successful double-lung transplantation from a donor exposed to SARS-CoV-2 who had mild COVID-19-like symptoms 3 months earlier. The lungs were successfully transplanted without viral transmission to the recipient, as shown by repetitive bronchoalveolar lavage and serology after transplantation.
See also the Video abstract: https://www.thelancet.com/cms/10.1016/S2213-2600(20)30524-5/attachment/9385e393-669b-466b-b39e-c756b87ea947/mmc1.mp4 and the comment by Meyer KC. Risks of lung transplantation in the SARS-CoV-2 era. Lancet Respir Med 2020 published 1 December. Full-text: https://doi.org/10.1016/S2213-2600(20)30561-0
Knoouhuizen SA, Aday A, Lee WM. Ketamine‐Induced Sclerosing Cholangitis (KISC) in a Critically Ill Patient with COVID‐19. Hepatology 23 November 2020. Full-text: https://doi.org/10.1002/hep.31650
Prior reports of recreational ketamine abuse have been associated with findings of secondary sclerosing cholangitis. The authors report here a novel presentation of the syndrome in association with prolonged ketamine use in the intensive care unit.
Fiacchini G, Tricò D, Ribechini A, et al. Evaluation of the Incidence and Potential Mechanisms of Tracheal Complications in Patients With COVID-19. JAMA Otolaryngol Head Neck Surg. Published online November 19, 2020. Full-text: https://doi.org/10.1001/jamaoto.2020.4148
Giacomo Fiacchini and colleagues from Pisa, Italy demonstrate a high tracheal complication rate of invasive mechanical ventilation. In their cohort study of 98 patients with COVID-19 and severe respiratory failure, the incidence of full-thickness tracheal lesions or tracheoesophageal fistulas after prolonged (≥ 14 days) invasive mechanical ventilation was significantly higher in patients with COVID-19 (46,7%) than matched controls (2,2%). Attempts to prevent these lesions should be made and quickly recognized when they occur to avoid potentially life-threatening complications in ventilated patients with COVID-19.
Sun L, Hymowitz M, Pomeranz HD. Eye Protection for Patients With COVID-19 Undergoing Prolonged Prone-Position Ventilation. JAMA Ophthalmol. Published online November 19, 2020. Full-text: https://doi.org/10.1001/jamaophthalmol.2020.4988
Clinicians should also be aware of the possible presence of elevated intraocular pressure from periorbital edema due to direct compression of the eye and orbit, and optic disc edema and retinal hemorrhages, which may be associated with a hypercoagulable state, in patients in prolonged prone position. Lucy Sun and colleagues report on two patients with periorbital edema in the prone position with bilateral findings of optic disc edema and retinal hemorrhages as well as a substantial increase in intraocular pressure.
Al-Salameh A, Lanoix JP, Bennis Y, et al. The association between body mass index class and coronavirus disease 2019 outcomes. Int J Obes (2020). Full-text: https://doi.org/10.1038/s41366-020-00721-1
Being overweight (and not only obesity) is associated with ICU admission, but is not associated with death. This is the result of a retrospective study from Amiens University Hospital, France. In total, 433 consecutive patients were included, and BMI data were available for 329: 20 were underweight (6,1%), 95 had a normal weight (28,9%), 90 were overweight (27,4%), and 124 were obese (37,7%). The ORs for ICU admission were similar for overweight (3.16) and obesity (3.05).
Jain A, Chaurasia R, Sengar NS, et al. Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers. Sci Rep 10, 20191 (2020). https://doi.org/10.1038/s41598-020-77093-z
A higher fatality rate in vitamin D deficient patients (21% vs 3.1%)? Vitamin D levels markedly low in patients with severe COVID-19? These are the conclusions of a study including asymptomatic 91 COVID-19 patients (Group A) and 63 severely ill patients requiring ICU admission (Group B). The prevalence of vitamin D deficiency was 32.96% and 96.82% respectively in Group A and Group B.
Gu SX, Tyagi T, Jain K, et al. Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nat Rev Cardiol (2020). https://doi.org/10.1038/s41569-020-00469-1
The authors summarize evidence pointing to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19. Discover potential therapeutic strategies in the management of patients with COVD-19.
Zietz M, Zucker J, Tatonetti NP. Associations between blood type and COVID-19 infection, intubation, and death. Nat Commun 11, 5761 (2020). Full-text: https://doi.org/10.1038/s41467-020-19623-x
This next study is about the association between ABO and Rh blood types and infection, intubation, and death. Here, the authors used observational healthcare data on 14,112 individuals tested for SARS-CoV-2 with known blood type in the New York Presbyterian hospital system. Risk of intubation was decreased among A and increased among AB and B types, compared with type O, while risk of death was increased for type AB and decreased for types A and B. Rh-negative blood type might have a protective effect for all three outcomes.
Gude F, Riveiro V, Rodríguez-Núñez N, et al. Development and validation of a clinical score to estimate progression to severe or critical state in COVID-19 pneumonia hospitalized patients. Sci Rep 10, 19794 (2020). Full-text: https://doi.org/10.1038/s41598-020-75651-z
Five predictors determined within 24 h of hospital admission may identify patients at risk for COVID-19 disease progression: diabetes, higher age, a low lymphocyte count, decreasing SaO2, and any pH alteration. This is the outcome of a study by Lucía Ferreiro, Francisco Gude and colleagues who analyzed 229 patients who were admitted for pneumonia. The prediction model showed a good clinical performance, including discrimination (AUC 0.87 CI 0.81, 0.92) and calibration (Brier score = 0.11). In total, 0%, 12%, and 50% of patients with severity risk scores ≤ 5%, 6–25%, and > 25% exhibited disease progression, respectively.
Ledford H. Why do COVID death rates seem to be falling? Nature 2020, published 11 November. Full-text: https://www.nature.com/articles/d41586-020-03132-4
Hard-won experience, changing demographics and reduced strain on hospitals are all possibilities — but no one knows how long this change will last. By Heidi Ledford.
Wang F, Huang S, Gao R. Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility. Cell Discov 6, 83 (2020). Full-text: https://doi.org/10.1038/s41421-020-00231-4
HLA-A*11:01, B*51:01, and C*14:02 alleles might predispose to severe COVID-19. This is the result of a host genetic study deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity. Lei Liu, Fang Wang and colleagues conducted single-variant and gene-based association tests among five severity groups: asymptomatic, mild, moderate, severe, and critically ill patients. Find out more about genes involved in the interleukin-1 (IL-1) signaling pathway and the stability of the TMPRSS2 protein.
Liu Y, Lv J, Liu J. et al. Mucus production stimulated by IFN-AhR signaling triggers hypoxia of COVID-19. Cell Res November 6, 2020. Full-text: https://doi.org/10.1038/s41422-020-00435-z
It’s mucus: this great work may potentially explain the silent hypoxia that has emerged as a unique feature of COVID-19. Yuying Liu and colleagues from Beijing, China show that mucins are accumulated in the bronchoalveolar lavage fluid and are up-regulated in the lungs of severe SARS-CoV-2-infected mice and macaques. They also found that induction of either interferon (IFN)-β or IFN-γ on SARS-CoV-2 infection results in activation of aryl hydrocarbon receptor (AhR) signaling through an IDO-Kyn-dependent pathway, leading to transcriptional upregulation of the expression of mucins, both the secreted and membrane-bound, in alveolar epithelial cells. Consequently, accumulated alveolar mucus affects the blood-gas barrier, thus inducing hypoxia and diminishing lung capacity, which can be reversed by blocking AhR activity.
Evans RM, Lippman SM. Shining Light on the COVID-19 Pandemic: A Vitamin D Receptor Checkpoint in Defense of Unregulated Wound Healing. Cell Metab. 2020 Sep 11;32(5):704-9. PubMed: https://pubmed.gov/32941797. Full-text: https://doi.org/10.1016/j.cmet.2020.09.007
Ronald Evans and Scott Lippman propose repurposing paricalcitol (vitamin D analog) infusion therapy to restrain the COVID-19 cytokine storm, reasoning that vitamin D deficiency and the failure to activate the vitamin D receptor can aggravate this respiratory syndrome by igniting a wounding response in stellate cells of the lung. Find out what could be the appropriate dose and the potential complications.
Mastrangelo A, Germinarkio BN, Ferrante M, et al. Candidemia in COVID-19 patients: incidence and characteristics in a prospective cohort compared to historical non-COVID-19 controls. Clinical Infectious Diseases, 30 October 2020, ciaa1594. Full-text: https://doi.org/10.1093/cid/ciaa1594
This study found an increased incidence of candidemia in hospitalized patients with COVID-19 compared to a historical non-COVID-19 cohort (11 vs. 1.5 cases per 10.000-PDFU). The authors found no imbalance in several predisposing risk factors for candidemia, with the notable exception of a higher proportion of subjects in ICU and on immunosuppressive agents in the COVID-19 cohort.
Yu J, Yuan X, Chen H, Chaturvedi S, Braunstein EM, Brodsky RA. Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition. Blood. 2020 Oct 29;136(18):2080-2089. PubMed: https://pubmed.gov/32877502. Full-text: https://doi.org/10.1182/blood.2020008248
COVID-19 often results in hypercoagulability, thrombotic microangiopathy, and severe endothelial damage. The role of complement activation and its contribution to disease severity is increasingly recognized, but the mechanism of complement activation was unknown. Here, Robert A Brodsky and collegues from John Hopkins University demonstrate that SARS-CoV-2 spike protein, but not spike protein from benign human coronaviruses, are potent activators of the alternative pathway of complement (APC). Both S1 and S2 subunits activate the APC, but only in the presence of cells, demonstrating that APC activation is occurring on the cell surface and not the fluid phase. Both C5 inhibitors and ACH145951, a small molecule factor D inhibitor, were able to block the APC activation, preventing complement-mediated damage.
Mueller AA, Tamura T, Crowley CP, et al. Inflammatory biomarker trends predict respiratory decline in COVID-19 patients. Cell Rep Med 2020, published 28 October. Full-text: https://doi.org/10.1016/j.xcrm.2020.100144
Increasing C-reactive protein (CRP) values during the first 48 hours of hospitalization is a better predictor of respiratory decline than initial CRP levels. A rapid rise in CRP levels precedes respiratory deterioration and intubation, while CRP levels plateau in patients that remain stable. A finding of a single-center retrospective cohort analysis of 100 hospitalized COVID-19 patients.
Identifying the determinants of the clinical spectrum, from people with asymptomatic disease to patients with severe COVID-19 is one of the pressing questions surrounding SARS-CoV-2. The spectrum varies from asymptomatic SARS-CoV-2 infection (up to 40%) to severe COVID-19 (fatality near 1%). David Beck and Ivona Aksentijevich discuss two analyses of >1600 patients infected with SARS-CoV-2 from >15 countries to identify endogenous factors that determine susceptibility to severe COVID-19. We presented the papers on September 25:
Bastard P, Rosen LB, Zhang Q, et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science 2020, published 24 September. Full-text: https://science.sciencemag.org/content/early/2020/09/23/science.abd4585
Zhang Q, Bastard P, Liu Z, et al: Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 2020, published 24 September. Full-text: https://science.sciencemag.org/content/early/2020/09/23/science.abd4570
Botta M, Tsonas AM, Pillay J, et al. Ventilation management and clinical outcomes in invasively ventilated patients with COVID-19 (PRoVENT-COVID): a national, multicentre, observational cohort study. Lancet Resp Med October 23, 2020. Full-text: https://doi.org/10.1016/S2213-2600(20)30459-8
A retrospective observational study at 18 intensive care units in the Netherlands, with a detailed analysis of 553 patients who received mechanical ventilation during the first month of the national outbreak in the country. Median duration of ventilation was long with 13,5 days, placing an enormous burden on ICUs. Lung-protective ventilation with low tidal volume (52%) and low driving pressure was broadly applied and prone positioning was often used. The applied PEEP varied widely (from 5 to 20 cm!), despite an invariably low respiratory system compliance. Of note, the PEEP had no impact on outcome. In total, 186/530 (35%) patients died by day 28. Predictors of 28-day mortality were gender, age, tidal volume, respiratory system compliance, arterial pH, and heart rate on the first day of invasive ventilation. In total, 21% had thromboembolic complications.
Cates J, Lucero-Obusan C, Dahl RM, et al. Risk for In-Hospital Complications Associated with COVID-19 and Influenza — Veterans Health Administration, United States, October 1, 2018–May 31, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1528–1534. Full-text: http://dx.doi.org/10.15585/mmwr.mm6942e3
COVID-19 is deadlier than influenza. Now, Jordan Cates and colleagues have quantified the difference: hospitalized patients with COVID-19 had a more-than-five-times-higher risk for in-hospital death and increased risk for 17 respiratory and non-respiratory complications than did hospitalized patients with influenza. The risks for sepsis and respiratory, neurologic, and renal complications of COVID-19 were higher among non-Hispanic Black or African American and Hispanic patients than among non-Hispanic White patients.
“While we try to heal from the collective trauma we experienced in our hospital over the worst 4 months of the local epidemic, I struggle to know where to look. Peering into the future, given what we see on the news, saturates me with dread. And yet it’s too early to look back. Perspective can’t develop in the presence of open wounds.”
Rodrigues JY, Le Pape P, Lopez O, et al. Candida auris: a latent threat to critically ill patients with COVID-19, Clinical Infectious Diseases. Full-text: https://doi.org/10.1093/cid/ciaa1595
Jose Y Rodrigues and colleagues report on 20 cases of fungemia in hospitalized patients with SARS-CoV-2 infection in 4 institutions in the northern region of Colombia from June to September 2020. Nineteen of the 20 patients had received steroids and 15/19 were had non-albicans Candida fungemia.
Thomas R, Lotfi T, Morgano GP, et al. Update Alert 2: Ventilation Techniques and Risk for Transmission of Coronavirus Disease, Including COVID-19. Annals Int Med 13 October 2020. Full-text: https://doi.org/10.7326/L20-1211
Update of a living systematic review on ventilation techniques, analyzing all new studies published until the end of July. Bottom line: Nothing new. Non-invasive ventilation may have similar effects to IMV on mortality, but the evidence is uncertain.
de Nooijer AH, Grondman I, Janssen NAF, et al. Complement activation in the disease course of COVID-19 and its effects on clinical outcomes. J Infect Dis 2020, published 10 October. Full-text: https://doi.org/10.1093/infdis/jiaa646
In this prospective, longitudinal, single center study, Leo Joosten, Aline de Nooijer and colleagues analyzed plasma concentrations of complement factors C3a, C3c, and terminal complement complex (TCC) for 197 patients with confirmed COVID-19. Complement factors C3a, C3c and TCC were significantly increased in plasma of COVID-19 patients compared to healthy controls (p<0.05). These complement factors were especially elevated in ICU patients during the entire disease course (p<0.005 for C3a and TCC).
Overmyer KA, Shishkova E, Miller IJ, et al. Large-scale Multi-omic Analysis of COVID-19 Severity. Cell Systems 2020, published 7 October. Full-text: https://doi.org/10.1016/j.cels.2020.10.003
In this cohort study involving 128 patients with and without COVID-19 diagnosis, Ariel Jaitovich, Katherine Overmyer and colleagues monitored thousands of biomolecules in relation to the COVID-19 disease severity and outcomes. They mapped more than 200 molecular features with high significance to COVID-19 status and severity, many involved in complement activation, dysregulated lipid transport, and neutrophil activation. The authors make their data available through a free web resource – https://covid-omics.app, calling for experts worldwide to mine these data.
Avilés-Jurado FX, Prieto-Alhambra D, González-Sánchez N, et al. Timing, Complications, and Safety of Tracheotomy in Critically Ill Patients With COVID-19. JAMA Otolaryngol Head Neck Surg. Published online October 08, 2020. Full-text: http://doi.org/10.1001/jamaoto.2020.3641
How safe is an early bedside surgical tracheotomy in patients with coronavirus disease 2019 (COVID-19)? The authors analyze data from 50 patients (mean [SD] age, 63.8 [9.2] years; 33 [66%] male). The median time from intubation to tracheotomy was 9 days (interquartile range, 2-24 days). The successful weaning rate was higher in the early tracheotomy group than in the late tracheotomy group (adjusted hazard ratio, 2.55), but the difference was not statistically significant. There was no infection among surgeons within 4 weeks after the last tracheotomy.
Altschul DJ, Unda SR, Benton J, et al. A novel severity score to predict inpatient mortality in COVID-19 patients. Sci Rep 10, 16726 (2020). Full-text: https://doi.org/10.1038/s41598-020-73962-9
Determining which patients are at high risk of severe illness or mortality is essential for appropriate clinical decision making. By analyzing the date from 4711 SARS-CoV-2 infected patients, the authors developed a COVID-19 severity score ranging from 0 to 10, consisting of age, oxygen saturation, mean arterial pressure, blood urea nitrogen, C-reactive protein, and the international normalized ratio. The probability of mortality was 11.8%, 39% and 78% for patients with either a low (0–3), moderate (4–6) or high (7–10) COVID-19 severity score.
Moiseev S, Avdeev S, Brovko M, et al. Outcomes of intensive care unit patients with COVID-19: a nationwide analysis in Russia. Anaesthesia. 2020 Oct 5. PubMed: https://pubmed.gov/33015828. Full-text: https://doi.org/10.1111/anae.15265
Same bad outcomes of ICU patients in Russia. In a nationwide study, the authors have evaluated the mortality rate in 1522 consecutive ICU patients with SARS‐CoV‐2 pneumonia who had completed their hospital stay (death or recovery) up to 7 July 2020. The 14- and 28-day mortality rates were 44.0% and 63.6%, respectively.
Brown J, Gregson FKA, Shrimpton A, et al. A quantitative evaluation of aerosol generation during tracheal intubation and extubation. Anaesthesia. 2020 Oct 6. PubMed: https://pubmed.gov/33022093. Full-text: https://doi.org/10.1111/anae.15292
This group conducted real‐time, high‐resolution environmental monitoring in ultraclean ventilation operating theatres during tracheal intubation and extubation sequences. Interestingly, both intubation and extubation sequences produced less aerosol than voluntary coughing. For the sequence of tracheal intubation, in particular, the concentration of aerosol generated was several orders of magnitude less than a single cough and was only very modestly above background levels of circulating particles.
Liu YM, Xie J, Chen MM, et al. Kidney function indicators predict adverse outcomes of COVID-19. Med 2020, published 2 October. Full-text: https://doi.org/10.1016/j.medj.2020.09.001
Kidney injury is one more of the clinical COVID-19 complications. In this retrospective study, the authors analyzed data from 12,413 patients. At admission, the prevalence of elevated blood urea nitrogen (BUN), elevated serum creatinine (Scr), and decreased blood uric acid (BUA) at admission was 6.29%, 5.22%, 11.66%, respectively. The authors found that elevated baseline levels of BUN and Scr, and decreased level of BUA, were associated with a high risk of mortality.
Webb BJ, Pletan ID, Jensen P, et al. Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study. Lancet Rheumatology September 29, 2020DOI: https://doi.org/10.1016/S2665-9913(20)30343-X
Brandon Webb and colleagues propose criteria for hyperinflammation in COVID-19. Based on 299 hospitalized patients, a six-criterion additive scale was developed using the following biomarkers: fever, macrophage activation (hyperferritinemia), hematological dysfunction (neutrophil to lymphocyte ratio), hepatic injury (lactate dehydrogenase or asparate aminotransferase), coagulopathy (D dimer), and cytokinaemia (C reactive protein, interleukin-6, or triglycerides). This hyperinflammatory state, cHIS, is commonly associated with progression to mechanical ventilation and death. External validation is needed. The cHIS scale might be helpful in defining target populations for trials and immunomodulatory therapies.
Hattenstone S. Michael Rosen on his Covid-19 coma: ‘It felt like a pre-death, a nothingness’. The Guardian 2020, published 30 September. Full-text: https://www.theguardian.com/books/2020/sep/30/michael-rosen-on-his-covid-19-coma-it-felt-like-a-pre-death-a-nothingness
Earlier this year, the beloved children’s writer Michael Rosen spent six weeks on a ventilator with coronavirus. He talks about the magic of the NHS, the mismanagement of the crisis and how his near-death experience has changed him
Barbaro RP, MacLaren G, Boonstra PS, et al. Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry. Lancet 2020, published 25 September. Full-text: https://doi.org/10.1016/S0140-6736(20)32008-0
Initial reports of extracorporeal membrane oxygenation (ECMO) use in patients with COVID-19 described very high mortality. Here Ryan Barbaro et al. report data for 1035 patients who received ECMO support from 213 hospitals in 36 countries. Of these, 6% remained hospitalized, 30% were discharged home or to an acute rehabilitation center, 10% were discharged to a long-term acute care center or unspecified location, 17% were discharged to another hospital, and 37% died.
Yadaw AS, Li YC, Bose S, et al. Clinical features of COVID-19 mortality: development and validation of a clinical prediction model. Lancet Digital Health 2020, published 1 October. Full-text: https://doi.org/10.1016/S2589-7500(20)30217-X
Predicting mortality among patients with COVID-19 is difficult. Here, the authors developed a COVID-19 mortality prediction model that showed high accuracy when applied to test datasets of retrospective (n=961) and prospective (n=249) patients. The authors showed that input of three highly accessible clinical parameters for a patient—age, minimum oxygen saturation, and type of patient encounter—into an automatable eXtreme Gradient Boosting (XGBoost) algorithm has the potential to accurately classify patients as likely to live or die.
Ho EP, Neo HY. COVID 19: Prioritise Autonomy, Beneficence and Conversations Before Score-based Triage. Age Ageing 2020, published 25 September. Full-text: https://doi.org/10.1093/ageing/afaa205
In the coming weeks, demand for intensive COVID-19 care may overwhelm ICU capacities in Spain, France, the UK and other European countries. Decisions regarding ICU admission are particularly challenging in older people, who are most likely to require critical care, but for whom benefits are most uncertain. The authors suggest that physicians should first discern if older people will benefit from critical care (beneficence) and second, if they want critical care (autonomy). Decisions should be based on individualized risk-stratification and survival weighed against burden of treatment, as well as longer-term functional deficits and quality-of-life. Tough times ahead.
Shah GL, DeWolf S, Lee YJ, et al. Favorable outcomes of COVID-19 in recipients of hematopoietic cell transplantation. J Clin Invest. 2020 Sep 8:141777. PubMed: https://pubmed.gov/32897885. Full-text: https://doi.org/10.1172/JCI141777
Can you safely perform hematopoietic cell transplantation in patients with COVID-19? In this retrospective study, Miguel-Angel Perales, Gunjan Shah and colleagues identified 77 SARS-CoV-2 + cellular therapy recipients (Allo = 35, Auto = 37, CAR-T = 5; median time from cellular therapy 782 days. Without active malignancy, overall clinical outcome was favorable. Survival at 30 days was 78%. In the Discussion, you’ll find information about the lymphocyte populations that are key for the anti-viral response and immune reconstitution.
Schultz MJ, Teng MS, Brenner MJ. Timing of Tracheostomy for Patients With COVID-19 in the ICU—Setting Precedent in Unprecedented Times. JAMA Otolaryngol Head Neck Surg September 3, 2020. Full-text: https://doi.org/10.1001/jamaoto.2020.2630
When to perform tracheostomy (and how)? Marcus J. Schultz and colleagues review the current evidence and give a nice overview of misconceptions that predispose to uncontrolled variation in tracheostomy among COVID-19 patients. However, the bottom line is: Decisions on tracheostomy must be personalized; some patients may be awake but cannot yet be extubated (favoring tracheostomy), whereas other patients may have immediate, severe hypoxemia when lying supine or with any period of apnea (favoring deferral).
Charre C, Icard V, Pradat P, et al. Coronavirus disease 2019 attack rate in HIV-infected patients and in preexposure prophylaxis users. AIDS. 2020 Oct 1;34(12):1765-1770. PubMed: https://pubmed.gov/32889852. Full-text: https://doi.org/10.1097/QAD.0000000000002639
Caroline Charre analyzed the COVID-19 attack rate in a small group of HIV-infected patients and in PrEP users in the Rhône county, France, and compared it with the general population. No differences were observed.
Lang C, Jaksch P, Hoda MA, et al. Lung transplantation for COVID-19-associated acute respiratory distress syndrome in a PCR-positive patient. Lancet Resp Med, August 25, 2020. Full-text: https://doi.org/10.1016/S2213-2600(20)30361-1
An incredible case of a brave, otherwise healthy 44-year-old woman from Klagenfurt, Austria. After a battle of 52 days with critical COVID-19, ECMO and several complications, a comprehensive interdisciplinary discussion on the direction of treatment resulted in a consensus that the lungs of the patient had no potential for recovery. On day 58, a suitable donor organ became available and a sequential bilateral lung transplant was performed. At day 144, the patient remained well. Despite the success of this case, Christian Lang and his colleagues emphasize that lung transplantation is an option for only a small proportion of patients.
Cypel M, Keshavjee S. When to consider lung transplantation for COVID-19. Lancet Resp Med, August 25, 2020. Full-text: https://doi.org/10.1016/S2213-2600(20)30393-3
Well written editorial reviewing this case. The authors list ten considerations that they believe should be carefully weighed when assessing a patient with COVID-19-associated ARDS regarding potential candidacy for lung transplantation (< 65 years, only single-organ dysfunction, sufficient time for lung recovery, radiological evidence of irreversible lung disease, such as severe bullous destruction or established fibrosis etc.).
Manson JJ, Crooks C, Naja M, et al. COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study. Lancet Rheumatol 2020, published 21 August. Full-text: https://doi.org/10.1016/S2665-9913(20)30275-7
Jessica Manson et al. define a phenotype of COVID-19-associated hyperinflammation (COV-HI) by measurement of readily available routine clinical parameters:
- C-reactive protein (greater than 150 mg/L or doubling within 24 h from greater than 50 mg/L) and 2)
- Ferritin (greater than 1500 μg/L)
Of patients with COV-HI on admission, 36/90 patients (40%) died during follow-up compared with 46/179 (26%) of the patients without COV-HI on admission, indicating the existence of a high-risk inflammatory phenotype. The authors conclude that COV-HI might be useful to stratify patients in trial design. See also the critical comment by Kiran Reddy and colleagues (Reddy K, Rogers AJ, McAuley DF: Delving beneath the surface of hyperinflammation in COVID-19. Lancet Rheumatol 2020, published 21 August. Full-text: https://doi.org/10.1016/S2665-9913(20)30304-0).
Hanley B, Naresh KN, Roufosse C, et al. Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study. Lancet Microbe August 20, 2020. Full-text: https://doi.org/10.1016/S2666-5247(20)30115-4
Ten cases of fatal COVID-19 showed diffuse alveolar damage, thrombosis, hemophagocytosis, and immune cell depletion. The authors report several novel autopsy findings including pancreatitis, pericarditis, adrenal micro-infarction, secondary disseminated mucormycosis, and brain microglial activation.
Mustafa AK, Alexander PJ, Joshi DJ, et al. Extracorporeal Membrane Oxygenation for Patients With COVID-19 in Severe Respiratory Failure. JAMA Surg. 2020 Aug 11. PubMed: https://pubmed.gov/32780089. Full-text: https://doi.org/10.1001/jamasurg.2020.3950
According to this retrospective report on 40 patients, single-access, dual-stage venovenous ECMO with early extubation appears to be safe and effective in patients with COVID-19 respiratory failure. Ongoing studies are required, however, to further define the long-term outcomes of this approach.
Prescott HC, Girard TD. Recovery From Severe COVID-19: Leveraging the Lessons of Survival From Sepsis. JAMA 2020, published 5 August. Full-text: https://doi.org/10.1001/jama.2020.14103
Up to 20% of patients hospitalized with COVID-19 will develop viral sepsis and acute respiratory distress syndrome (ARDS). Of those who survive, how many patients are likely to experience long-lasting morbidity? Hallie Prescott and Timothy Girard review what is known about long-term outcomes after severe disease caused by other coronaviruses (SARS and MERS)***. Despite the limited data available for severe COVID-19, they suggest following the practices that are recommended for recovery from sepsis.
Ahmed H, Patel K, Greenwood DC, et al. Long-term clinical outcomes in survivors of severe acute respiratory syndrome and Middle East respiratory syndrome coronavirus outbreaks after hospitalisation or ICU admission: A systematic review and meta-analysis. J Rehabil Med. 2020 May 31;52(5):jrm00063. PubMed: https://pubmed.gov/32449782. Full-text: https://www.medicaljournals.se/jrm/content/abstract/10.2340/16501977-2694
Bartoletti M, Pascale R, Cricca M, et al. Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: a prospective study. Clin Inf Dis 2020, published 28 July. Full-text: https://doi.org/10.1093/cid/ciaa1065
Michele Bartoletti and colleagues enrolled 108 patients in a prospective, multicenter study to evaluate the incidence of invasive pulmonary aspergillosis among intubated patients with critical COVID-19. Coronavirus associated pulmonary aspergillosis (CAPA) was diagnosed in 30 patients (27.7%) after a median of 4 (2-8) days from intensive care unit (ICU) admission. Kaplan-Meier curves showed a significant higher 30-day mortality rate from ICU admission among patients with either CAPA (44% vs 19%, p = 0.002) or PIPA (74% vs 26%, p < 0.001) when compared with patients not fulfilling criteria for aspergillosis.
Kon ZN, Smith DE, Chang SH, et al. Extracorporeal Membrane Oxygenation Support in Severe COVID-19. Ann Thorac Surg. 2020 Jul 17:S0003-4975(20)31152-8. PubMed: https://pubmed.gov/32687823. Full-text: https://doi.org/10.1016/j.athoracsur.2020.07.002
The authors describe their institutional practice regarding ECMO support for 27 patients with COVID-19. At the time of paper submission, survival was 96.3% (one death) in over 350 days of total ECMO support. Thirteen patients (48.1%) remained on ECMO support, while 13 patients (48.1%) were successfully decannulated. Seven patients (25.9%) were discharged from the hospital while six patients (22.2%) remained in the hospital, of which four were on (unmodified) room air. The authors rightly conclude that the judicious use of ECMO support may be clinically beneficial.
Grasselli G, Greco M, Zanella A, et al. Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy. JAMA Intern Med July 15, 2020. Full-text: https://doi.org/10.1001/jamainternmed.2020.3539
If you are in the ICU, it’s 50/50. In this large cohort study of 3,988 critically ill patients, most required invasive mechanical ventilation, and mortality rate was high. In the subgroup of the first 1715 patients, 915 patients died in the hospital for an overall hospital mortality of (53.4%).
Gupta S, Hayek SS, Wang W, et al. Factors Associated With Death in Critically Ill Patients With Coronavirus Disease 2019 in the US. JAMA Intern Med July 15, 2020. –Full-text: https://doi.org/10.1001/jamainternmed.2020.3596
But it depends where you are. In this US cohort of 2,215 adults with COVID-19 who were admitted to ICUs at 65 sites, 784 (35.4%) died within 28 days. However, mortality showed an extremely wide variation among hospitals (range, 6.6%-80.8%). Factors associated with death included older age, male sex, obesity, coronary artery disease, cancer, acute organ dysfunction, and, importantly, admission to a hospital with fewer intensive care unit beds. Patients admitted to hospitals with fewer than 50 ICU beds versus at least 100 ICU beds had a higher risk of death (OR 3.28; 95% CI, 2.16-4.99).
Liao D, Zhou F, Luo L, et al. Haematological characteristics and risk factors in the classification and prognosis evaluation of COVID-19: a retrospective cohort study. Lancet Hematology July 10, 2020. Full-text: https://doi.org/10.1016/S2352-3026(20)30217-9
This retrospective cohort study focussed on hematological and coagulation parameters in patients with moderate, severe, and critical COVID-19, along with specific analyses of coagulopathy in non-survivors. Among 380 patients, thrombocytopenia was more frequent in patients with critical disease (49%) than in those with severe (14%) or moderate (6%). In multivariate analyses, death was associated with increased neutrophil to lymphocyte ratio (odds ratio 5.39), thrombocytopenia (OR 8.33), prolonged prothrombin time (OR 4.94), and increased D-dimer (OR 4.41). The onset of sepsis-induced coagulopathy was typically before overt disseminated intravascular coagulation.
Kander T. Coagulation disorder in COVID-19. Lancet Hematology July 10, 2020. Full-text: https://doi.org/10.1016/S2352-3026(20)30218-0
Careful comment on these findings. According to the author, the study is a valuable contribution to the knowledge of the coagulation profile of patients with COVID-19 and highlights the established role of routine coagulation tests as predictive variables for mortality and morbidity. However, the question of whether the observed changes in routine coagulation tests are just markers of the severity of illness or whether they show a significant and specific pathophysiology that drives morbidity and mortality in itself is still unanswered.
Moezinia CH, Ji-Xu A, Azari A, et al. Iloprost for COVID-19-related vasculopathy. Lancet Rheumatology July 10, 2020. Full-text: https://doi.org/10.1016/S2665-9913(20)30232-0
Interesting new finding: iloprost as a therapy to mitigate the pathological effects of COVID-19. Iloprost is a prostacyclin receptor agonist that promotes vasodilation of circulatory beds with minimal impact on hemodynamic parameters. It is licensed for the treatment of pulmonary arterial hypertension and is widely used for the management of peripheral vascular disease and digital vasculopathy, including digital ulcers and critical digital ischemia in systemic sclerosis. The authors describe three morbidly obese patients with severe COVID-19 and systemic microvasculopathy who obviously benefitted from its use. Its potential ability to reduce endothelial dysfunction and systemic inflammation could make iloprost a key player in management of COVID-19 vasculopathy.
Ackermann M, Verlden SE, Kuehnel M, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. NEJM July 9, 2020; 383:120-128. Full-text: https://doi.org/10.1056/NEJMoa2015432 l (Important)
This study examined the morphologic and molecular features of seven lungs obtained during autopsy from COVID-19 patients and found three distinctive angiocentric features: 1. Severe endothelial injury associated with intracellular virus and disrupted endothelial cell membranes. 2. Widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries (9 times as prevalent as in patients with influenza). 3. significant new vessel growth through a mechanism of intussusceptive angiogenesis (2.7 x higher).
Fan E, Beitler JR, Brochard L, et al. COVID-19-associated acute respiratory distress syndrome: is a different approach to management warranted? Lancet Respir Med July 06, 2020. Full-text: https://doi.org/10.1016/S2213-2600(20)30304-0 l (Important)
In their Viewpoint, the authors address ventilation strategies in the context of recent discussions on phenotypic heterogeneity in patients with COVID-19-associated ARDS. Although early reports suggested distinctive features that set it apart from historical ARDS, emerging evidence indicates that the respiratory system mechanics are broadly similar. In the absence of evidence to support a shift away from the current paradigm of ventilatory management, we strongly recommend adherence to evidence-based management, informed by bedside physiology, as resources permit.
Kollias A, Kyriakoulis KG, Stergiou GS, Syrigos K. Heterogeneity in reporting venous thromboembolic phenotypes in COVID-19: Methodological issues and clinical implications. Br J Haematol. 2020 Jul 4. PubMed: https://pubmed.gov/32621757. Full-text: https://doi.org/10.1111/bjh.16993
Some thoughts about the heterogeneity in the reported VTE risk as well as in the thromboembolic phenotypes of COVID-19 patients (isolated DVT, isolated pulmonary embolism/thrombosis, concurrent DVT and pulmonary embolism/thrombosis). It might be suggested that variation in VTE accounts for this heterogeneity: characteristics of the patients include well-established risk factors for VTE, hospitalization conditions and interventions as well as SARS-CoV-2 specific factors.
Nightingale R, Nwosu N, Kutubudin F, et al. Is continuous positive airway pressure (CPAP) a new standard of care for type 1 respiratory failure in COVID-19 patients? A retrospective observational study of a dedicated COVID-19 CPAP service. BMJ Open Respir Res. 2020 Jul;7(1):e000639. PubMed: https://pubmed.gov/32624495. Full-text: https://doi.org/10.1136/bmjresp-2020-000639
Small retrospective study of 24 patients. According to the authors, with careful patient selection and close monitoring, CPAP can be a successful treatment strategy in critically ill patients with type 1 respiratory failure in COVID-19, and that it can be safely deployed outside the critical care environment.
Sinha P, Matthay MA, Calfee CS. Is a “Cytokine Storm” Relevant to COVID-19? JAMA Intern Med June 30, 2020. Full-text: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2767939 l (Important)
“Cytokine storm” has no definition. Broadly speaking, it denotes a hyperactive immune response characterized by the release of interferons, interleukins, tumor necrosis factors, chemokines, and several other mediators. In this editorial, a critical evaluation of the term cytokine storm and its relevance is given. The authors point out that although the term “cytokine storm” conjures up dramatic imagery and has captured the attention of the mainstream and scientific media, the current data do not support its use. Until new data establish otherwise, the linkage of cytokine storm to COVID-19 may be nothing more than a tempest in a teapot.
Goshua G, Pine AB, Meizlish ML, et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet June 30, 2020. Full-text: https://doi.org/10.1016/S2352-3026(20)30216-7
In 68 COVID-19 patients, the authors assessed several markers of endothelial cell and platelet activation, including von Willebrand Factor (VWF) antigen, soluble thrombomodulin, soluble P-selectin, and soluble CD40 ligand, as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes. Markers of endothelial cell and platelet activation were significantly elevated in ICU patients compared with non-ICU patients, including VWF antigen and soluble P-selectin. Some were of prognostic value, indicating that endotheliopathy is present in COVID-19 and is likely to be associated with critical illness and death.
McGonagle D, O’Donnell JS, Sharif K. Pulmonary intravascular coagulopathy in COVID-19 pneumonia – Authors’ reply. Lancet June 29, 2020. Full-text: https://doi.org/10.1016/S2665-9913(20)30174-0
Interesting discussion about the diffuse, alveolar-centred inflammation that triggers immunothrombosis in the lung microvasculature of patients with COVID-19 pneumonia. It seems highly probable that multiple mechanisms contribute to the pulmonary intravascular coagulopathy.
Mangalmurti N, Hunter CA. Cytokine Storms: Understanding COVID-19. Immunity June 28, 2020. Full-text: https://doi.org/10.1016/j.immuni.2020.06.017 l (Important)
Facing the storm: In their nice overview, the authors explain the protective function of cytokines in “ideal” responses; the multi-factorial origins that can drive these responses to become pathological; and how this ultimately leads to vascular damage, immunopathology, and worsening clinical outcomes. Of note, not all cytokine storms are the same, and there are many variables—the nature of the insult, host immune status, tissue affected, crosstalk with immune thrombosis, and complement activation—that influence the magnitude and kinetics of these responses and thus the clinical manifestations.
Pfeifer M, Ewig S, Voshaar T, et al. Position Paper for the State-of-the-Art Application of Respiratory Support in Patients with COVID-19. Respiration. 2020 Jun 19:1-21. PubMed: https://pubmed.gov/32564028. Full-text: https://doi.org/10.1159/000509104 ll (Outstanding)
Important statements including observations about the pathophysiology of acute respiratory failure (ARF). Pulmonary damage in advanced COVID-19 often differs from acute respiratory distress syndrome (ARDS). Two types (type L and type H) are differentiated, corresponding to early- and late-stage lung damage. This differentiation should be taken into consideration in respiratory support. Based on current knowledge, inhalation therapy, nasal high-flow therapy (NHF), continuous positive airway pressure (CPAP), or non-invasive ventilation (NIV) can be performed without an increased risk of infection to staff if PPE is provided. In ARF, NIV should be carried out in an intensive care unit or a comparable setting by experienced staff. If the ARF progresses under CPAP/NIV, intubation should be implemented without delay in patients who do not have a “do not intubate”.
Colling ME, Kanthi Y. COVID-19-associated coagulopathy: An exploration of mechanisms. Vasc Med. 2020 Jun 19:1358863X20932640. PubMed: https://pubmed.gov/32558620. Full-text: https://doi.org/10.1177/1358863X20932640 l (Important)
Nice review of the laboratory and clinical findings of patients with COVID-19-associated coagulopathy. The authors hypothesize that an imbalance between coagulation and inflammation may result in a hypercoagulable state. Although thrombosis initiated by the innate immune system is hypothesized to limit SARS-CoV-2 dissemination, aberrant activation of this system can cause endothelial injury resulting in loss of thromboprotective mechanisms, excess thrombin generation, and dysregulation of fibrinolysis and thrombosis.
Thompson AE, Ranard BL, Wei Y. Prone Positioning in Awake, Nonintubated Patients With COVID-19 Hypoxemic Respiratory Failure. JAMA Intern Med June 17, 2020. Full-text: https://doi.org/10.1001/jamainternmed.2020.3030
The next study on proning. In this small single-center cohort study, use of the prone position for 25 awake, spontaneously breathing patients with COVID-19 was associated with improved oxygenation. In addition, patients with an Spo2 of 95% or greater after 1 hour of the prone position was associated with a lower rate of intubation. Unfortunately, there was no control group and the sample size was very small. Ongoing clinical trials of prone positioning in non–mechanically ventilated patients (NCT04383613, NCT04359797) will hopefully help clarify the role of this simple, low-cost approach for patients with acute hypoxemic respiratory failure.
Endeman H, van der Zee P, van Genderen ME, van den Akker JPC, Gommers D. Progressive respiratory failure in COVID-19: a hypothesis. Lancet Infect Dis. 2020 Apr 29:S1473-3099(20)30366-2. PubMed: https://pubmed.gov/32530428. Full-text: https://doi.org/10.1016/S1473-3099(20)30366-2
Of 90 patients with severe COVID-19, 17 deteriorated within 2 weeks and no longer responded to prone positioning. All (!) of these patients had major pulmonary embolism established by lung CT or cardiac ultrasound. A plasma D-dimer concentration greater than 4 μg/mL, combined with increasing inflammatory markers such as interleukin-6 (the authors recommend to measure it regularly), and loss of response to prone positioning might be useful parameters to identify patients at risk of pulmonary embolism.
Gabarre P, Dumas G, Dupont T, Darmon M, Azoulay E, Zafrani L. Acute kidney injury in critically ill patients with COVID-19. Intensive Care Med. 2020 Jun 12. PubMed: https://pubmed.gov/32533197. Full-text: https://doi.org/10.1007/s00134-020-06153-9
One of the best reviews on this topic to date. AKI is prevalent in critically ill COVID-19 patients. Several mechanisms are possibly involved, including direct invasion of SARS-CoV-2 into the renal parenchyma, an imbalanced RAAS and microthrombosis, but also kidney injury secondary to hemodynamic instability, inflammatory cytokines and the consequences of therapeutics that are used in ICU (nephrotoxic drugs, mechanical ventilation).
Carsana L, Sonzogni A, Nasr A, et al. Pulmonary post-mortem findings in a series of COVID-19 cases. Lancet 2020, June 08. Full-text: https://doi.org/10.1016/S1473-3099(20)30434-5
Lung tissue samples from 38 patients who died from COVID-19 in two hospitals in northern Italy were analyzed. The predominant pattern was diffuse alveolar damage, as described in patients infected with SARS and MERS. Hyaline membrane formation and pneumocyte atypical hyperplasia were frequent. However, the presence of platelet–fibrin thrombi in small arterial vessels was consistent with coagulopathy, which appears to be common in patients with COVID-19.
Ferreyro BL, Angriman F, Munshi L, et al. Association of Noninvasive Oxygenation Strategies With All-Cause Mortality in Adults With Acute Hypoxemic Respiratory Failure. JAMA June 4, 2020. Full-text: https://doi.org/10.1001/jama.2020.9524
For this network meta-analysis of trials of adult patients with acute hypoxemic respiratory failure, the authors included 25 studies with 3,804 patients. Compared with standard oxygen therapy, helmet NIV (3 trials with 330 patients), face mask NIV (14 trials with 1725 patients) and HFNC (5 trials with 1479 patients) were associated with a lower risk of endotracheal intubation. Both forms of NIV, helmet and face mask, were also associated with a lower risk of death.
Patel BK, Kress JP, Hall JB. Alternatives to Invasive Ventilation in the COVID-19 Pandemic. JAMA June 4, 2020. Full-text: https://doi.org/10.1001/jama.2020.9611
This article reviews the meta-analysis and describes how COVID-19 has accelerated the need to add clarity to the ongoing debate of whether to intubate early and, if not, which type of non-invasive support (NIV, HFNC, or standard oxygen therapy) is the most efficacious. Future clinical trials comparing these strategies should not focus on declaring a “winner” per se but rather on identifying the patient phenotypes that stand to benefit from each non-invasive oxygenation support method. According to the authors, a heterogeneous syndrome like AHRF requires multiple options.
Von Weyhern C, Kaufmann I, Neff F, Kremer M. Early evidence of pronounced brain involvement in fatal COVID-19 outcomes. The Lancet, June 4, 2020. Full-text: https://doi.org/10.1016/S0140-6736(20)31282-4
Autopsy findings of six patients (four men and two women, aged 58–82 years) who died from COVID-19 in April 2020. A pronounced CNS involvement with pan-encephalitis, meningitis, and brainstem neuronal cell damage were key events in all cases. In patients younger than 65 years, CNS hemorrhage was a fatal complication of COVID-19.
Al-Samkari H, Karp Leaf RS, Dzik WH, et al. COVID and Coagulation: Bleeding and Thrombotic Manifestations of SARS-CoV2 Infection. Blood. 2020 Jun 3:blood.2020006520. PubMed: https://pubmed.gov/32492712. Full-text: https://doi.org/10.1182/blood.2020006520
Retrospective study, describing the rate and severity of hemostatic and thrombotic complications of 400 hospital-admitted COVID-19 patients (144 critically ill), receiving standard-dose prophylactic anticoagulation. The overall and major bleeding rates were 4.8% and 2.3%. RCTs are needed to determine any potential benefit of intensified anticoagulant prophylaxis in COVID-19 patients.
Tremblay D, van Gerwen M, Alsen M, et al. Impact of anticoagulation prior to COVID-19 infection: a propensity score-matched cohort study. Blood. 2020 May 27. PubMed: https://pubmed.gov/32462179. Full-text: https://doi.org/10.1182/blood.2020006941 l (Important)
Empiric therapeutic anti-coagulation (AC) is now being employed in clinical practice in many centers, and will be evaluated in randomized clinical trials. To adjust for bias due to non-random allocation of potential covariates among COVID-19 patients, the authors applied propensity score matching methods. Among > 3000 patients, propensity matching yielded 139 patients who received AC and 417 patients who did not receive treatment with balanced variables between the groups. Results suggest that AC alone is unlikely to be protective for COVID-19-related morbidity and mortality.
Maatman TK, Jalali F, Feizpour C, et al. Routine Venous Thromboembolism Prophylaxis May Be Inadequate in the Hypercoagulable State of Severe Coronavirus Disease 2019. Critical Care Medicine May 27, 2020. Full-text: https://doi.org/10.1097/CCM.0000000000004466 l (Important)
240 consecutive patients with confirmed SARS-CoV-2 were admitted to one of three US hospitals and 109 were critically ill. Venous thromboembolism was diagnosed in 31 patients (28%) 8 ± 7 days after hospital admission. Authors conclude that routine chemical venous thromboembolism prophylaxis may be inadequate in preventing venous thromboembolism in severe COVID-19.
Cummings MJ, Baldwin MR, Abrams D, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet. 2020 May 19:S0140-6736(20)31189-2. PubMed: https://pubmed.gov/32442528. Full-text: https://doi.org/10.1016/S0140-6736(20)31189-2l (Important)
More on critically ill patients. Among 1,150 adults who were admitted to two NYC hospitals with COVID-19 in March, 257 (22%) were critically ill. The median age of patients was 62 years (IQR 51-72), 67% were men and 82% patients had at least one chronic illness. As of the end of April, 101 (39%) patients had died and 94 (37%) remained hospitalised. 203 (79%) patients received invasive mechanical ventilation for a median of 18 days, 66% received vasopressors and 31% received renal replacement therapy. In the multivariable Cox model, older age, chronic cardiac disease (adjusted HR 1.76), chronic pulmonary disease (2.94) were independently associated with in-hospital mortality. This was also seen for higher concentrations of interleukin-6 and D-dimer, highlighting the role of systemic inflammation and endothelial-vascular damage in the development of organ dysfunction. Studies on immunomodulating and anticoagulant drugs are urgently needed.
Varga Z, Flammer AJ, Steiger P, et al. Electron microscopy of SARS-CoV-2: a challenging task – Authors’ reply. Lancet. 2020 May 19:S0140-6736(20)31185-5. PubMed: https://pubmed.gov/32442527. Full-text: https://doi.org/10.1016/S0140-6736(20)31185-5
Endothelial cell dysfunction may explain the vascular microcirculatory complications seen in different organs in patients with COVID-19. The authors discuss the framework of endotheliitis, providing explanation for the unique predilection of SARS-CoV-2 in those individuals with hypertension, diabetes, or established cardiovascular disease, groups known to have pre-existing endothelial dysfunction.
Schünemann HJ, Khabsa J, Solo K, et al. Ventilation Techniques and Risk for Transmission of Coronavirus Disease, Including COVID-19. A Living Systematic Review of Multiple Streams of Evidence. Ann Int Med 2020, May 22. Full-text: https://www.acpjournals.org/doi/10.7326/M20-2306 l (Important)
The authors reviewed evidence regarding the benefits and harms of ventilation techniques. Indirect and low-certainty evidence suggests that use of non-invasive ventilation, similar to invasive mechanical ventilation, probably reduces mortality but may increase the risk for transmission of COVID-19 to health care workers.
Bhatraju PK, Ghassemieh BJ, Nichols M, et al. Covid-19 in Critically Ill Patients in the Seattle Region — Case Series. N Engl J Med 2020, May 21; 382:2012-2022. Full-text: https://doi.org/10.1056/NEJMoa2004500
This report describes clinical characteristics, imaging findings, and outcomes among 24 critically ill COVID-19 patients who presented with acute hypoxemic respiratory failure in the Seattle metropolitan area. Mortality was high (at least 50%, three patients still intubated at last follow-up).
Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020 May 21. PubMed: https://pubmed.gov/32437596. Full-text: https://doi.org/10.1056/NEJMoa2015432 l (Important)
It’s not influenza. The authors carefully examined lungs from 7 deceased COVID-19 patients with lungs from 7 patients who died from ARDS secondary to influenza A and 10 age-matched, uninfected control lungs. In COVID-19 or influenza, the histologic pattern was diffuse alveolar damage with perivascular T-cell infiltration. However, the COVID-19 lungs showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi and the amount of vessel growth were 9 and almost 3 times as prevalent as in influenza, respectively.
George PM, Wells AU, Jenkins RG. Pulmonary Fibrosis and COVID-19: The Potential Role for Antifibrotic Therapy. Lancet Respir Med 2020 May 15; S2213-2600(20)30225-3. https://doi.org10.1016/S2213-2600(20)30225-3. Full-text: https://linkinghub.elsevier.com/retrieve/pii/S2213260020302253
This brilliant article gives an overview on the (potentially high) burden of fibrotic lung disease following SARS-CoV-2 infection. Post-viral fibrosis may lead to severe physiological impairment. Available antifibrotic therapies such as pirfenidone (a pyridone with a poorly understood mechanism of action) and the thyrosine kinase inhibitor nintedanib have broad antifibrotic activity regardless of etiology, and these drugs might have a role in attenuating profibrotic pathways in SARS-CoV-2 infection. Current knowledge and future strategies are discussed.
Heman-Ackah SM, Su YS, Spadola M, MD. Neurologically Devastating Intraparenchymal Hemorrhage in COVID-19 Patients on Extracorporeal Membrane Oxygenation: A Case Series. Neurosurgery 2020. Full-text: https://doi.org/10.1093/neuros/nyaa198
Two patients required ECMO for refractory hypoxia secondary to COVID-19 and developed neurologically devastating intra-parenchymal hemorrhage despite lacking the classical risk factors. Authors recommend CT screening to identify brain injury that would otherwise go undetected due to the poor reliability of classic coagulation markers as accurate clinical predictors of hemorrhage in this cohort, as well as the inability to perform neurological assessments in the setting of paralysis, sedation, and proning.
Elharrar X, Trigui Y, Dols AM, et al. Use of Prone Positioning in Nonintubated Patients With COVID-19 and Hypoxemic Acute Respiratory Failure. JAMA. May 15, 2020. Full-text: https://jamanetwork.com/journals/jama/fullarticle/2766292
This prospective, before-after study was conducted in Aix-en-Provence (France) among 24 awake, non-intubated, spontaneously breathing patients with COVID-19 and hypoxemic acute respiratory failure requiring oxygen supplementation. Efficacy of prone positioning was only moderate. Only 63% were able to tolerate PP for more than 3 hours. Oxygenation increased in only 25% and was not sustained in half of those after resupination. However, prone sessions were short, partly because of limited patient tolerance.
Telias I, Katira BH, Brochard L, et al. Is the Prone Position Helpful During Spontaneous Breathing in Patients With COVID-19? JAMA. Published online May 15, 2020. Full-text: https://doi.org/10.1001/jama.2020.8539
This editorial summarizes current knowledge on prone position. PP during spontaneous and assisted breathing may become a therapeutic intervention. Tolerance may be a limitation of the technique and the benefits of short sessions remain to be seen. Several larger trials are ongoing, addressing the question whether PP prevents intubation.
Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. May 15, 2020. Full-text: https://www.nejm.org/doi/full/10.1056/NEJMcp2009575 l (Important)
Comprehensive overview about current knowledge (and knowledge gaps) about treatment of patients who develop severe disease. Basics of respiratory care, ventilation management and supportive care. Areas of uncertainties are also discussed.
Lax SF, Skok K, Zechner P. Pulmonary Arterial Thrombosis in COVID-19 With Fatal Outcome: Results From a Prospective, Single-Center, Clinicopathologic Case Series. Annals Int Med 2020, May 14. Full-text: https://www.acpjournals.org/doi/10.7326/M20-2566
The next autopsy study on 11 deceased patients with COVID-19 (10 selected randomly). Death may be caused by the thrombosis observed in segmental and subsegmental pulmonary arterial vessels despite the use of prophylactic anticoagulation.
Deshpande C. Thromboembolic Findings in COVID-19 Autopsies: Pulmonary Thrombosis or Embolism? Annals Int Med 2020, May 15. Full-text: https://doi.org/10.7326/M20-3255.
Well-balanced editorial, condensing current knowledge on the contributions of pulmonary thrombosis, embolism, or their combination to deaths of patients with COVID-19. Some studies have found pulmonary embolism with or without deep venous thrombosis, as well as presence of recent thrombi in prostatic venous plexus, in patients with no history of VTE, suggesting de novo coagulopathy in these patients with COVID-19. Others have highlighted changes consistent with thrombosis occurring within the pulmonary arterial circulation, in the absence of apparent embolism.
Ziehr DR, Alladina J, Petri CR, et al. Respiratory Pathophysiology of Mechanically Ventilated Patients with COVID-19: A Cohort Study. Am J Respir Crit Care Med. 2020 Apr 29. PubMed: https://pubmed.gov/32348678. Full-text: https://doi.org/10.1164/rccm.202004-1163LE
Treat it like ARDS! The authors provide a pathophysiologic justification for the use of established ARDS therapies, including low tidal volume and early prone ventilation. In their retrospective cohort of 66 COVID-19 patients (median age 58 years) with respiratory failure, fatality was only 17%. The authors conclude that their patients exhibit similar gas exchange, respiratory system mechanics, and response to prone ventilation as prior large cohorts of patients with ARDS.
Matheny Antommaria AH, Gibb TS, McGuire AL, et al. Ventilator Triage Policies During the COVID-19 Pandemic at U.S. Hospitals Associated With Members of the Association of Bioethics Program Directors. Ann Intern Med. 2020 Apr 24. PubMed: https://pubmed.gov/32330224. Full-text: https://doi.org/10.7326/M20-1738
Triage? Nobody is prepared, according to this survey among 67 Bioethics Program Directors from North American hospitals. Over one half of respondents did not have ventilator triage policies. Policies have substantial heterogeneity, and many omit guidance on fair implementation. Of note, among the most frequently cited triage criteria was “lottery” (35%). Great.
Wadman M, Couzin-Frankel J, Kaiser J, et al. A rampage through the body. Science 24 Apr 2020: Vol. 368, Issue 6489, pp. 356-360. Full-text: https://science.sciencemag.org/content/368/6489/356 l (Important)
Is there anybody still twaddling about herd immunity? Let him read this detailed feature, describing the map of the devastation that COVID-19 can inflict not only on the lungs but on other organs as well, including blood vessels, heart, brain, kidneys and other organs. Scientists are just beginning to probe the nature of that harm.
Servick K. Survivors’ burden. Science 24 Apr 2020: Vol. 368, Issue 6489, pp. 359. https://science.sciencemag.org/content/368/6489/359
Discharge from ICU is not the end of it. Clinicians are now turning their attention to potential lingering effects of both the virus and the emergency treatments that allow people to survive. Scarring can cause long-term breathing problems. This article also discusses other topics of concern such as muscle atrophy and weakness, mental problems but also cognitive impairment after leaving long-term intensive care.
Useful review on the unique lung injury induced by SARS-CoV-2 infection. It has become clear that acute respiratory distress syndrome (ARDS) in COVID-19 is different from ARDS. “CARDs” appears to include an important vascular insult that potentially mandates a different treatment approach than customarily applied for ARDS. The authors review their experiences and propose to categorize patients. In type L (low lung elastance, high compliance, low response to PEEP), infiltrates are often limited in extent and initially characterized by a ground-glass pattern on CT that signifies interstitial rather than alveolar edema. Many patients do not appear overtly dyspneic and may stabilize at this stage without deterioration. Others may transit to a clinical picture more characteristic of typical ARDS: Type H shows extensive CT consolidations, high elastance (low compliance) and high PEEP response. Clearly, types L and H are the conceptual extremes of a spectrum that includes intermediate stages.
Poissy J, Goutay J, Caplan M, et al. Pulmonary Embolism in COVID-19 Patients: Awareness of an Increased Prevalence. Circulation. 2020 Apr 24. PubMed: https://pubmed.gov/32330083. Full-text: https://doi.org/10.1161/CIRCULATIONAHA.120.047430
Case series from Lille, France showing a high prevalence of Pulmonary Embolism (PE) in severe COVID-19. Among the first 107 COVID-19 patients admitted to the ICU for pneumonia in March, the authors identified 22 (20.6%) cases. It is of note that at the time of diagnosis of PE, 20/22 were receiving prophylactic antithrombotic treatment (UFH or LWMH) according to the current guidelines in critically ill patients.
Caputo ND, Strayer RJ, Levitan R. Early Self-Proning in Awake, Non-intubated Patients in the Emergency Department: A Single ED´s Experience during the COVID-19 Pandemic. Acad Emerg Med. 2020 Apr 22. PubMed: https://pubmed.gov/32320506. Full-text: https://doi.org/10.1111/acem.13994
Proning helps, even in awake, non-intubated patients. Among 50 patients, the median SpO2 at triage was 80%. After application of supplemental oxygen was given to patients on room air it was 84%. After 5 minutes of proning was added, SpO2 improved to 94%.
Barnes BJ, Adrover JM, Baxter-Stoltzfus A, et al. Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J Exp Med. 2020 Jun 1;217(6). PubMed: https://pubmed.gov/32302401. Full-text: https://doi.org/10.1084/jem.20200652
Case report of a patient who succumbed to COVID-19. Hypothesis that a powerful function of neutrophils – the ability to form neutrophil extracellular traps (NETs) – may contribute to organ damage and mortality in COVID-19. Targeting NETs directly and/or indirectly with existing drugs may reduce clinical severity.
Spiezia L, Boscolo A, Poletto F, et al. COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure. Thromb Haemost. 2020 Apr 21. PubMed: https://pubmed.gov/32316063. Full-text: https://doi.org/10.1055/s-0040-1710018
Case series of 22 patients with acute respiratory failure present a severe hypercoagulability rather than consumptive coagulopathy. Fibrin formation and polymerization may predispose to thrombosis and correlate with a worse outcome.
Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 17 Apr 2020: eabb8925. Full-text: https://science.sciencemag.org/content/early /2020/04/16/science.abb8925 l (Important)
Brief but fantastic overview about the current knowledge and the pathways leading to cytokine release syndrome.