Comparison of chest radiograph and lung ultrasound in children with acute respiratory failure.

PURPOSE: Chest x-ray (CXR) is the standard imaging used to evaluate children in acute respiratory distress and failure. Our objective was to compare the lung-imaging techniques of CXR and lung ultrasound (LUS) in the evaluation of children with acute respiratory failure (ARF) to quantify agreement and to determine which technique identified a higher frequency of pulmonary abnormalities. METHODS: This was a secondary analysis of a prospective observational study evaluating the sensitivity and specificity of LUS in children with ARF from 12/2018 to 02/2020 completed at the University of Wisconsin-Madison (USA). Children > 37.0 weeks corrected gestational age and ≤ 18 years of age admitted to the PICU with ARF were evaluated with LUS. We compared CXR and LUS completed within 6 h of each other. Kappa statistics (k) adjusted for maximum attainable agreement (k/kmax) were used to quantify agreement between imaging techniques and descriptive statistics were used to describe the frequency of abnormalities. RESULTS: Eighty-eight children had LUS completed, 32 with concomitant imaging completed within 6 h are included. There was fair agreement between LUS and CXR derived diagnoses with 58% agreement (k/kmax = 0.36). Evaluation of imaging patterns included: normal, 57% agreement (k = 0.032); interstitial pattern, 47% agreement (k = 0.003); and consolidation, 65% agreement (k = 0.29). CXR identified more imaging abnormalities than LUS. CONCLUSIONS: There is fair agreement between CXR and LUS-derived diagnoses in children with ARF. Given this, clinicians should consider the benefits and limitations of specific imaging modalities when evaluating children with ARF. Additional studies are necessary to further define the role of LUS in pediatric ARF given the small sample size of our study.

Regular Use of Ivermectin as Prophylaxis for COVID-19 Led Up to a 92% Reduction in COVID-19 Mortality Rate in a Dose-Response Manner: Results of a Prospective Observational Study of a Strictly Controlled Population of 88,012 Subjects.

Background We have previously demonstrated that ivermectin used as prophylaxis for coronavirus disease 2019 (COVID-19), irrespective of the regularity, in a strictly controlled citywide program in Southern Brazil (Itajaí, Brazil), was associated with reductions in COVID-19 infection, hospitalization, and mortality rates. In this study, our objective was to determine if the regular use of ivermectin impacted the level of protection from COVID-19 and related outcomes, reinforcing the efficacy of ivermectin through the demonstration of a dose-response effect. Methods This exploratory analysis of a prospective observational study involved a program that used ivermectin at a dose of 0.2 mg/kg/day for two consecutive days, every 15 days, for 150 days. Regularity definitions were as follows: regular users had 180 mg or more of ivermectin and irregular users had up to 60 mg, in total, throughout the program. Comparisons were made between non-users (subjects who did not use ivermectin), and regular and irregular users after multivariate adjustments. The full city database was used to calculate and compare COVID-19 infection and the risk of dying from COVID-19. The COVID-19 database was used and propensity score matching (PSM) was employed for hospitalization and mortality rates. Results Among 223,128 subjects from the city of Itajaí, 159,560 were 18 years old or up and were not infected by COVID-19 until July 7, 2020, from which 45,716 (28.7%) did not use and 113,844 (71.3%) used ivermectin. Among ivermectin users, 33,971 (29.8%) used irregularly (up to 60 mg) and 8,325 (7.3%) used regularly (more than 180 mg). The remaining 71,548 participants were not included in the analysis. COVID-19 infection rate was 49% lower for regular users (3.40%) than non-users (6.64%) (risk rate (RR): 0.51; 95% CI: 0.45-0.58; p < 0.0001), and 25% lower than irregular users (4.54%) (RR: 0.75; 95% CI: 0.66-0.85; p < 0.0001). The infection rate was 32% lower for irregular users than non-users (RR: 0.68; 95% CI: 0.64-0.73; p < 0.0001). Among COVID-19 participants, regularusers were older and had a higher prevalence of type 2 diabetes and hypertension than irregular and non-users. After PSM, the matched analysis contained 283 subjects in each group of non-users and regular users, between regular users and irregular users, and 1,542 subjects between non-users and irregular users. The hospitalization rate was reduced by 100% in regular users compared to both irregular users and non-users (p < 0.0001), and by 29% among irregular users compared to non-users (RR: 0.781; 95% CI: 0.49-1.05; p = 0.099). Mortality rate was 92% lower in regular users than non-users (RR: 0.08; 95% CI: 0.02-0.35; p = 0.0008) and 84% lower than irregular users (RR: 0.16; 95% CI: 0.04-0.71; p = 0.016), while irregular users had a 37% lower mortality rate reduction than non-users (RR: 0.67; 95% CI: 0.40-0.99; p = 0.049). Risk of dying from COVID-19 was 86% lower among regular users than non-users (RR: 0.14; 95% CI: 0.03-0.57; p = 0.006), and 72% lower than irregular users (RR: 0.28; 95% CI: 0.07-1.18; p = 0.083), while irregular users had a 51% reduction compared to non-users (RR: 0.49; 95% CI: 0.32-0.76; p = 0.001). Conclusion Non-use of ivermectin was associated with a 12.5-fold increase in mortality rate and a seven-fold increased risk of dying from COVID-19 compared to the regular use of ivermectin. This dose-response efficacy reinforces the prophylactic effects of ivermectin against COVID-19.

Lung Ultrasound Artifact Findings in Pediatric Patients Admitted to the Intensive Care Unit for Acute Respiratory Failure.

PURPOSE: To describe point-of-care lung ultrasound (POC-LUS) artifact findings in children admitted to the pediatric intensive care unit (PICU) for acute respiratory failure (ARF). METHODS: This is a secondary analysis of a prospective observational study completed in a 21-bed PICU. Children > 37 weeks gestational age and ≤ 18 years were enrolled from December 2018 to February 2020. POC-LUS was completed and interpreted by separate physicians blinded to all clinical information. POC-LUS was evaluated for the presence of lung sliding, pleural line characteristics, ultrasound artifacts, and the ultrasound diagnosis. RESULTS: Eighty-seven subjects were included. A-lines were the most frequent artifact, occurring in 58% of lung zones (163/281) in those with bronchiolitis, 39% of lung zones (64/164) in those with pneumonia, and 81% of lung zones (48/59) in those with status asthmaticus. Sub-pleural consolidation was second most common, occurring in 28% (80/281), 30% (50/164), and 12% (7/59) of those with bronchiolitis, pneumonia, and status asthmaticus, respectively. The pattern a priori defined as bronchiolitis, pneumonia, and status asthmaticus was demonstrated in 31% (15/48), 10% (3/29), and 40% (4/10) of subjects with bronchiolitis, pneumonia, and status asthmaticus, respectively. CONCLUSION: We found significant heterogeneity and overlap of POC-LUS artifacts across the most common etiologies of ARF in children admitted to the PICU. We have described the POC-LUS artifact findings in pediatric ARF to support clinicians using POC-LUS and to guide future pediatric POC-LUS studies. Determining the optimal role of POC-LUS as an adjunct in the care of pediatric patients requires further study.

Correction: Ivermectin Prophylaxis Used for COVID-19: A Citywide, Prospective, Observational Study of 223,128 Subjects Using Propensity Score Matching.

[This corrects the article DOI: 10.7759/cureus.21272.].

"MATH+" Multi-Modal Hospital Treatment Protocol for COVID-19 Infection: Clinical and Scientific Rationale.

In December 2019, coronavirus disease 2019 (COVID-19), a severe respiratory illness caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China. The greatest impact that COVID-19 had was on intensive care units (ICUs), given that approximately 20% of hospitalized cases developed acute respiratory failure (ARF) requiring ICU admission. Based on the assumption that COVID-19 represented a viral pneumonia and no anti-coronaviral therapy existed, nearly all national and international health care societies recommended "supportive care only" avoiding other therapies outside of randomized controlled trials, with a specific prohibition against the use of corticosteroids in treatment. However, early studies of COVID-19-associated ARF reported inexplicably high mortality rates, with frequent prolonged durations of mechanical ventilation (MV), even from centers expert in such supportive care strategies. These reports led the authors to form a clinical expert panel called the Front-Line COVID-19 Critical Care Alliance (www.flccc.net). The panel collaboratively reviewed the emerging clinical, radiographic, and pathological reports of COVID-19 while initiating multiple discussions among a wide clinical network of front-line clinical ICU experts from initial outbreak areas in China, Italy, and New York. Based on the shared early impressions of "what was working and what wasn't working", the increasing medical journal publications and the rapidly accumulating personal clinical experiences with COVID-19 patients, a treatment protocol was created for the hospitalized patients based on the core therapies of methylprednisolone, ascorbic acid, thiamine, heparin and non-antiviral co-interventions (MATH+). This manuscript reviews the scientific and clinical rationale behind MATH+ based on published in-vitro, pre-clinical, and clinical data in support of each medicine, with a special emphasis of studies supporting their use in the treatment of patients with viral syndromes and COVID-19 specifically.

Ivermectin Prophylaxis Used for COVID-19: A Citywide, Prospective, Observational Study of 223,128 Subjects Using Propensity Score Matching.

BACKGROUND: Ivermectin has demonstrated different mechanisms of action that potentially protect from both coronavirus disease 2019 (COVID-19) infection and COVID-19-related comorbidities. Based on the studies suggesting efficacy in prophylaxis combined with the known safety profile of ivermectin, a citywide prevention program using ivermectin for COVID-19 was implemented in Itajaí, a southern city in Brazil in the state of Santa Catarina. The objective of this study was to evaluate the impact of regular ivermectin use on subsequent COVID-19 infection and mortality rates. MATERIALS AND METHODS: We analyzed data from a prospective, observational study of the citywide COVID-19 prevention with ivermectin program, which was conducted between July 2020 and December 2020 in Itajaí, Brazil. Study design, institutional review board approval, and analysis of registry data occurred after completion of the program. The program consisted of inviting the entire population of Itajaí to a medical visit to enroll in the program and to compile baseline, personal, demographic, and medical information. In the absence of contraindications, ivermectin was offered as an optional treatment to be taken for two consecutive days every 15 days at a dose of 0.2 mg/kg/day. In cases where a participating citizen of Itajaí became ill with COVID-19, they were recommended not to use ivermectin or any other medication in early outpatient treatment. Clinical outcomes of infection, hospitalization, and death were automatically reported and entered into the registry in real time. Study analysis consisted of comparing ivermectin users with non-users using cohorts of infected patients propensity score-matched by age, sex, and comorbidities. COVID-19 infection and mortality rates were analyzed with and without the use of propensity score matching (PSM). RESULTS: Of the 223,128 citizens of Itajaí considered for the study, a total of 159,561 subjects were included in the analysis: 113,845 (71.3%) regular ivermectin users and 45,716 (23.3%) non-users. Of these, 4,311 ivermectin users were infected, among which 4,197 were from the city of Itajaí (3.7% infection rate), and 3,034 non-users (from Itajaí) were infected (6.6% infection rate), with a 44% reduction in COVID-19 infection rate (risk ratio [RR], 0.56; 95% confidence interval (95% CI), 0.53-0.58; p < 0.0001). Using PSM, two cohorts of 3,034 subjects suffering from COVID-19 infection were compared. The regular use of ivermectin led to a 68% reduction in COVID-19 mortality (25 [0.8%] versus 79 [2.6%] among ivermectin non-users; RR, 0.32; 95% CI, 0.20-0.49; p < 0.0001). When adjusted for residual variables, reduction in mortality rate was 70% (RR, 0.30; 95% CI, 0.19-0.46; p < 0.0001). There was a 56% reduction in hospitalization rate (44 versus 99 hospitalizations among ivermectin users and non-users, respectively; RR, 0.44; 95% CI, 0.31-0.63; p < 0.0001). After adjustment for residual variables, reduction in hospitalization rate was 67% (RR, 0.33; 95% CI, 023-0.66; p < 0.0001). CONCLUSION: In this large PSM study, regular use of ivermectin as a prophylactic agent was associated with significantly reduced COVID-19 infection, hospitalization, and mortality rates.

The Inter-Rater Reliability of Pediatric Point-of-Care Lung Ultrasound Interpretation in Children With Acute Respiratory Failure.

OBJECTIVES: Use of point-of-care lung ultrasound (POC-LUS) has increased significantly in pediatrics yet it remains under-studied in the pediatric intensive care unit (PICU). No studies explicitly evaluate the reliability of POC-LUS artifact interpretation among critically ill children with acute respiratory failure (ARF) in the PICU. We thus designed this study to determine the inter-rater reliability of POC-LUS interpretation in pediatric ARF among pediatric intensivists trained in POC-LUS and an expert intensivist. METHODS: We compared the interpretation of lung sliding, pleural line characteristics, ultrasound artifacts, and POC-LUS diagnoses among pediatric intensivists and an expert intensivist in a cohort of children admitted to the PICU for ARF. Kappa statistics (k) adjusted for maximum attainable agreement (k/kmax ) were used to quantify chance-correct agreement between the pediatric intensivist and expert physician. RESULTS: We enrolled 88 patients, evaluating 3 zones per hemithorax (anterior, lateral, and posterior) for lung sliding, pleural line characteristics, ultrasound artifacts, and diagnosis. There was moderate agreement between the PICU intensivist and expert-derived diagnoses with 56% observed agreement (k/kmax  = 0.46, 95% confidence interval [CI] 0.31-0.65). Agreement in identification of lung sliding (k = 0.19, 95% CI -0.17 to 0.56) and pleural line characteristics (k = 0.24, 95% CI 0.08-0.40) was slight and fair, respectively, while agreement in the interpretation of ultrasound artifacts ranged from moderate to substantial. CONCLUSIONS: Evidence supporting the evaluation of neonatal and adult patients with POC-LUS should not be extrapolated to critically ill pediatric patients. This study adds to the evidence supporting use of POC-LUS in the PICU by demonstrating moderate agreement between PICU intensivist and expert-derived POC-LUS diagnoses.

Treatment barriers in PANS/PANDAS: Observations from eleven health care provider families.

INTRODUCTION: Pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) are severe but highly treatable postinfectious inflammatory brain conditions. Despite published diagnostic and treatment guidelines for this condition, there are long delays in obtaining appropriate care. The reasons for these delays are poorly understood. We sought to identify health care system barriers to timely treatment by examining cases of PANDAS/PANS occurring in children of health care professionals. METHOD: We recruited families via e-mail request through the PANDAS Physicians Network. Participating parents completed a structured questionnaire and provided a written case description. RESULTS: Eleven families completed data collection, representing a broad spectrum of disease (child disease onset age 4-15, 7 males/4 females, mild to severe). Parents included 11 physicians, 2 mental health professionals, 2 nurses, and a PharmD. Nine cases (82%) had "very delayed" diagnosis and treatment (>4 weeks after onset). The most commonly encountered causes for treatment delay were clinician lack of awareness (82%), clinician skepticism (82%), overdependence on diagnostic testing (91%), and out-of-pocket expenses >$100 US (82%). Other common challenges included difficulties finding a provider to spearhead care (64%), psychological misdiagnosis (55%), and children's suppression of behaviors during assessments (55%). CONCLUSIONS: We found numerous barriers to treatment of PANDAS/PANS among children of health care providers. Our findings suggest that even among the medically sophisticated, PANDAS/PANS diagnosis and treatment remains challenging. Improvement in PANDAS/PANS education of clinicians who may encounter children with this disorder is 1 key step toward addressing our identified barriers. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A scoping review of the pathophysiology of COVID-19.

COVID-19 is a highly heterogeneous and complex medical disorder; indeed, severe COVID-19 is probably amongst the most complex of medical conditions known to medical science. While enormous strides have been made in understanding the molecular pathways involved in patients infected with coronaviruses an overarching and comprehensive understanding of the pathogenesis of COVID-19 is lacking. Such an understanding is essential in the formulation of effective prophylactic and treatment strategies. Based on clinical, proteomic, and genomic studies as well as autopsy data severe COVID-19 disease can be considered to be the connection of three basic pathologic processes, namely a pulmonary macrophage activation syndrome with uncontrolled inflammation, a complement-mediated endothelialitis together with a procoagulant state with a thrombotic microangiopathy. In addition, platelet activation with the release of serotonin and the activation and degranulation of mast cells contributes to the hyper-inflammatory state. Auto-antibodies have been demonstrated in a large number of hospitalized patients which adds to the end-organ damage and pro-thrombotic state. This paper provides a clinical overview of the major pathogenetic mechanism leading to severe COVID-19 disease.

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19.

BACKGROUND: After COVID-19 emerged on U.S shores, providers began reviewing the emerging basic science, translational, and clinical data to identify potentially effective treatment options. In addition, a multitude of both novel and repurposed therapeutic agents were used empirically and studied within clinical trials. AREAS OF UNCERTAINTY: The majority of trialed agents have failed to provide reproducible, definitive proof of efficacy in reducing the mortality of COVID-19 with the exception of corticosteroids in moderate to severe disease. Recently, evidence has emerged that the oral antiparasitic agent ivermectin exhibits numerous antiviral and anti-inflammatory mechanisms with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups including Unitaid/World Health Organization have undertaken a systematic global effort to contact all active trial investigators to rapidly gather the data needed to grade and perform meta-analyses. DATA SOURCES: Data were sourced from published peer-reviewed studies, manuscripts posted to preprint servers, expert meta-analyses, and numerous epidemiological analyses of regions with ivermectin distribution campaigns. THERAPEUTIC ADVANCES: A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large "natural experiments" occurred in regions that initiated "ivermectin distribution" campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns. CONCLUSIONS: Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.

Point-of-Care Lung Ultrasound to Diagnose the Etiology of Acute Respiratory Failure at Admission to the PICU.

OBJECTIVES: Determine the sensitivity and specificity of point-of-care lung ultrasound in identifying the etiology of acute respiratory failure at admission to the PICU. DESIGN: Prospective observational study. SETTING: Tertiary PICU. PATIENTS: Children older than 37 weeks gestational age and less than or equal to 18 years old admitted to the PICU with acute respiratory failure from December 2018 to February 2020. INTERVENTION: Point-of-care lung ultrasound performed within 14 hours of admission to the PICU by physicians blinded to patient history and clinical course. Two physicians, blinded to all clinical information, independently interpreted the point-of-care lung ultrasound and then established a consensus diagnosis (ultrasound diagnosis). The ultrasound diagnosis was compared with an independent, standardized review of the medical record following hospital discharge (final diagnosis). MEASUREMENTS AND RESULTS: Eighty-eight patients were enrolled in the study. Forty-eight patients had a final diagnosis of bronchiolitis/viral pneumonitis (55%), 29 had pneumonia (33%), 10 had status asthmaticus (11%), and one was excluded because of an inability to differentiate the final diagnosis. Point-of-care lung ultrasound correctly identified the etiology of acute respiratory failure in 56% of patients (49/87; 95% CI, 46-66%). It identified bronchiolitis/viral pneumonitis with 44% sensitivity (95% CI, 0.31-0.58) and 74% specificity (95% CI, 0.59-0.85), pneumonia with 76% sensitivity (95% CI, 0.58-0.88) and 67% specificity (95% CI 0.54-0.78), and status asthmaticus with 60% sensitivity (95% CI, 0.31-0.83) and 88% specificity (95% CI, 0.79-0.94). CONCLUSIONS: In contrast to literature demonstrating high utility differentiating the cause of acute respiratory failure in adults, blinded point-of-care lung ultrasound demonstrates moderate sensitivity and specificity in identifying the etiology of pediatric acute respiratory failure at admission to the PICU among children with bronchiolitis, pneumonia, and status asthmaticus.

The time to offer treatments for COVID-19.

Background: COVID-19 has several overlapping phases. Treatments to date have focused on the late stage of disease in hospital. Yet, the pandemic is by propagated by the viral phase in out-patients. The current public health strategy relies solely on vaccines to prevent disease.Methods: We searched the major national registries, pubmed.org, and the preprint servers for all ongoing, completed and published trial results.Results: As of 2/15/2021, we found 111 publications reporting findings on 14 classes of agents, and 9 vaccines. There were 62 randomized controlled studies, the rest retrospective observational analyses. Only 21 publications dealt with outpatient care. Remdesivir and high titer convalescent plasma have emergency use authorization for hospitalized patients in the U.S.A. There is also support for glucocorticoid treatment of the COVID-19 respiratory distress syndrome. Monoclonal antibodies are authorized for outpatients, but supply is inadequate to treat all at time of diagnosis. Favipiravir, ivermectin, and interferons are approved in certain countries.Expert Opinion: Vaccines and antibodies are highly antigen specific, and new SARS-Cov-2 variants are appearing. We call on public health authorities to authorize treatments with known low-risk and possible benefit for outpatients in parallel with universal vaccination.

The Importance of Understanding the Stages of COVID-19 in Treatment and Trials.

COVID-19, caused by SARS-CoV-2, continues to be a major health problem since its first description in Wuhan, China, in December 2019. Multiple drugs have been tried to date in the treatment of COVID-19. Critical to treatment of COVID-19 and advancing therapeutics is an appreciation of the multiple stages of this disease and the importance of timing for investigation and use of various agents. We considered articles related to COVID-19 indexed on PubMed published January 1, 2020-November 15, 2020, and considered papers on the medRxiv preprint server. We identified relevant stages of COVID-19 including three periods: pre-exposure, incubation, and detectable viral replication; and five phases: the viral symptom phase, the early inflammatory phase, the secondary infection phase, the multisystem inflammatory phase, and the tail phase. This common terminology should serve as a framework to guide when COVID-19 therapeutics being studied or currently in use is likely to provide benefit rather than harm.

MANAGEMENT OF MEDICAL COMPLICATIONS ASSOCIATED WITH A PRESUMED TETANUS INFECTION IN A NORTHWEST BORNEAN ORANGUTAN (PONGO PYGMAEUS PYGMAEUS).

An 18-yr-old female orangutan (Pongo pygmaeus pygmaeus) developed opisthotonus after sustaining conspecific bite wounds 3 wk earlier. The orangutan developed progressive tetraparesis and dysphagia, despite normal mentation, suggestive of tetanus. A tetanus vaccine had been administered at 2 yr of age, but none since. Brain magnetic resonance imaging, computed tomography, cerebral spinal fluid tap, and bloodwork were unremarkable. Viral, Baylisascaris, and tetanus toxin testing were negative. A femoral central venous catheter (CVC) was placed to provide medications, fluids, and parenteral nutrition. The orangutan received human tetanus immunoglobulin, tetanus toxoid, penicillin, methocarbamol, and analgesia. After 1 wk, the catheterized limb became edematous; a deep vein thrombosis (DVT) was diagnosed ultrasonographically. A cephalic CVC was placed, the limb casted, intravenous therapy reinitiated, and enoxaparin started. The orangutan became mobile days later, and progressively improved. Despite no compliance with enoxaparin, the DVT resolved without residual signs. This is the first reported case of presumptive tetanus and DVT in a great ape.

MATH+ protocol for the treatment of SARS-CoV-2 infection: the scientific rationale.

INTRODUCTION: COVID-19 disease progresses through a number of distinct phases. The management of each phase is unique and specific. The pulmonary phase of COVID-19 is characterized by an organizing pneumonia with profound immune dysregulation, activation of clotting, and a severe microvascular injury culminating in severe hypoxemia. The core treatment strategy to manage the pulmonary phase includes the combination of methylprednisolone, ascorbic acid, thiamine, and heparin (MATH+ protocol). The rationale for the MATH+ protocol is reviewed in this paper. AREAS COVERED: We provide an overview on the pathophysiological changes occurring in patients with COVID-19 respiratory failure and a treatment strategy to reverse these changes thereby preventing progressive lung injury and death. EXPERT OPINION: While there is no single 'Silver Bullet' to cure COVID-19, we believe that the severely disturbed pathological processes leading to respiratory failure in patients with COVID-19 organizing pneumonia will respond to the combination of Methylprednisone, Ascorbic acid, Thiamine, and full anticoagulation with Heparin (MATH+ protocol).We believe that it is no longer ethically acceptable to limit management to 'supportive care' alone, in the face of effective, safe, and inexpensive medications that can effectively treat this disease and thereby reduce the risk of complications and death.

Clinical and Scientific Rationale for the "MATH+" Hospital Treatment Protocol for COVID-19.

In December 2019, COVID-19, a severe respiratory illness caused by the new coronavirus SARS-CoV-2 (COVID-19) emerged in Wuhan, China. The greatest impact that COVID-19 had was on intensive care units (ICUs), given that approximately 20% of hospitalized cases developed acute respiratory failure (ARF) requiring ICU admission. Based on the assumption that COVID-19 represented a viral pneumonia and no anti-coronaviral therapy existed, nearly all national and international health care societies' recommended "supportive care only" avoiding other therapies outside of randomized controlled trials, with a specific prohibition against the use of corticosteroids in treatment. However, early studies of COVID-19-associated ARF reported inexplicably high mortality rates, with frequent prolonged durations of mechanical ventilation (MV), even from centers expert in such supportive care strategies. These reports led the authors to form a clinical expert panel called the Front-Line COVID-19 Critical Care Alliance (www.flccc.net). The panel collaboratively reviewed the emerging clinical, radiographic, and pathological reports of COVID-19 while initiating multiple discussions among a wide clinical network of front-line clinical ICU experts from initial outbreak areas in China, Italy, and New York. Based on the shared early impressions of "what was working and what wasn't working," the increasing medical journal publications and the rapidly accumulating personal clinical experiences with COVID-19 patients, a treatment protocol was created for the hospitalized patients based on the core therapies of methylprednisolone, ascorbic acid, thiamine, heparin and co-interventions (MATH+). This manuscript reviews the scientific and clinical rationale behind MATH+ based on published in-vitro, pre-clinical, and clinical data in support of each medicine, with a special emphasis of studies supporting their use in the treatment of patients with viral syndromes and COVID-19 specifically. The review concludes with a comparison of published multi-national mortality data with MATH+ center outcomes.

Assessment of dynamic changes in cardiac function during resuscitation of patients with suspected septic shock: A prospective, observational, cohort study.

STUDY OBJECTIVE: To describe changes in cardiac function throughout the course of resuscitation of patients with suspected septic shock. METHODS: Prospective observational cohort study of Point-of-Care Transthoracic Echocardiograms (TTE) obtained in Emergency Department (ED) patients with a presumed infectious cause of hypotension within one hour of initiating IV fluid resuscitation. Findings of this pre-resuscitation TTE were compared to mid-resuscitation TTE (obtained upon disposition from the ED), and post-resuscitation TTE (obtained after admission to hospital). RESULTS: 22 enrolled patients had a second TTE available for comparison to the initial, pre-resuscitation TTE. 12 patients had a mid-resuscitation TTE and 16 patients had a post-resuscitation TTE. We observed a high incidence of changes on TTE during the clinical course of resuscitation (14/22 [64%]). Patients who developed LV or RV dysfunction during resuscitation were more likely to require vasopressor infusion and ICU admission (Spearman's coefficients [95% CI] of 0.68 [0.36-0.86] and 0.47 [0.04;0.75] respectively). Development of RV dysfunction alone was associated with increased use of positive pressure ventilation and vasopressor infusion (Spearman's coefficients [95% CI] of 0.43 [0;0.72] and 0.47 [0.05,0.75] respectively). CONCLUSIONS: Cardiac function changes assessed by TTE are common during the resuscitation of patients with septic shock. These changes likely reflect the underlying physiology of patients with septic shock and correlate with need for interventions and higher level of care. Further work is required to characterize these changes and to elucidate how to use these physiologic data to guide management.

Thromboelastography to Detect Hypercoagulability and Reduced Fibrinolysis in Coronavirus Disease 2019 Acute Respiratory Distress Syndrome Patients.

OBJECTIVES: Microvascular thrombosis contributes to acute respiratory distress syndrome pathophysiology and has been demonstrated in coronavirus disease 2019-associated acute respiratory distress syndrome. Clinical laboratory measurements of coagulation and disseminated intravascular coagulation, such as coagulation factor function, platelet count, and fibrinogen, may not fully reflect the extent of microvascular thrombosis present in these patients. We investigated thromboelastography in patients with coronavirus disease 2019-associated acute respiratory distress syndrome with the objective of characterizing suspected coagulopathy and impaired fibrinolysis. DESIGN: Retrospective observational cohort study. SETTING: Single-center academic medical center. PATIENTS: Ten patients with polymerase chain reaction-confirmed coronavirus disease 2019 disease complicated by acute respiratory distress syndrome. INTERVENTIONS: Measurement of thromboelastography (n = 10) and thrombolysis with alteplase (n = 4). MEASUREMENTS AND MAIN RESULTS: Hypercoagulability and decreased or absent fibrinolysis were demonstrated by thromboelastography. Thrombocytopenia and hypofibrinogenemia were not observed, while seven of 10 patients had elevated d-dimer values. For patients who received thrombolytic therapy, repeat thromboelastography demonstrated improvements in coagulation index and lysis at 30 minutes reflecting reduced hypercoagulability and increased fibrinolysis. One major bleeding complication was detected following thrombolysis. Eight of 10 patients survived and were successfully extubated, and six of 10 have since been discharged. CONCLUSIONS: In coronavirus disease 2019 patients with acute respiratory distress syndrome in whom thromboelastography was performed, hypercoagulability and impaired fibrinolysis were observed. In the context of autopsy studies demonstrating pulmonary microvascular thromboses in coronavirus disease 2019 patients, noninvasive detection of hypercoagulability and deficient fibrinolysis in coronavirus disease 2019 acute respiratory distress syndrome using thromboelastography could improve understanding and management of coronavirus disease 2019.

SARS-CoV-2 organising pneumonia: 'Has there been a widespread failure to identify and treat this prevalent condition in COVID-19?'

Reviews of COVID-19 CT imaging along with postmortem lung biopsies and autopsies indicate that the majority of patients with COVID-19 pulmonary involvement have secondary organising pneumonia (OP) or its histological variant, acute fibrinous and organising pneumonia, both well-known complications of viral infections. Further, many publications on COVID-19 have debated the puzzling clinical characteristics of 'silent hypoxemia', 'happy hypoxemics' and 'atypical ARDS', all features consistent with OP. The recent announcement that RECOVERY, a randomised controlled trial comparing dexamethasone to placebo in COVID-19, was terminated early due to excess deaths in the control group further suggests patients present with OP given that corticosteroid therapy is the first-line treatment. Although RECOVERY along with other cohort studies report positive effects with corticosteroids on morbidity and mortality of COVID-19, treatment approaches could be made more effective given that secondary OP often requires prolonged duration and/or careful and monitored tapering of corticosteroid dose, with 'pulse' doses needed for the well-described fulminant subtype. Increasing recognition of this diagnosis will thus lead to more appropriate and effective treatment strategies in COVID-19, which may lead to a further reduction of need for ventilatory support and improved survival.