Mass General FLARE is a collaborative effort within the Pulmonary and Critical Care Division and the Department of Medicine. Its mission is to appraise the rapidly evolving literature on SARS-CoV-2 with a focus on critical care issues.

Core members include Laura Brenner, MD; Tiara Calhoun, MD; Raghu Chivukula, MD, PhDDavid Dudzinski, MD; Jason Maley, MD; Camille Petri, MD; and Vlad Vinarsky, MD. The group is led by Corey Hardin, MD, PhD. Please send questions, comments or concerns about FLARE to

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Latest Letters

Are the Two Newly Authorized COVID-19 Vaccines Safe and Effective? (December 28, 2020)
  1. The FDA has now issued emergency use authorizations (EUA) for the mRNA-based SARS-CoV-2 vaccines made by Pfizer and Moderna
  2. Data from phase 3 trials, now publicly available, is consistent with remarkable efficacy across broad range of ages, comorbidities and risk of SARS-CoV-2 exposure
  3. Phase 3 data additionally show few significant safety concerns. But isolated reports of allergic reactions remind us of the possibility that widespread vaccination will reveal the occurrence of additional rare adverse events, as can occur with any vaccine
  4. Questions remain about the duration of immunity, efficacy/safety in certain groups (pregnant women, immunocompromised individuals, children and adolescents). Work is ongoing to obtain definitive answers to these important questions
COVID-19 Vaccine Candidates (November 19, 2020)
  1. Five vaccine candidates that induce an immune response to the SARS-CoV-2 spike protein are in or entering phase 3 trials in the United States. All five have been demonstrated in phase 1 and 2 trials to induce an immune response that compares favorably to that produced by natural SARS-CoV-2 infection
  2. Duration of vaccine-induced immunity to SARS-CoV-2, safety information and detailed phase 3 efficacy data remain unreported. However, in recent days, two candidate vaccines (from Moderna and Pfizer) have announced unpublished results from the first interim analysis of their phase 3 trials demonstrating roughly 95% efficacy
  3. Manufacture of candidate vaccines and planning for distribution have already begun. Thus, successful interim analysis of a phase 3 trial and emergency use authorization (EUA) will be rapidly followed by the start of vaccine distribution in the coming weeks to months. Vaccine availability is expected to be limited in the initial phase of distribution
  4. Important ethical challenges will arise around (1) continuing placebo arms in ongoing vaccine trials once there is an approved vaccine and (2) equitable vaccine distribution in the setting of initial scarcity
What is a Superspreader Event? (October 21, 2020)
  1. Communicable diseases like COVID-19 may be characterized by a basic reproductive number, R0 or "R naught," that describes the number of secondary cases expected from a single infected person in a population
  2. Circumstances may occur, however, in which a single person infects many more people than would be expected from R0. These superspreader events may result from a combination of factors in the infected index case
  3. Currently available testing techniques do not obviate the need for physical distancing and masking. Even with regular testing, breaches of masking and physical distancing recommendations result in a risk of transmission
  4. Persons exposed to individuals infected with SARS-CoV-2 should quarantine and seek testing per public health guidance. A negative test during the exposure window does not change the duration and does not exclude the possibility of a later positive result
What We Have Learned About COVID-19: Part One (September 30, 2020)
  1. In the months since the first cases of COVID-19 were reported, an astounding amount of research (of varying quality) has been published
  2. Despite early confusion, there is now substantial consensus on optimal treatment of the critically ill patient with COVID-19. This is based on established evidence for pre-COVID-19 ARDS as well as data from new randomized controlled trials
  3. Several early hypotheses that gained widespread attention have been refuted by subsequent investigation, including the assertions that: COVID-19 caused a unique pulmonary pathology, was associated with a startlingly high mortality among ventilated patients, had an unexpected clinical presentation (some termed “Happy Hypoxemia”), was treatable with hydroxychloroquine or was primarily a cytokine storm syndrome similar to that seen in CAR T-cell therapy
  4. Critical questions remain, but we now have a solid foundation, including two new drug treatments (remdesivir and dexamethasone), with which to establish a standard of care. Moreover, with many ongoing trials, we can look forward to additional high quality evidence in the near future
The RECOVERY Trial (June 27, 2020)
  1. Yes. Recently released, preliminary, (not yet peer-reviewed) data from the RECOVERY trial demonstrate that dexamethasone has a mortality benefit in COVID-19 patients requiring oxygen or mechanical ventilation and should likely be used
  2. Prior studies on steroids in ARDS suggested heterogeneous effects, with benefit for some subgroups and harm for others. In particular, observational data on influenza suggests increased mortality with steroid use in viral pneumonia and ARDSnet RCT data suggests harm in patients greater than 13 days from ARDS onset
  3. Observational data is subject to potential confounding by indication. RCT data from RECOVERY should allay some concerns about harm from low dose steroid use in COVID-19
  4. Although significant questions remain in regards to longer-term follow-up, use of concurrent medications in the control arm, and further identification of potential effect modifiers, clinicians should strongly consider the use of dexamethasone in their COVID-19 patients with an oxygen requirement or hypoxemic respiratory failure
Expedited Publication the in Era of COVID-19 (June 12, 2020)
  1. A critical need for therapies and preventative strategies for COVID-19 has led major journals to adopt expedited review processes and publish preliminary and observational reports that may not have received wide attention prior to the pandemic
  2. Rapidly drafted and reviewed papers have had a number of errors in experimental methods, analysis, and presentation resulting in misunderstandings, corrections and retractions. These errors are especially problematic in a time when clinicians and policymakers may change clinical practice and policy based on early findings
  3. Publication of preliminary findings has arguably not resulted in more rapid development of new therapies - the sole approved therapeutic approach (remdesivir) was approved by the FDA only after a randomized controlled trial
  4. In future public health emergencies, the scientific press should consider the balance between expediency and careful peer review to ensure the integrity of findings prior to widespread dissemination
Cardiac Arrest and COVID-19 (June 4, 2020)
  1. Early reports from China indicated very poor outcomes with cardiac arrest in COVID-19
  2. These reports likely reflected a high prevalence of factors such as primary respiratory (as opposed to cardiac) arrest and out-of-ICU arrest, which were known to worsen prognosis in the pre-COVID-19 era
  3. Cardiac arrest in COVID-19 does present unique infection control challenges which are addressed by national guidelines
  4. Post-arrest care does not meaningfully differ from post-arrest care in the pre-COVID-19 era
Will COVID-19 cause more IPF? (June 2, 2020)
  1. Many ARDS survivors have evidence of persistent fibrotic lung disease such as radiographic abnormalities and findings of restriction on pulmonary function testing. This has led to concern that the COVID-19 pandemic will result in an increase in the incidence of fibrotic lung disease
  2. Pre-COVID-19, post-ARDS fibrosis did not appear to behave like progressive interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF)
  3. COVID-19 and IPF share similar risk factors. It will therefore be difficult to definitively attribute the development of fibrosis in a patient who has survived COVID-19 specifically to COVID-19
  4. There are no data yet on the incidence or consequences of COVID-19 in patients with pre-existing IPF, though we would expect that they will have worse outcomes
How is SARS-CoV-2 transmitted? (May 31, 2020)
  1. Respiratory particles, produced every time we talk, cough, sneeze, shout, or sing, vary in size, from fine aerosol particles and droplet nuclei (< 5 µm) to large droplets (> 5 µm). Airborne transmission of respiratory pathogens occurs via the dissemination of respirable fine aerosol particles containing organisms that remain infectious over distance and time
  2. The possible routes of transmission of SARS-CoV-2 are not fully understood, but larger droplets are thought to be the primary mode of transmission. The possibility of so-called opportunistic aerosol spread, wherein special circumstances such as aerosol generating procedures in the hospital facilitate airborne transmission of a normally droplet-transmitted disease, has been proposed (but not proven) for the closely related viruses SARS-CoV and MERS-CoV
  3. While recent evidence suggests that the SARS-CoV-2 virus may remain aerosolized for hours after aerosol generation, the presence of aerosols should be distinguished from infectious aerosols
  4. To date, epidemiological analyses of COVID-19 outbreaks and exposure investigations in healthcare settings have not demonstrated airborne transmission of SARS-CoV-2, i.e. there is little evidence that the SARS-CoV-2 virus remains infective over distance and time. However, more data are needed
RV failure in COVID-19 (May 28, 2020)
  1. Right ventricular dysfunction commonly occurs in critical illness, particularly in patients with sepsis and ARDS, and is associated with increased risk of death
  2. Case series suggest that right ventricular failure can occur in COVID-19
  3. Diagnosis of right ventricle failure requires high clinical suspicion. While formal echocardiography may not be readily available during the SARS-CoV-2 pandemic, point-of-care ultrasound (with appropriate training), clinical exam, EKG and hemodynamic monitoring can be used to make the diagnosis
  4. To date, there is no convincing evidence that critically ill patients with SARS-CoV-2 are more prone to developing right ventricular dysfunction or failure than similar ICU patients without SARS-CoV-2
The long-awaited awaited remdesivir trial (May 26, 2020)
  1. Remdesivir is a nucleoside analog that inhibits the RNA-dependent RNA polymerase of SARS-CoV-2. Previous studies of remdesivir in COVID-19 have suffered from serious methodological flaws. ACTT-1 is a randomized, placebo-controlled trial of remdesivir in COVID-19
  2. In a preliminary analysis of ACTT-1, participants who received remdesivir had a shorter time to recovery than those who received placebo (11 days vs. 15 days)
  3. This benefit of remdesivir was observed among the subgroup of patients with serious, though not critical disease (those requiring oxygen, but not HFNC, NIPPV or mechanical ventilation)
  4. ACTT-1 did not enroll equally across all classes of disease severity, with fewer patients enrolled in low (no oxygen) and high (HFNC, NIPPV, mechanical ventilation) severity categories. Therefore, the trial may not have been adequately powered to detect benefit in other subgroups
Using Antibody Tests for COVID-19 (May 22, 2020)
  1. Accurate SARS-CoV-2 serology will be critical for managing the COVID-19 pandemic, allowing diagnosis of previous infection, assessment of seroprevalence, and potentially the identification of individuals with protective immunity
  2. Serological assays vary with regard to their sensitivity, specificity, and ability to generate quantitative versus qualitative readouts
  3. Technical limitations of serological assays as well as kinetics of the antibody response and pre-test probability of seropositivity must be considered when interpreting these test results
  4. Attempts have been made to utilize antibody testing to determine the prevalence of SARS-CoV-2 antibodies in the general population, but these studies suffer from significant methodological issues
Pediatric Multisystem Inflammatory Syndrome and COVID-19 (May 21, 2020)
  1. Thus far, critical illness due to COVID-19 is rare among pediatric patients. In most case series, pediatric patients represent 1-2% of all COVID-19 cases, with lower illness severity and mortality when compared to adults
  2. In recent weeks, reports have surfaced of children presenting with a critical illness similar to Kawasaki Shock Syndrome (KDSS) associated with COVID-19 infection. This has been labeled Pediatric Multi-system Inflammatory Syndrome (PMIS) or Multi-system Inflammatory Syndrome in Children (MIS-C)
  3. Affected children present with a wide spectrum of illness, with the sickest developing shock and respiratory failure and small numbers requiring VA-ECMO. Elevated inflammatory markers (D-dimer, fibrinogen, IL-1, and IL-6) are common. While most patients improve, a few fatalities have been reported
  4. Treatment has generally been modelled on successful approaches to Kawasaki Disease and include IVIG, aspirin, and consideration of steroids or other immunomodulatory medications. However, no standard has been established
Survivors of Critical Illness in COVID-19 (May 20, 2020)
  1. The majority of survivors of shock and respiratory failure develop post-intensive care syndrome (PICS). PICS is defined as new or worsened impairment after critical illness, which persists beyond hospital discharge, in one or more of three domains: cognition, mental health, or physical function. Similarly, PICS-Family (PICS-F) describes mental health impairments experienced by families of ICU patients
  2. Risk factors for developing PICS include shock, mechanical ventilation, prolonged sedation, delirium, and long periods of immobility. During an ICU course, assessment and management of pain/agitation/delirium, minimization of sedation, spontaneous awakening and breathing trials, early mobilization, and family engagement may improve patient and family outcomes. After hospital discharge, post-ICU clinics and peer support groups likely play an important role
  3. PICS can persist for months to years and may severely impair quality of life. These impairments may impact patients’ ability to return to work, adding to caregiver burden and compounding the financial toxicity of critical illness. Survivors of critical illness in general have reduced health-related quality of life, a higher risk of rehospitalization, and decreased long-term survival
  4. It remains unclear how many patients will experience PICS after COVID-19. However, given the increased number of patients experiencing critical illness, ARDS, and often long periods of sedation/immobility, we should be prepared to support a large population of patients and families experiencing long-term impairments after the ICU
What causes hypoxemia in COVID-19? (Part II) (May 19, 2020)
  1. The fundamental mechanisms of hypoxemia are common to all pulmonary disease. In ARDS, the primary mechanisms of hypoxemia are shunt and V/Q mismatch
  2. Shunt in ARDS is often seen in the setting of alveolar collapse/filling leading to substantial opacities on chest imaging. COVID-19 patients are reported to be hypoxemic in the absence of significant consolidation on chest imaging, leading some to postulate that the hypoxemia must be due to a novel mechanism. This ignores the known contribution of V/Q mismatch to hypoxemia in ARDS
  3. It has been further alleged that COVID-19 patients exhibit a unique failure of hypoxic pulmonary vasoconstriction (HPV). The strength of HPV varies between individuals and also depends on extent of pulmonary involvement, amount of supplemental O2, and ventilation strategy. The degree of HPV in any individual patient is therefore difficult to predict
  4. Observations of hypoxemia in COVID-19 are entirely consistent with known mechanisms and therefore do not require the invocation of novel processes specific to SARS-CoV-2
What causes hypoxemia in COVID-19? (Part I) (May 18, 2020)
  1. Critical COVID-19 is characterized by hypoxemic respiratory failure
  2. The perceived discordance between severity of hypoxemia and both the extent of radiographic disease and level of clinical distress has led many to propose novel and unlikely mechanisms of hypoxemia in COVID-19
  3. Distinguishing between hypoxemia and true hypoxia is essential to understanding the phenomenon of so-called “happy hypoxics” in COVID-19
  4. Fundamental mechanisms of hypoxemia are shared by all pulmonary diseases, including COVID-19. The most common causes of severe hypoxemia are low V/Q and its extreme, pulmonary shunt
Pets and COVID-19 (May 17, 2020)
  1. Scattered reports have emerged of positive viral testing in household pets, raising concern for human-to-pet transmission or vice versa
  2. SARS-CoV-2 infection in domesticated animals appears to lead to a mild and limited disease, if any
  3. The CDC and professional veterinary medicine groups have provided specific advice to pet owners regarding cautious care and interaction with their own animals, should pet owners become sick
  4. Available evidence does not indicate that domestic animals are playing a major part in the spread of COVID-19, though further study is needed
Considerations for pregnant women and their neonates (May 16, 2020)
  1. COVID-19 may be associated with critical illness, including during pregnancy
  2. Treatment of critical illness in pregnancy may require consideration of the timing of delivery. This decision must balance the effects of delivery on the neonate as well as on the mother
  3. COVID-19, by itself, is currently not an indication for cesarean delivery. Instead, a decision to proceed with cesarean delivery should be made based on standard obstetrical indications
  4. The desire to prevent peripartum transmission of SARS-CoV-2 complicates decisions around breastfeeding and contact between mother and infant
The second to last HCQ trial? (May 15, 2020)
  1. Initial interest in the use of hydroxychloroquine for the treatment of COVID-19 was spurred by a somewhat plausible mechanism of action and a small study which has since been widely criticized
  2. While generally well tolerated, hydroxychloroquine is associated with worrisome side effects including cardiac arrhythmia
  3. Despite a lack of randomized controlled trial data pointing to efficacy, many continue to advocate for the use of hydroxychloroquine. Indeed, the issue of its efficacy has become somewhat polarizing
  4. An open-label, randomized controlled trial from China shows no benefit of hydroxychloroquine in non-severe COVID-19. The negative result reported here should likely reserve the use of hydroxychloroquine to patients participating in a clinical trial - including the currently enrolling, hopefully definitive PETAL network ORCHID study
Can a CT Tell You How to Ventilate in COVID-19? (May 14, 2020)
  1. ARDS, like much critical illness, is a heterogeneous disease. Heterogeneity is a major challenge for critical care research and clinical practice, as it is expected that patients with the same clinical syndrome may yet respond differently to the same treatment
  2. A large body of rigorous research exists that attempts to identify clinical, radiographic, or imaging features that predict treatment response. To date, no subphenotype has been identified that clearly predicts treatment response in a prospective trial. Interventions that have been found to reduce mortality in randomized controlled trials have been found to do so even when applied to unselected populations of patients with ARDS
  3. Attempts have been made to rapidly define subphenotypes in COVID-19 ARDS based on a small number of observations. An informative new report, reviewed tonight, confirms that such rapidly identified phenotypes do not accurately describe COVID-19 related ARDS and should not be used to determine treatment strategies
  4. Research into subphenotypes of ARDS is ongoing and will be vital to the development of specific therapies. When carefully conducted, such studies promise to overcome a central challenge in critical care research, the profound heterogeneity of our patients
Mechanical Ventilation in the Era of COVID-19: An Ongoing Debate (May 13, 2020)
  1. Current knowledge of COVID-19 is largely based on descriptive case series and anecdotal experience
  2. The description of purported “phenotypes” of COVID-19 patients has led to vigorous debate about mechanical ventilation strategies
  3. COVID-19 patients represent a spectrum of disease, just as other etiologies of ARDS, and resemble historic non-COVID cohorts in their respiratory mechanics
  4. Future directions examining long-term outcomes in patients with COVID-19 are necessary next steps
Cats and Bats and Pangolins: the Origin of SARS-CoV-2 (May 12, 2020)
  1. SARS-CoV-2 shares 96% whole genome identity with a coronavirus found in bats, BatCoV RaTG13
  2. The key differences between SARS-CoV-2 and BatCoV localize to the receptor binding domain (RBD) of the spike protein, required for engaging the host receptor ACE2
  3. The RBD of SARS-CoV-2 is closely related to a coronavirus found in pangolins near the origin of the pandemic in China. It is therefore extremely likely that SARS-CoV-2 emerged from a recombination event between bat and pangolin virus, though the exact nature of the event is hard to determine
  4. There is nothing to suggest SARS-CoV-2 is human-made
A Positive Trial for COVID-19 Therapy (May 11, 2020)
  1. There is an intense need for antiviral therapies targeted against SARS-CoV-2, but positive results so far are limited to observational reports and a press release (with no published data) describing a shorter time to recovery with remdesivir
  2. Given the negative results for antiviral therapies to date, many have wondered if combination therapy might be more effective
  3. A recent report, described tonight, explores the results of interferon beta-1b in combination with antiviral therapies
  4. Despite a complicated trial design, the report by Huang and colleagues suggests that such an approach speeds recovery in COVID-19
ECMO for COVID-19 (Part II) (May 10, 2020)
  1. ECMO is an established rescue intervention for ARDS as reviewed in Part I of this FLARE
  2. While relatively resource intensive, a number of centers have successfully integrated ECMO into their management of COVID-19
  3. Outcomes after the use of ECMO for COVID-19 are currently unknown, but extrapolation from pre-COVID-19 use would suggest that they are likely to be encouraging 
  4. Complications of ECMO (not unique to COVID-19) include bleeding, issues related to vascular access, and infection
ECMO for COVID-19 (Part I) (May 9, 2020)
  1. Veno-venous extracorporeal membrane oxygenation (VV ECMO) is a form of pulmonary bypass that allows oxygenation to occur via an external membrane
  2. ECMO use has rapidly expanded in recent years, spurred on by the last respiratory virus pandemic—the 2009 H1N1 influenza outbreak—and the completion of two large randomized controlled trials
  3. Use of ECMO has been advocated for based on its ability to improve gas exchange and potentially prevent or reduce ventilator-induced lung injury
  4. Trial data and guidelines support the use of ECMO as rescue therapy in severe ARDS after failure of conventional ARDS management
New Observational Reports on Anticoagulation and Immunomodulation (May 8, 2020)
  1. There is intense interest in developing novel treatment strategies for COVID-19…and significant incentives for publishing reports of those strategies
  2. Notable papers from this week include observational data on therapeutic anticoagulation and immunomodulation in COVID-19
  3. The observational studies discussed in this FLARE have flaws in study design and analysis, which severely limit their utility in evaluating the proposed interventions
  4. Ultimately, only well-designed RCTs can determine the efficacy of new treatments for COVID-19
Helmet Ventilation in COVID-19 (May 7, 2020)
  1. Small studies suggest a benefit of NIPPV in ARDS, particularly mild ARDS. For this reason, some have suggested more widespread use of NIPPV in COVID-19
  2. NIPPV may decrease need for sedation and/or intubation but may also lead to worse outcomes due to suboptimal tidal volumes, PEEP, and patient-ventilator asynchrony. The role of NIPPV in the treatment of ARDS has yet to be substantiated in large randomized clinical trials
  3. Some have advocated for the use of helmet NIPPV specifically given initial data demonstrating success in treating ARDS patients and the perception that it is associated with a lower risk of aerosolization
  4. Currently available studies of NIPPV, including helmet NIPPV, indicate the risk of aerosolization cannot be completely dismissed and should be weighed when deciding to use NIPPV on a given patient during the COVID-19 pandemic
LFTs in COVID-19 (May 6, 2020)
  1. Elevated liver biochemistries (LFTs) are common in hospitalized patients with COVID-19, and higher in sicker patients; however, mortality in COVID-19 does not appear to be driven, even to a small degree, by liver failure
  2. If there are “classic” COVID-19 LFTs, they consist of a hepatocellular pattern of injury with transaminases 1 to 5 times the upper limit of normal and AST > ALT
  3. While non-hepatic sources can increase the level of some tests (AST, for example), elevated LFTs in most cases of COVID-19 probably do represent a primary liver injury
  4. Primary liver injury, however, may result from a complicated mixture of underlying liver disease, COVID-19-related liver injury, drug-induced liver injury, ischemia, cholestasis of sepsis, and other forms of liver injury not specific to COVID-19
New Data on Protective Immunity After COVID-19 (May 5, 2020)
  1. The world is eager for an “immunity test” for SARS-CoV-2, but the level and duration of protective immunity after recovery from COVID-19 remain to be defined
  2. Protective immunity depends on both production of antibodies by B cells and development of virus-specific T cell responses
  3. A new paper suggests not only that SARS-CoV-2-specific antibodies are detected in convalescent subjects, but that, in most of these individuals, antibodies are neutralizing and there is also evidence of a virus-specific T cell response
  4. While more work is needed, these results continue to provide assurance that natural infection will confer protective immunity, and that future vaccination may be effective
LTVV in non-ARDS (May 4, 2020)
  1. Low tidal volume ventilation is a cornerstone of therapy for ARDS and has a well-demonstrated mortality benefit
  2. Low tidal volume ventilation has also been associated with improved outcomes in non-ARDS patients
  3. Implementation of low tidal volume ventilation has costs in the form of increased sedation and even paralysis. These costs must be balanced against the benefits of achieving low tidal volume ventilation in a particular patient
  4. Given demonstrated benefits of low tidal volume ventilation in both ARDS and non-ARDS respiratory failure, it should not be assumed that protocolized use of higher tidal volumes, as has been advocated, is ever without harm
Ventilator Liberation in COVID-19 (May 3, 2020)
  1. COVID-19 patients with respiratory failure have been reported to require long durations of mechanical ventilation, though it is not yet clear if duration will be longer than that seen with other ARDS patients
  2. An extensive body of literature exists on liberation from mechanical ventilation and standard approaches should be applied to COVID-19 patients
  3. Given the risk to providers associated with intubation, it may be appropriate to aim for a lower re-intubation rate than is typically seen in ICUs
  4. Some clinicians may also have a higher threshold to extubate given a desire to avoid aerosol-generating respiratory support such as HFNC and NIPPV
Sedation in COVID-19 (May 2, 2020)
  1. ICU sedation should be minimized to the extent possible and protocols should avoid agents which lead to prolonged sedation such as benzodiazepines, as these can increase the rate of ICU related complications
  2. However, respiratory drive is increased in hypoxemic respiratory failure and this can lead to a perceived need for deep sedation in patients maintained on lung protective ventilation
  3. Preferred sedatives like propofol are also associated with complications such as hypertriglyceridemia and propofol infusion syndrome (PRIS) but severe side effects are fortunately rare
  4. Little data exists on safe de-escalation of sedation but patients who have been maintained on high doses of agents such as opiates or benzodiazepines likely require protocolized weaning
Lung Pathology in COVID-19 (May 1, 2020)
  1. Clinical lung injury and ARDS can be associated with a variety of histologic patterns
  2. In COVID-19, the limited available histologic evidence predominantly reveals classic DAD with very little organization and fibrosis (at least in the acute setting)
  3. AFOP has been described in one small case series; however, definitive diagnosis is hampered by sampling techniques. Additionally, there are a multitude of other pathologic findings noted in multiple other COVID-19 post-mortem series
  4. There are unanswered questions regarding the timing of lung injury and development of DAD, and there is a dearth of data regarding histological correlates in patients who recover from SARS-CoV-2 infection
Anticoagulation in COVID-19 (April 30, 2020)
  1. Increased activation of the coagulation cascade and reduced fibrinolytic activity are observed in ARDS, but no human trial in ARDS has demonstrated a clinical benefit to therapeutic anticoagulation
  2. Observational data and case reports have suggested a high rate of thrombotic complications in COVID-19, particularly in those with ARDS
  3. These data have generated excitement and controversy regarding empiric systemic anticoagulation and alternative therapies (including tissue plasminogen activator and post-discharge thromboprophylaxis) in severe COVID-19
  4. Guideline data support the use of thromboprophylaxis in acutely ill and critically ill patients with COVID-19 without bleeding contraindications. The utility of augmented anticoagulation strategies in the critically ill COVID-19 population is presently unknown
HCQ Update (April 29, 2020)
  1. Initial enthusiasm for chloroquine and hydroxychloroquine for treatment of SARS-CoV-2 infection spurred a number of clinical trials, some with newly published data
  2. Though the majority of available clinical data have not been peer reviewed, no studies demonstrate significant differences in relevant clinical outcomes
  3. Furthermore, enthusiasm for these medications has waned amidst worrisome safety signals in patients receiving hydroxychloroquine and azithromycin
  4. We eagerly await the peer-reviewed published data from these hydroxychloroquine trials (and from the publicized, but not yet released, remdesivir NIAID trial), to further refine the armamentarium for COVID-19
The Interplay Between Diabetes and SARS-CoV-2 (April 28, 2020)
  1. Observational data indicate that patients with diabetes are at higher risk for severe COVID-19 illness and death
  2. It is possible that an interaction between the inflammatory response to SARS-CoV-2 and acute hyperglycemia contributes to the morbidity and mortality seen in patients with diabetes and COVID-19
  3. Efforts to improve blood glucose monitoring and management in critically ill patients may therefore improve outcomes in COVID-19
  4. More research is needed to determine if there are factors intrinsic to SARS-CoV-2 that interact with diabetes and lead to more severe presentations
Superinfection in COVID-19 (April 27, 2020)
  1. Secondary bacterial infection has been reported to be a major cause of mortality in viral respiratory infections prior to COVID-19
  2. Available data on secondary infections in COVID-19 are limited but do indicate that nosocomial infections are associated with increased COVID-19 severity and death
  3. Risk factors for secondary bacterial and fungal infections include invasive devices (central venous catheters), diabetes, combination antibiotic therapy, and glucocorticoid treatment
  4. Given long ICU stays associated with COVID-19, it is likely that rates of secondary bacterial infection will reflect, in part, nosocomial infections that are common in critical illness
Surfactant and COVID-19 (April 26, 2020)
  1. Pulmonary surfactant is a complex mixture of lipids and proteins synthesized in alveolar epithelial cells that is essential to stability of the airspaces and simultaneously contributes to innate immune function. Alveoli are, in some superficial ways, similar to “tiny bubbles”—their stability depends on a balance between surface tension and transpulmonary “pressure”. Alveolar instability and disruption of surfactant activity is a hallmark of lung diseases like ARDS
  2. Some forms of acute lung injury, particularly in neonates, are effectively treated with surfactant administration and provide proof of concept for surfactant-based therapy of ARDS
  3. To date, clinical trials have failed to identify a clear signal for mortality benefit of surfactant replacement in unselected ARDS patients
  4. The biologic plausibility of surfactant therapy for ARDS is strong. Prior trials do demonstrate safety and have identified a suggestion of benefit in forms of ARDS driven by primary direct lung injury. COVID-19 associated respiratory failure (a primary lung process) provides a unique and valuable opportunity to revisit the utility of surfactant therapy in a large ARDS cohort with a single etiology
Stem Cells and COVID-19 (April 25, 2020)
  1. Based on small case series, MSCs have been proposed as an immunomodulatory therapy for COVID-19
  2. The literature on MSCs suffers from a lack of consensus on the definition of MSC and vague descriptions of their mechanism of action
  3. Phase 1 and Phase 2a clinical trials of MSC therapy in ARDS demonstrated MSC safety but did not demonstrate efficacy
  4. Even though MSC therapy has not shown benefit for any human disease in a rigorous setting, clinical trials of MSCs are enrolling COVID-19 patients throughout the world
Protective Immunity to SARS-CoV-2 (April 24, 2020)
  1. Evidence suggests that humans will develop protective immunity after infection with SARS-CoV-2, although immunity may wane with time
  2. An effective SARS-CoV-2 vaccine will not be available for the first wave of the pandemic, but will be critical if SARS-CoV-2 establishes itself within the human population
  3. There are six distinct vaccine platforms being pursued, some with the potential for rapid expansion and large-scale production
  4. Investment in vaccine development infrastructure is needed to allow for more effective vaccines in response to novel pathogens
Of Ventilators and the Undiscovered Country (April 23, 2020)
  1. A report from Northwell Health in New York, published yesterday (April 22, 2020) in JAMA (Richardson et al. 2020), has received substantial attention due to a stated 88.1% mortality rate among mechanically ventilated patients
  2. This mortality rate is calculated by including 282 deaths among 320 total mechanically ventilated patients who were discharged alive or dead with a short median length-of-stay
  3. 831 patients (72%) receiving invasive ventilation in the cohort remained alive and in the hospital at the time of data censoring but were excluded from the calculation. Since the excluded patients were, in fact, not deceased at the time of the report, 88.1% is not a valid representation of the mortality rate associated with mechanical ventilation in this cohort
  4. Out of a desire to provide timely information on outcomes in COVID-19, many journals have allowed publication of papers with substantial amounts of missing outcomes data. Mortality outcomes from these studies generally cannot be meaningfully interpreted, but should at least include all patients with the exposure of interest (in this case ventilation) in the denominator. Depending on the fate of the excluded patients, true mortality in the Northwell cohort could be as low as 25% or as high as 97%. This range is currently too broad to meaningfully inform clinical decisions
APRV and HFOV in COVID-19 (April 22, 2020)
  1. High frequency oscillatory ventilation (HFOV) and airway pressure release ventilation (APRV) are non-conventional modes of ventilation for ARDS that are designed to achieve recruitment and avoid atelectrauma
  2. It has been suggested that these non-traditional modes are better suited to COVID-19 associated ARDS than traditional lung protective ventilation
  3. Unlike traditional lung protective ventilation, neither HFOV nor APRV has ever been shown to reduce mortality in ARDS. One large trial of HFOV actually suggested an increase in mortality
  4. Traditional lung protective ventilation, by which we mean low tidal volume and minimal driving pressure, remains the best approach to mechanical ventilation in COVID-19 and in ARDS more generally
Inequities in COVID-19 (April 21, 2020)
  1. As the COVID-19 outbreak progresses in the U.S., it is becoming clear that communities are not equally affected
  2. Racial and socioeconomic disparities in incidence are apparent in highly impacted communities, such as New York and Boston, as well as outside the Northeast, in places like Charlotte, Chicago, and the Navajo Nation
  3. In addition to disparate incidence of disease, disadvantaged communities face higher rates of comorbidities such as diabetes and hypertension that are known to contribute to poor outcomes in COVID-19
  4. Some of these communities with elevated rates of high-risk health conditions have greater proportions of uninsured residents, which may lead to under-financed and under-resourced healthcare systems, ill-prepared for a COVID-19 patient surge
Pregnancy and SARS-CoV-2 infection (April 20, 2020)
  1. Small case series from prior coronavirus outbreaks (SARS, MERS) have suggested poor outcomes in pregnant patients
  2. Preliminary reports about COVID-19 in pregnancy indicate that pregnant women do not experience substantially worse outcomes
  3. Similarly, only rare reports indicate neonatal complications in COVID-19
  4. Management of pregnant patients with SARS-CoV-2 does not differ significantly from standard critical care of non-pregnant patients
New Data From NYC (April 19, 2020)
  1. As the global pandemic due to SARS-CoV-2 progresses, more and more data are becoming available about the clinical course and outcomes of patients with COVID-19
  2. Tonight we review a recent case series from New York, New York
  3. Clinical characteristics of patients described in this Open Letter to New York, are broadly similar to those described in earlier reports
  4. Due to the short follow-up period, final outcome data are not yet available, but outcomes of ventilated patients thus far provide some reassurance
Antibodies in Severe COVID-19 (April 18, 2020)
  1. A subset of individuals with severe COVID-19 exhibit high levels of inflammatory cytokines, suggesting that an over-exuberant immune response may play a key role in pathogenesis
  2. Antibody-dependent enhancement (ADE) is an immune phenomenon best described in dengue virus infection, where antibodies elicited by infection with one viral serotype paradoxically enhance both infection and host inflammatory response upon exposure to a newly infecting serotype
  3. ADE may occur during SARS-CoV-2 infection, leading to enhanced viral replication within immune cells while simultaneously promoting inflammation
  4. However, ADE is unlikely to be the sole determinant of severe COVID-19. For example, children exhibit ADE in other contexts but rarely develop severe COVID-19. Future studies will be needed to define any immune-mediated mechanisms driving severe SARS-CoV-2 infection
Will SARS-CoV-2 Disappear in the Summer? (April 17, 2020)
  1. Respiratory viral infections often have a defined seasonality
  2. The determinants of seasonality include host behavior, changes in immunity, as well as absolute humidity and temperature
  3. Pandemics often do not adhere to typical viral seasonality
  4. We do not know whether transmission of SARS-CoV-2 will be different in the summer, but there is hope that viral transmission could be reduced
Update on Remdesivir (April 16, 2020)
  1. Remdesivir is a nucleoside analog, previously studied in Ebola, which may have activity against SARS-CoV-2
  2. A recent paper in the NEJM reported the clinical course of COVID-19 patients treated with remdesivir through compassionate use protocols
  3. This industry-sponsored study was uncontrolled, and rife with methodological issues
  4. Evidence on the effectiveness of remdesivir will require additional trials. Fortunately, many such trials are ongoing
Post-extubation Stridor in COVID-19 (April 15, 2020)
  1. There are anecdotal reports of a high incidence of post-extubation stridor and extubation failure in COVID-19
  2. COVID-19 patients possess many of the traditional risk factors for post-extubation complications, the most important of which is prolonged mechanical ventilation
  3. A number of tests (cuff leak, ultrasound, video laryngoscopy) have been investigated as means of predicting which patients will develop post-extubation stridor. None have both high sensitivity and high specificity 
  4. Short courses of steroids prior to a planned extubation have been shown to reduce the incidence of post-extubation stridor and reintubation
Fluid Management in ARDS (April 14, 2020)
  1. The three best evidence-based interventions in ARDS are lung-protective ventilation (March 23 FLARE), prone positioning (March 29 FLARE), and conservative fluid management 
  2. Conservative fluid management is generally defined and guided by the results of the landmark 2006 FACTT (Fluid and Catheter Treatment Trial) study and includes avoidance of positive fluid balance and normalization of intravascular volume in patients post-resuscitation and without ongoing shock (ARDS Clinical Trials Network, 2006)
  3. In addition to conservative management post-resuscitation, it is appropriate to guide fluid resuscitation by measures of volume responsiveness
  4. Volume responsiveness should be assessed with dynamic rather than static measures
Why COVID-19 Is Not like HAPE (April 13, 2020)
  1. The presenting symptoms of COVID-19 and high altitude pulmonary edema (HAPE) are common to many acute respiratory illnesses, and do not constitute a unique link between the two processes
  2. HAPE is a non-inflammatory process occurring when low atmospheric oxygen pressure triggers excessive hypoxic pulmonary vasoconstriction, resulting in markedly elevated pulmonary arterial pressure and non-cardiogenic pulmonary edema
  3. The primary treatment of HAPE is descent to lower altitude and supplemental oxygen therapy. This corrects the root cause of HAPE, hypoxic pulmonary vasoconstriction. The resulting edema typically resolves within 6-48 hours
  4. There is no pathophysiologic or clinical basis for comparing COVID-19 to HAPE. Further, this comparison risks misguided use of HAPE therapies which may harm patients with COVID-19 by worsening ventilation-perfusion mismatch
BCG Vaccine and COVID-19 (April 12, 2020)
  1. The BCG vaccine likely has some efficacy in preventing TB infection or decreasing severity of TB disease, especially in children
  2. The BCG vaccine may boost the innate immune response against a myriad of infections through “trained immunity”
  3. There are no peer-reviewed studies on BCG vaccine and COVID-19; medRxiv pre-print entries have deep methodological flaws
  4. Articles deposited on medRxiv, bioRxiv, ChemRxiv, and other online “pre-print servers” need to be interpreted with an abundance of caution
Viral Load in COVID-19 (April 11, 2020)
  1. In most cases of SARS-CoV-2, viral load decreases as adaptive immunity develops 
  2. Severe COVID-19 is also characterized by significantly elevated inflammatory markers (e.g. CRP, IL-6, ferritin), which some speculate reflects an irrationally exuberant immune response 
  3. During the 2003 SARS epidemic, there were reports of poor outcomes with both prolonged and suppressed viral replication, suggesting some patients have poor outcomes due to failure to contain the virus, while some suffer from a maladaptive immune response 
  4. Tonight, we review data on the association of viral load with disease outcome
Is COVID-19 ARDS? (April 10, 2020)
  1. It has been alleged that COVID-19 associated respiratory failure is the result of a novel pathophysiology and is therefore not ARDS
  2. Such sentiments are frequently based on a misunderstanding of the definition of ARDS, its spectrum of disease, optimal treatment, and the physiology of hypoxemia
  3. Almost all commentators, even those who argue it is not ARDS, appear to agree that large distending pressures in the inflamed lung can be injurious and lead to worsening of gas exchange and pulmonary mechanics. This is the essential pathophysiology of ARDS
  4. COVID-19 associated respiratory failure is characterized clinically by hypoxemia and bilateral infiltrates, pathologically by diffuse alveolar damage, and is optimally treated by a strategy that minimizes distending alveolar pressure and lung stretch. On this basis, COVID-19 associated respiratory failure is ARDS
Procalcitonin and SARS-CoV-2 (April 9, 2020)
  1. Procalcitonin level is frequently elevated by bacterial infections, but should not be the sole criterion for administering antibiotics
  2. Procalcitonin may be helpful in identifying bacterial co-infection in viral pneumonia
  3. Severity of SARS-CoV-2 infection is correlated with higher levels of procalcitonin. It is unclear if this is related to bacterial co-infection or severity of the viral infection itself
  4. As in other conditions, procalcitonin should be interpreted in the broader clinical context of COVID-19 associated respiratory failure. Elevated levels may suggest severe disease, bacterial co-infection, or both
New ICU Data from Italy (April 8, 2020)
  1. To date, most published data on critical illness in association with COVID-19 consist of uncontrolled case series with relatively small numbers 
  2. Grasselli et al. have reported the experience of 1591 ICU patients with COVID-19 in the Lombardy region of Italy
  3. Median P:F was 160 mmHg in this cohort. Little data on respiratory mechanics is provided but median PEEP was 14 cmH2O. The ICU population, therefore, consisted mostly of mild-to-moderate ARDS by Berlin criteria and was broadly similar to prior ARDS observational cohorts such as LUNG-SAFE
  4. Follow-up was limited in the Italian study, but ICU mortality to date is reported as 26%. The majority of patients described (58%), however, were still in the ICU at the end of the follow-up period
SARS-CoV-2 Affects Children Differently Than Adults (April 7, 2020)
  1. The kids are alright: When infected with SARS-CoV-2, children may have lower rates of symptomatic infection and decreased illness severity compared to adults
  2. Infants (<1 year old) seem to have a slightly higher risk for severe or critical illness compared to other pediatric age groups
  3. Overall mortality in children is extremely low
  4. The mechanisms leading to lower rates of severe illness in children are unknown
Testing for SARS-CoV-2 (April 6, 2020)
  1. Two major types of assays are used to detect respiratory viral infections: Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR) and Direct Fluorescent Antibody (DFA); RT-PCR continues to be the method of choice for detecting SARS-CoV-2 due to its wider availability and high sensitivity
  2. True positive predictive value and negative predictive value for SARS-CoV-2 RT-PCR remain unknown this early in the COVID-19 pandemic. Without a clear gold standard test, clinical sensitivity and specificity are difficult to determine
  3. Sampling, anatomic location, and disease stage and severity likely play critical roles in determining the sensitivity and specificity of PCR testing testing
  4. Serological tests for COVID-19 promise to supplement PCR based strategies testing
COVID-19 Risk Factor Round-Up (April 5, 2020)
  1. To date, over a dozen studies have attempted to identify risk factors associated with severe COVID-19 or related death
  2. A minority of patients with COVID-19 require ICU-level care. Early reports from China indicated that risk factors for severe disease included advanced age, cardiac disease and diabetes
  3. More recent reports are largely consistent with early reports and emphasize that risk factors for severe COVID-19 are qualitatively similar to risk factors for mortality in general critical illness
Investigational Therapies for ARDS (Part II) (April 4, 2020)
  1. The therapy for ARDS, including ARDS associated with COVID-19, is centered on lung-protective ventilation, conservative fluid management and treatment of the underlying process
  2. ARDS is thought to result from a complex interaction between the inciting insult and the host response
  3. Numerous studies are currently evaluating novel therapies targeting the pathologic cascade of ARDS and the host response to SARS-CoV-2
  4. It is important to consider future studies in the historical context of failed investigational therapies for ARDS
Investigational Therapies for ARDS (Part I) (April 3, 2020)
  1. The therapy for ARDS, including ARDS associated with COVID-19, is essentially supportive
  2. To date, the only specific therapies that have been found to help in cases of ARDS are those that target the underlying process that led to ARDS, such as antibiotics for bacterial infection
  3. There are many suggestions for novel therapies targeting the pathologic cascade of ARDS and the host response to SARS-CoV-2. Many of these are being evaluated in trials. Some have been suggested for clinical use
  4. Proposed therapies must be evaluated in light of the long history of failed investigational therapies for ARDS
Managing PEEP and Recruitment (April 2, 2020)
  1. ARDS is a disease of surfactant dysfunction and alveolar collapse that results in regions of V/Q mismatch and shunt. The application of PEEP can open, or "recruit," poorly ventilated alveoli. Opening alveoli decreases shunt, improves oxygenation and can simultaneously improve pulmonary mechanics since the higher regional volume may be associated with higher compliance
  2. Overdistension of lung units, however, results in decreased compliance and barotrauma. PEEP must be titrated to balance the benefit from recruitment of affected lung units against the risk of over distending unaffected units
  3. Many people are saying that patients with COVID-19 oxygenate well on low to moderate levels of PEEP but do not improve with more aggressive maneuvers. Patients are thus simultaneously easy to recruit (i.e. fully open at low PEEP), but do not respond to (aggressive) recruitment
  4. Care must therefore be taken to choose the PEEP that captures the benefit of recruiting the easily recruitable lung units without the pitfall of over distending the large amount of normal lung. No method of PEEP optimization is known to be superior to any other. Tabulated PEEP-FiO2 tables are likely a reasonable first approach while a select group of patients may benefit from more individualized PEEP titration
Myocarditis and COVID-19 (April 1, 2020)
  1. Prior reports from outbreaks of SARS and MERS suggest that coronaviruses may have tropism for cardiac tissue
  2. SARS-CoV-2 has been reported to cause a variety of cardiac manifestations in the current pandemic. Some have posited that myocarditis, an inflammatory disease with a variety of etiologies, may be a culprit
  3. Reports of COVID-19-related myocarditis are extremely limited, and do not abide by the clearly defined criteria for diagnosis of myocarditis
  4. Though patients with COVID-19 may suffer from cardiac compromise, the underlying mechanism is currently not understood. Providers should seek clear evidence of a diagnosis and exercise caution prior to initiating empiric therapy for myocarditis
Coagulation and ARDS in COVID-19 (March 31, 2020)
  1. Damage to the alveolar endothelium in ARDS activates the coagulation cascade, causing accumulation of platelet-fibrin thrombi in the alveolus. This can promote further lung injury
  2. Case series of patients with severe COVID-19 have suggested that coagulation abnormalities in the serum are associated with ARDS and higher mortality
  3. Anticoagulants and thrombolytics have been studied in both pre-clinical models and patients with ARDS, but studies have been plagued by heterogeneity in methods and study design
  4. Though ARDS and COVID-19 are associated with hypercoagulability, the currently available evidence does not suggest that therapeutic anticoagulation or fibrinolytics will improve patient outcomes
iNO in COVID-19 (March 30, 2020)
  1. Inhaled pulmonary vasodilators (iNO, epoprostenol) are periodically used to improve oxygenation in ARDS
  2. Despite frequent use, inhaled pulmonary vasodilators have never been shown to improve outcomes
  3. There may be a role for these interventions when there is an emergent need to improve oxygenation
  4. There are postulated, but unproven, direct antiviral effects of iNO
  5. iNO may be preferable to other pulmonary vasodilators due to both direct antiviral effects and mode of delivery
Prone Position in the Non-intubated Patient (March 29, 2020)
  1. What is the effect of prone position in a non-intubated patient?
  2. Should it be considered in patients with severe COVID-19?
Of ACEs, ARBs and COVID-19 (March 28, 2020)
  1. The basic biology of the ACE2 pathway, explore the existing data regarding ACE2 and lung injury
  2. Existing data regarding ACE2 and lung injury
  3. Implications for patients receiving these medications in the setting of COVID-19
Use of Convalescent Plasma (March 27, 2020)
  1. The rationale and evidence for utilizing convalescent plasma in COVID-19
  2. Current trials and biotech developments
CT Scans & Early Tracheostomy (March 26, 2020)
  1. What is the utility of chest CT in patients with suspected or confirmed COVID-19?
  2. What is the role for early tracheostomy in patients with respiratory failure from COVID-19?
The Spectrum of Disordered Inflammation in Critical Illness (March 25, 2020)
  1. Elevated inflammatory biomarkers are common in critical illness, including severe COVID-19
  2. Hypothesis: a dysregulated immune response, or “cytokine storm”, contributes to the progression of critical illness and/or SARS-CoV-2 infection
  3. The pathophysiology of cytokine storm and the evidence for immune modulation in the treatment of critical illnesses
FAQs, GI Disease, Washington and Italy (March 24, 2020)
  1. FAQs about the Mass General Critical Care Guidance
  2. COVID-19 presenting as GI disease
  3. Analysis and comparison of newly published clinical data from Washington State and Italy
PEEP, ARDS and COVID-19 Associated Respiratory Failure (March 23, 2020)
  1. Discussion of ARDS, PEEP strategy and ARDS subphenotypes in COVID-19 by Dr. Corey Hardin

  2. Summary of major PEEP strategy trials

    • ALVEOLI – High PEEP vs. Low PEEP

    • EXPRESS – High PEEP vs. Moderate PEEP

    • LOVS – Open lung approach vs. Low Vt

Additional Therapeutics for SARS-CoV-2 (March 22, 2020)
  1. Chloroquine and its potential role in COVID-19

  2. Data re-analysis and review of recent HCQ +/- Azithromycin trial

  3. COVID-relative points about ARDS management

    • Use of methylprednisolone in ARDS via the LaSRS Trial

    • ARDS phenotyping and differential response to treatments