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Researchers have used CRISPR gene-editing technology to come up with a test that detects the pandemic coronavirus in just 5 minutes. The diagnostic doesn’t require expensive lab equipment to run and could potentially be deployed at doctor’s offices, schools, and office buildings.
“It looks like they have a really rock-solid test,” says Max Wilson, a molecular biologist at the University of California (UC), Santa Barbara. “It’s really quite elegant.”
CRISPR diagnostics are just one way researchers are trying to speed coronavirus testing. The new test is the fastest CRISPR-based diagnostic yet. In May, for example, two teams reported creating CRISPR-based coronavirus tests that could detect the virus in about an hour, much faster than the 24 hours needed for conventional coronavirus diagnostic tests.CRISPR tests work by identifying a sequence of RNA—about 20 RNA bases long—that is unique to SARS-CoV-2. They do so by creating a “guide” RNA that is complementary to the target RNA sequence and, thus, will bind to it in solution. When the guide binds to its target, the CRISPR tool’s Cas13 “scissors” enzyme turns on and cuts apart any nearby single-stranded RNA. These cuts release a separately introduced fluorescent particle in the test solution. When the sample is then hit with a burst of laser light, the released fluorescent particles light up, signaling the presence of the virus. These initial CRISPR tests, however, required researchers to first amplify any potential viral RNA before running it through the diagnostic to increase their odds of spotting a signal. That added complexity, cost, and time, and put a strain on scarce chemical reagents. Now, researchers led by Jennifer Doudna, who won a share of this year’s Nobel Prize in Chemistry yesterday for her co-discovery of CRISPR, report creating a novel CRISPR diagnostic that doesn’t amplify coronavirus RNA. Instead, Doudna and her colleagues spent months testing hundreds of guide RNAs to find multiple guides that work in tandem to increase the sensitivity of the test.
That’s still not as good as the conventional coronavirus diagnostic setup, which uses expensive lab-based machines to track the virus down to one virus per microliter, says Melanie Ott, a virologist at UC San Francisco who helped lead the project with Doudna. However, she says, the new setup was able to accurately identify a batch of five positive clinical samples with perfect accuracy in just 5 minutes per test, whereas the standard test can take 1 day or more to return results.
The new test has another key advantage, Wilson says: quantifying a sample’s amount of virus. When standard coronavirus tests amplify the virus’ genetic material in order to detect it, this changes the amount of genetic material present—and thus wipes out any chance of precisely quantifying just how much virus is in the sample.
By contrast, Ott’s and Doudna’s team found that the strength of the fluorescent signal was proportional to the amount of virus in their sample. That revealed not just whether a sample was positive, but also how much virus a patient had. That information can help doctors tailor treatment decisions to each patient’s condition, Wilson says.
Doudna and Ott say they and their colleagues are now working to validate their test setup and are looking into how to commercialize it.
In 13 Viewpoints in this issue,2–14 JAMA Network editors reflect on the clinical, public health, operational, and workforce issues related to COVID-19 in each of their specialties. Questions and concerns they identify in their clinical communities include the following:
Benefits and harms of treatments and identifying mortality risk markers beyond age and comorbidities
Cardiovascular consequences of COVID-19 infection, including risks to those with comorbid hypertension and risks for myocardial injury
Risk for direct central nervous system invasion and COVID-19 encephalitis and for long-term neuropsychiatric manifestations in a post–COVID-19 syndrome
Risks related to SARS-CoV-2 infection for patients with compromised immunity, such as those receiving treatment for cancer
Challenges unique to patients with acute kidney injury and chronic kidney disease
Risks of viral transmission from aerosol-generating procedures, including most minimally invasive surgeries, and the need for eye protection as well as personal protective equipment as part of universal precautions
The prevalence and pathophysiology of skin findings in patients with COVID-19, determining if they are primary or secondary cutaneous manifestations of infection, and how best to manage them
The prevalence and significance of eye findings in patients with COVID-19 and the risk of transmission and infection through ocular surfaces
The role of anticoagulation for managing the endotheliopathy and coagulopathy characteristic of the infection in some patients
Developmental effects on children of the loss of family routines, finances, older loved ones, school and education, and social-based activities and milestone events
Effects of the pandemic, mitigation efforts, and economic downturn on the mental health of patients and frontline clinicians
Seasonality of transmission as the pandemic enters its third season
How to implement reliable seroprevalence surveys to document progression of the pandemic and effects of public health measures
Effects of the pandemic on access to care and the rise of telehealth
Consequences of COVID-19 for clinical capabilities, such as workforce availability in several specialties, delays in performing procedures and operations, and implications for medical education and resident recruitment.
Additional important questions that require careful observation and research include
Randomized evaluations of treatment: what is effective and safe, and what timing of which drug will reduce morbidity and mortality? Will a combination of therapies be more effective than any single drug?
Randomized evaluations of preventive interventions, including convalescent plasma, monoclonal antibodies, and vaccines. Which are effective and safe enough to prevent COVID-19 at a population level?
How can COVID-19 vaccines and therapeutics be distributed and paid for in ways that are fair and equitable?
Is immunity complete or partial, permanent or temporary, what is its mechanism, and how best is it measured? Can the virus mutate around host defenses?
How important are preadolescent children to the spread of infection to older family members and adult communities, and what are the implications for parent, caregiver, and teacher personal risk and disease transmission?
Is SARS-CoV-2 like influenza (continually circulating without or with seasonality), measles (transmissible but containable beneath threshold limits), or smallpox and polio (eradicable, or nearly so)?
Has the pandemic fundamentally altered the way health care is financed and delivered? By shining a spotlight on health inequities, can the pandemic motivate changes in health care finance, organization, and delivery to reduce those inequities?
The initial reports on the epidemiology of coronavirus disease 2019 (COVID-19) emanating from Wuhan, China, offered an ominous forewarning of the risks of severe complications in elderly patients and those with underlying cardiovascular disease, including the development of acute respiratory distress syndrome, cardiogenic shock, thromboembolic events, and death. These observations have been confirmed subsequently in numerous reports from around the globe, including studies from Europe and the US. The mechanisms responsible for this vulnerability have not been fully elucidated, but there are several possibilities. Some of these adverse consequences could reflect the basic fragility of older individuals with chronic conditions subjected to the stress of severe pneumonia similar to influenza infections. In addition, development of type 2 myocardial infarction related to increased myocardial oxygen demand in the setting of hypoxia may be a predominant concern, and among patients with chronic coronary artery disease, an episode of acute systemic inflammation might also contribute to plaque instability, thus precipitating acute coronary syndromes, as has also been reported during influenza outbreaks.
However, in the brief timeline of the current pandemic, numerous publications highlighting the constellation of observed cardiovascular consequences have emphasized certain distinctions that appear unique to COVID-19.1 Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gains entry via the upper respiratory tract, its affinity and selective binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which is abundant in the endothelium of arteries and veins as well as in the respiratory tract epithelium, create a scenario in which COVID-19 is as much a vascular infection as it is a respiratory infection with the potential for serious vascular-related complications. This may explain why hypertension is one of the cardiovascular conditions associated with adverse outcomes. In the early stages of the pandemic, the involvement of the ACE2 receptor as the target for viral entry into cells created concerns regarding the initiation or continuation of treatment with ACE inhibitors and angiotensin receptor antagonists in patients with hypertension, left ventricular dysfunction, or other cardiac conditions. Subsequently, many studies have shown that these drugs do not increase susceptibility to infection or increase disease severity in those who contract the disease,2 thus supporting recommendations from academic societies that these drugs should not be discontinued in patients who develop COVID-19 infections.
Thrombosis, arterial or venous, is a hallmark of severe COVID-19 infections, related both to vascular injury and the prothrombotic cytokines released during the intense systemic inflammatory and immune responses.3 This sets the stage for serious thrombotic complications including acute coronary syndromes, ischemic strokes, pulmonary embolism, and ischemic damage to multiple other organ systems. Such events can complicate the course of any patient with COVID-19 but would be particularly devasting to individuals with preexisting cardiovascular disease.
Another unique aspect of COVID-19 infections that is not encountered by patients with influenza is myocardial injury, manifested by elevated levels of circulating troponin, creatinine kinase-MB, and myoglobin. Hospitalized patients with severe COVID-19 infections and consequent evidence of myocardial injury have a high risk of in-hospital mortality.4 Troponin elevations are most concerning, and when accompanied by elevations of brain natriuretic peptide, the risk is further accentuated. Although myocardial injury could reflect a COVID-19–related acute coronary event, most patients with troponin elevations who undergo angiography do not have epicardial coronary artery obstruction. Rather, those with myocardial injury have a high incidence of acute respiratory distress syndrome, elevation of D-dimer levels, and markedly elevated inflammatory biomarkers such as C-reactive protein and procalcitonin, suggesting that the combination of hypoxia, microvascular thrombosis, and systemic inflammation contributes to myocardial injury. Myocarditis is a candidate explanation for myocardial injury but has been difficult to confirm consistently. However, features of myocarditis have been reported in case reports5 based on clinical presentation and results of noninvasive imaging, but thus far confirmation of myocarditis based on myocardial biopsy or autopsy examinations has been a rare finding.6 Instead, myocardial tissue samples more typically show vascular or perivascular inflammation (endothelialitis) without leukocytic infiltration or myocyte damage.
There remain important unknowns regarding the intermediate and long-term sequelae of COVID-19 infection among hospital survivors. In an autopsy series of patients who died from confirmed COVID-19 without clinical or histological evidence of fulminant myocarditis,7 viral RNA was identified in myocardial tissue in 24 of 39 cases, with viral load of more than 1000 copies/μg of RNA in 16 cases. A cytokine response panel demonstrated upregulation of 6 proinflammatory genes (tumor necrosis factor, interferon γ, CCL4, and interleukin 6, 8, and 18) in the 16 myocardial samples with the high viral RNA levels.
Whether a subclinical viral load and associated cytokine response such as this in survivors of COVID-19 could translate into subsequent myocardial dysfunction and clinical heart failure require further investigation. However, the results of a recent biomarker and cardiac magnetic resonance (CMR) imaging study provide evidence to support this concern.6 Among 100 patients who were studied by CMR after recovery from confirmed COVID-19 infection, of whom 67 did not require hospitalization during the acute phase, left ventricular volume was greater and ejection fraction was lower than that of a control group. Furthermore, 78 patients had abnormal myocardial tissue characterization by CMR, with elevated T1 and T2 signals and myocardial hyperenhancement consistent with myocardial edema and inflammation, and 71 patients had elevated levels of high-sensitivity troponin T. Three patients with the most severe CMR abnormalities underwent myocardial biopsy, with evidence of active lymphocytic infiltration.6 It is noteworthy that all 100 patients in this series had negative COVID-19 test results at the time of CMR study (median, 71 days; interquartile range [IQR], 64-92 days after acute infection). The results of these relatively small series should be interpreted cautiously until confirmed by larger series with longer follow-up and with confirmed clinical outcomes. But the findings do underscore the uncertainty regarding the long-term cardiovascular consequences of COVID-19 in patients who have ostensibly recovered. Of note, a randomized clinical trial of anticoagulation to reduce the risk of thrombotic complications in the posthospital phase of COVID-19 infection is under development through the National Institutes of Health’s set of ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) initiatives.
In addition, the indirect effects of COVID-19 have become a major concern. Multiple observations during the COVID-19 pandemic confirm a sudden and inexplicable decline in rates of hospital admissions for ST–segment elevation myocardial infarction and other acute coronary syndromes beginning in March and April 2020. This has been a universal experience, with similar findings reported from multiple countries around the world in single-center observations, multicenter registries, and national databases. A concerning increase in out-of-hospital cardiac arrests has also been reported.8 These data suggest that COVID-19 has influenced health care–seeking behavior resulting in fewer presentations of acute coronary syndromes in emergency departments and more out-of-hospital events. Failure to seek appropriate emergency cardiac care could contribute to the observations of increased number of deaths and cardiac arrests, more than the anticipated average during this period8,9 with worse outcomes among those who ultimately do seek care.10 Recent data suggest that admission rates for myocardial infarction may be returning to baseline,10 but outcomes will improve only if patients seek care promptly and hospital systems are not overwhelmed by COVID-19 surges.
Given the ongoing activity of COVID-19, very clear messaging to the public and patients should include the following: heed the warning signs of heart attack, act promptly to initiate emergency medical services, and seek immediate care in hospitals, which have taken every step needed to be safe places. And especially, the messaging should continuously underscore the most important considerations that have been extant since this crisis began—wear a mask and practice physical distancing. In the meantime, the generation of rigorous evidence to inform best practices for diagnosis and management of COVID-19–related cardiovascular disease is a global imperative.
Corresponding Author: Robert O. Bonow, MD, MS, Division of Cardiology, Northwestern University Feinberg School of Medicine, 676 N St Clair St, Ste 600, Chicago, IL 60611 (r-bonow@northwestern.edu)
Indeed, many viruses can cause inflammation and weakening of the heart.
So far there is no established action to take for prevention, and management is based on clinical manifestations of heart failure: shortness of breath, particularly if worse laying flat or worse with exertion, leg swelling (edema), blood tests showing elevated brain natriuretic peptide (BNP or proBNP, a marker of heart muscle strain), and a basic metabolic panel that may show “pre-renal azotemia” (elevation of BUN and Creatinine, typically in a ratio >20:1) and/or hyponatremia (sodium concentration below 135 mEq/dL). If any of the above are suspected, it is reasonable to get transthoracic echocardiography for systolic and diastolic function. If either systolic or diastolic function by ultrasound show significant impairment not improved by usual therapy (diuretic, ACEI/ARB/ARNI, blocker, aldosterone inhibitor e.g. spironolactone) then an MRI scar map may be considered (MRI scar maps show retention of gadolinium contrast agent by injured heart muscle, first demonstrated by Dr. Justin Pearlman during angiogenesis research MRI studies).
There is no controversy in the above, the controversy is a rush to expanded referral for cardiac MRI without clear clinical evidence of heart impairment, at a stage when there is no established therapy for possible detection of myocarditis (cardiac inflammation). General unproven measures for inflammation may include taking ginger and tumeric supplements if well tolerated by the stomach, drinking 2 cups/day of Rooibos Tea if well tolerated by the liver.
Canakinumab was recommended by one research group to treat inflammation and risk to the heart if the blood test hsCRP is elevated (in addition to potential weakening of muscle, inflammation activates complement, makes atherosclerosis lesions unstable, and thus may elevate risk of heart attack, stroke, renal failure or limb loss from blocked blood delivery). The canakinumab studies were published in NEJM and LANCET with claims of significant improvement in outcomes, but that was not approved by FDA or confirmed by other groups, even though it has biologic plausibility. https://www.thelancet.com/journals/lancet/article/PIIS0140-67361732247-X/fulltext
Some Heart Societies Agree on Cautions for COVID-Myocarditis Screening
— Official response has been modest, though
by Crystal Phend, Senior Editor, MedPage Today September 18, 2020
Such evidence of myocardial injury and inflammation on CMR turned up in a German study among people who recovered from largely mild or moderate cases of COVID-19 compared with healthy controls and risk factor-matched controls.
Then an Ohio State University study showed CMR findings suggestive of myocarditis in 15% of collegiate athletes after asymptomatic or mild SARS-CoV-2 infection.
But an open letter from some 50 medical professionals across disciplines emphasized that “prevalence, clinical significance and long-term implications” of such findings aren’t known. The letter called on the 18 professional societies to which it was sent on Tuesday to release clear guidance against CMR screening in the general population to look for post-COVID heart damage in the absence of symptoms.
The Society for Cardiac Magnetic Resonance quickly responded with a brief statement from its chief executive officer, Chiara Bucciarelli-Ducci, MD, PhD, agreeing that routine CMR in asymptomatic patients after COVID-19 “is currently not justified… and it should not be encouraged.”
She referred clinicians to the multisociety guidelines on clinical indications of CMR when deciding whether to scan COVID-19 patients. “While CMR is an excellent imaging tool for diagnosing myocarditis in patients with suspected disease, we do not recommend its use in patients without symptoms,” she added.
The American Heart Association didn’t put out any written statement but offered spokesperson Manesh Patel, MD, chair of its Diagnostic and Interventional Cath Committee.
“The American Heart Association’s position on this is that in general we agree that routine cardiac MRI should not be conducted unless in the course of a study” for COVID-19 patients, he said. “There’s a lot of evolving information around people with COVID, and certainly asymptomatic status, whether it’s recent or prior, it’s not clearly known what the MRI findings will mean or what the long-term implications are without both a control group and an understanding around population.”
The ACC opted against taking a stand. It provided MedPage Today with the following statement from ACC President Athena Poppas, MD:
“We appreciate the authors’ concerns about the potential mischaracterization of the long-term impact of myocarditis after a COVID-19 diagnosis and the need for well-designed clinical trials and careful, long term follow-up. The pandemic is requiring everyone make real-time decisions on how to best care for heart disease patients who may be impacted by COVID-19. The ACC is committed to helping synthesize and provide the most up-to-date, high quality information possible to the cardiovascular care team. We will continue to review and assess the scientific data surrounding cardiac health and COVID-19 and issue guidance to help our care team.”
While the open letter noted that some post-COVID patients have been asking for CMR, Walsh noted that primary care would likely see the brunt of any such influx. She personally has not had any patients ask to be screened.
Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial
Inflammation in the tumour microenvironment mediated by interleukin 1β is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of interleukin-1β inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter cancer incidence.
Methods
We did a randomised, double-blind, placebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myocardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. To assess dose–response effects, patients were randomly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or placebo. Participants were followed up for incident cancer diagnoses, which were adjudicated by an oncology endpoint committee masked to drug or dose allocation. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, NCT01327846. The trial is closed (the last patient visit was in June, 2017).
Findings
Baseline concentrations of hsCRP (median 6·0 mg/L vs 4·2 mg/L; p<0·0001) and interleukin 6 (3·2 vs 2·6 ng/L; p<0·0001) were significantly higher among participants subsequently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3·7 years, compared with placebo, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26–41% and of interleukin 6 of 25–43% (p<0·0001 for all comparisons). Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0·0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individually (hazard ratio [HR] 0·49 [95% CI 0·31–0·75]; p=0·0009). Incident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0·61 [95% CI 0·39–0·97]; p=0·034) and 300 mg groups (HR 0·33 [95% CI 0·18–0·59]; p<0·0001; p<0·0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0·23 [95% CI 0·10–0·54]; p=0·0002) and in the pooled canakinumab population than in the placebo group (p=0·0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and placebo groups (HR 0·94 [95% CI 0·83–1·06]; p=0·31).
Interpretation
Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleukin-1β innate immunity pathway could significantly reduce incident lung cancer and lung cancer mortality. Replication of these data in formal settings of cancer screening and treatment is required.
Bradykinin Hypothesis: Potential Explanation for COVID-19
Reporter: Aviva Lev-Ari, PhD, RN
UPDATED on 9/14/2020
First Randomized Trial Backs Safety of ACE and ARB Heart Drugs in COVID-19 Patients
BRACE CORONA trial presented in a Hot Line Session at ESC Congress 2020
September 8, 2020 – Heart patients hospitalized with COVID-19 (SARS-CoV-2) can safely continue taking angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), according to the BRACE CORONA trial presented in a Hot Line session at the virtual European Society of Cardiology (ESC) Congress 2020.[1]
ACE inhibitors and ARBs are commonly taken by heart patients to reduce blood pressure and to treat heart failure. There is conflicting observational evidence about the potential clinical impact of ACE inhibitors and ARBs on patients with COVID-19.[2] Select preclinical investigations have raised concerns about their safety in patients with COVID-19. Preliminary data hypothesize that renin-angiotensin-aldosterone system (RAAS) inhibitors could benefit patients with COVID-19 by decreasing acute lung damage and preventing angiotensin-II-mediated pulmonary inflammation.
Given the frequent use of these agents worldwide, randomized clinical trial evidence is urgently needed to guide the management of patients with COVID-19.
The BRACE CORONA TRIAL compared outcomes for COVID19 patients previously on ACE inhibitor or ARB of holding the medication for a month, or not, and saw no significant benefit from withholding either class of medication. The basis for specific concern is the fact that the COVID19 virus utilizes ACE2 receptors for its invasion, and that disturbances in the renin-angiotensin and bradykinin levels and capillary leak have been observed with COVID19 infections. ACEI and ARB medications both modulate the renin angiotensin system, but with different impact on bradykinin levels. Changes in bradykinin levels cause for dry cough seen with ACE inhibitors like lisinopril that are not seen with angiotensin receptor blockers (ARB) such as Losartan. The absence of significant differences in outcome measures by holding either drug weakens the Jacobson’s bradykinin hypothesis based on a cascade of observations related to the ACE2 receptor and downstream effects. The new observations on safety of both ACEI and ARB weaken Jacobson’s hypothesis of a primary importance of renin angiotensin and bradykinin changes in the course and complications of COVID19 infection.
The ACE gene product degrades bradykinin. Jacobson’s bradykinin hypothesis suggested that the observations of capillary leak and disturbances in the renal angiotensin system may be prime factors rather than bystanders. Jacobson made strong statements from associations, but the lack of impact of stoppage of either ACE inhibitors or Angiotensin Receptor Blockers (ARB) argues that his observations are not major in determination of outcomes.
Bradykinin Hypothesis: Potential Explanation for COVID-19
The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin1-9 produced by ACE2.
critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomesexplain many of the symptoms being observed in COVID-19.
Jacobson says, “What we’ve found is that the imbalance in the renin-angiotensin system (RAS) pathway that appeared to be present in Covid-19 patients could be responsible for constantly resensitizing bradykinin receptors. So, this imbalance in the RAS pathways will take the brakes off the bottom of the bradykinin pathway at the receptor level. In addition, the downregulation of the ACE gene in Covid-19 patients, which usually degrades bradykinin, is another key imbalance in the regulation of bradykinin levels. We have also observed that the key negative regulator at the top of the bradykinin pathway is dramatically down-regulated. Thus, you likely have an increase in bradykin production as well, stopping many of the braking mechanisms usually in place, so the bradykinin signal spirals out of control.”
The bradykinin hypothesis also extends to many of Covid-19’s effects on the heart. About one in five hospitalized Covid-19 patients have damage to their hearts, even if they never had cardiac issues before. Some of this is likely due to the virus infecting the heart directly through its ACE2 receptors. But the RAS also controls aspects of cardiac contractions and blood pressure. According to the researchers, bradykinin storms could create arrhythmias and low blood pressure, which are often seen in Covid-19 patients.
“the pathology of Covid-19 is likely the result of Bradykinin Storms rather than cytokine storms,” which had been previously identified in Covid-19 patients, but that “the two may be intricately linked.”
According to Jacobson and his team, MRI studies in France revealed that many Covid-19 patients have evidence of leaky blood vessels in their brains.
bradykinin would indeed be likely to increase the permeability of the blood-brain barrier. In addition, similar neurological symptoms have been observed in other diseases that result from an excess of bradykinin.”
Increased bradykinin levels could also account for other common Covid-19 symptoms. ACE inhibitors — a class of drugs used to treat high blood pressure — have a similar effect on the RAS system as Covid-19, increasing bradykinin levels. In fact, Jacobson and his team note in their paper that “the virus… acts pharmacologically as an ACE inhibitor” — almost directly mirroring the actions of these drugs.
repurpose existing FDA approved drugs such as Danazol, Stanasolol, Icatibant, Ecallantide, Berinert, Cynryze, Haegarda, etc.. to reduce the amount of bradykinin signaling to prevent the escalation of the bradykinin storm.
Partnerships with pharmaceutical companies and clinical research are needed to design and implement the right clinical trials to see how these types of treatments can be applied.
Systems biology perspective and think that attempts to inhibit the virus itself will also probably require a combinatorial strategy it’s possible that we will need a combinatorial approach to therapies both on the human side and on the viral side
Other compounds could treat symptoms associated with bradykinin storms. Hymecromone, for example, could reduce hyaluronic acid levels, potentially stopping deadly hydrogels from forming in the lungs. And timbetasin could mimic the mechanism that the researchers believe protects women from more severe Covid-19 infections
A Supercomputer Analyzed Covid-19 — and an Interesting New Theory Has Emerged
A closer look at the Bradykinin hypothesis
Thomas Smith Sep 1, 2020
Earlier this summer, the Summit supercomputer at Oak Ridge National Lab in Tennessee set about crunching data on more than 40,000 genes from 17,000 genetic samples in an effort to better understand Covid-19. Summit is the second-fastest computer in the world, but the process — which involved analyzing 2.5 billion genetic combinations — still took more than a week.
When Summit was done, researchers analyzed the results. It was, in the words of Dr. Daniel Jacobson, lead researcher and chief scientist for computational systems biology at Oak Ridge, a “eureka moment.” The computer had revealed a new theory about how Covid-19 impacts the body: the bradykinin hypothesis. The hypothesis provides a model that explains many aspects of Covid-19, including some of its most bizarre symptoms. It also suggests 10-plus potential treatments, many of which are already FDA approved. Jacobson’s group published their results in a paper in the journal eLife in early July.
According to the team’s findings, a Covid-19 infection generally begins when the virus enters the body through ACE2 receptors in the nose, (The receptors, which the virus is known to target, are abundant there.) The virus then proceeds through the body, entering cells in other places where ACE2 is also present: the intestines, kidneys, and heart. This likely accounts for at least some of the disease’s cardiac and GI symptoms.
Oak Ridge National Laboratory, Biosciences Division, United States;
University of Tennessee Knoxville, The Bredesen Center for Interdisciplinary Research and Graduate Education, United States;
University of Kentucky, Department of Horticulture, United States;
Versiti Blood Research Institute, Medical College of Wisconsin, United States;
VA Connecticut Healthcare/General Internal Medicine, Yale University School of Medicine, United States;
University of Cincinnati, United States;
Biomedical Informatics, Cincinnati Children’s Hospital Research Foundation, United States;
University of Tennessee Knoxville, Department of Psychology, Austin Peay Building, United States
Abstract
Neither the disease mechanism nor treatments for COVID-19 are currently known. Here, we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin1-9 produced by ACE2.Here, we perform a new analysis on gene expression data from cells in bronchoalveolar lavage fluid (BALF) from COVID-19 patients that were used to sequence the virus. Comparison with BALF from controls identifies a critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomes explain many of the symptoms being observed in COVID-19.
*Correspondence
Joseph A. Roche, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA.
Email: ude.enyaw@ehcor.hpesoj,
Abstract
As of April 20, 2020, over time, the COVID‐19 pandemic has resulted in 157 970 deaths out of 2 319 066 confirmed cases, at a Case Fatality Rate of ~6.8%. With the pandemic rapidly spreading, and health delivery systems being overwhelmed, it is imperative that safe and effective pharmacotherapeutic strategies are rapidly explored to improve survival. In this paper, we use established and emerging evidence to propose a testable hypothesis that, a vicious positive feedback loop of des‐Arg(9)‐bradykinin‐ and bradykinin‐mediated inflammation → injury → inflammation, likely precipitates life threatening respiratory complications in COVID‐19. Through our hypothesis, we make the prediction that the FDA‐approved molecule, icatibant, might be able to interrupt this feedback loop and, thereby, improve the clinical outcomes. This hypothesis could lead to basic, translational, and clinical studies aimed at reducing COVID‐19 morbidity and mortality.
COVID-19 patients can present with pulmonary edema early in disease. We propose that this is due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2 that next to its role in RAAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the B1R. Without ACE2 acting as a guardian to inactivate the ligands of B1R, the lung environment is prone for local vascular leakage leading to angioedema. Here, we hypothesize that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19. We propose that blocking the B2R and inhibiting plasma kallikrein activity might have an ameliorating effect on early disease caused by COVID-19 and might prevent acute respiratory distress syndrome (ARDS). In addition, this pathway might indirectly be responsive to anti-inflammatory agents.
Kinins and cytokines in COVID-19: a comprehensive pathophysiological approach
Frank L. van de Veerdonk1*, Mihai G. Netea1,2, Marcel van Deuren1, Jos W.M. van der Meer1, Quirijn de Mast1, Roger J. Brüggemann3, Hans van der Hoeven4
doi:10.20944/preprints202004.0023.v1
Abstract
Most striking observations in COVID-19 patients are the hints on pulmonary edema (also seen on CT scans as ground glass opacities), dry cough, fluid restrictions to prevent more severe hypoxia, the huge PEEP that is needed while lungs are compliant, and the fact that antiinflammatory therapies are not powerful enough to counter the severity of the disease. We propose that the severity of the disease and many deaths are due to a local vascular problem due to activation of B1 receptors on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2, a cell membrane bound molecule with enzymatic activity that next to its role in RAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the bradykinin receptor type 1 (B1). In contrast to bradykinin receptor 2 (B2), the B1 receptor on endothelial cells is upregulated by proinflammatory cytokines. Without ACE2 acting as a guardian to inactivate the ligands of B1, the lung environment is prone for local vascular leakage leading to angioedema. Angioedema is likely a feature already early in disease, and might explain the typical CT scans and the feeling of people that they drown. In some patients, this is followed by a clinical worsening of disease around day 9 due to the formation antibodies directed against the spike (S)-antigen of the corona-virus that binds to ACE2 that could contribute to disease by enhancement of local immune cell influx and proinflammatory cytokines leading to damage. In parallel, inflammation induces more B1 expression, and possibly via antibody-dependent enhancement of viral infection leading to continued ACE2 dysfunction in the lung because of persistence of the virus. In this viewpoint we propose that a bradykinin-dependent local lung angioedema via B1 and B2 receptors is an important feature of COVID-19, resulting in a very high number of ICU admissions. We propose that blocking the B1 and B2 receptors might have an ameliorating effect on disease caused by COVID-19. This kinin-dependent pulmonary edema is resistant to corticosteroids or adrenaline and should be targeted as long as the virus is present. In addition, this pathway might indirectly be responsive to anti-inflammatory agents or neutralizing strategies for the anti-S-antibody induced effects, but by itself is likely to be insufficient to reverse all the pulmonary edema. Moreover, we provide a suggestion of how to ventilate in the ICU in the context of this hypothesis.
Emerging Pandemic Diseases: How We Got to COVID-19
David M. Morens1,* and Anthony S. Fauci1
1Office of the Director, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Infectious diseases prevalent in humans and animals are caused by pathogens that once emerged from other animal hosts. In addition to these established infections, new infectious diseases periodically emerge. In extreme cases they may cause pandemics such as COVID-19; in other cases, dead-end infections or smaller epidemics result. Established diseases may also re-emerge, for example by extending geographically or by becoming more transmissible or more pathogenic. Disease emergence reflects dynamic balances and imbalances, within complex globally distributed ecosystems comprising humans, animals, pathogens, and the environment. Understanding these variables is a necessary step in controlling future devastating disease emergences.
SARS-CoV-2 infects and damages the cells lining blood vessels, it could expose the tissue underneath
clotting results from inflammation. And here, many experts are eyeing a set of proteins called the complement system
These proteins, known collectively as complement, attack invaders and call in other parts of the immune system to assist. They also can activate platelets and promote clotting.
Claudia Kemper1,2,3 said “complementologists think that this is a massive part of the disease” signs of complement activity in the lungs and livers of people who died from Covid-19
Laurence found several active complement proteins in the skin and blood vessels of his early Covid-19 clotting cases
Genes involved in complement and clotting responses were more active when the virus was present in patients’ nasal swabs.
immune element may promote clotting in severe Covid-19 cases: an overreaction called a cytokine storm, in which the body releases an excess of inflammation-promoting cytokine molecules.
Body’s response in need of control: (1) control the clotting, (2) control the inflammation, (2) control the complement pathway in tandem with antiviral Remdesivir that controls the viral replication thus the viral load.
Balance the risk of clotting with the danger of bleeding (bleeds into the digestive system for these patients, but they may also hemorrhage in the lungs, brain or spots where medical devices pierce the skin)
Dosage of blood thinners is debated – 40 Studies found for: anticoagulation | Covid19
there is no evidence that people with less severe Covid-19, who do not require hospitalization, should take blood thinners or aspirin to ward off clots.
Management of Clotting: Argatroban, for example, is a Food and Drug Administration-approved anticoagulant that interferes with thrombin, an element of the clotting cascade. Eculizumab, which blocks one of the complement proteins, is approved for certain inflammatory conditions.
Clinical judgement is used in light of lack of evidence
SOURCES
Why Blood Clots Are a Major Problem in Severe Covid-19
Erin E. West,1 Martin Kolev,2 and Claudia Kemper1,2,3
1Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung and Blood Institute, Bethesda, Maryland 20892, United States; email: erin.west@nih.gov, claudia.kemper@nih.gov
2Division of Transplant Immunology and Mucosal Biology, King’s College London, London SE1 9RT, United Kingdom; email: martin.kolev@kcl.ac.uk
3Institute for Systemic Inflammation Research, University of Lübeck, 23562 Lübeck, Germany
The complement system is an evolutionarily ancient key component of innate immunity required for the detection and removal of invading pathogens. It was discovered more than 100 years ago and was originally defined as a liver-derived, blood-circulating sentinel system that classically mediates the opsonization and lytic killing of dangerous microbes and the initiation of the general inflammatory reaction. More recently, complement has also emerged as a critical player in adaptive immunity via its ability to instruct both B and T cell responses. In particular, work on the impact of complement on T cell responses led to the surprising discoveries that the complement system also functions within cells and is involved in regulating basic cellular processes, predominantly those of metabolic nature. Here, we review current knowledge about complement’s role in T cell biology, with a focus on the novel intracellular and noncanonical activities of this ancient system.
Complement Dysregulation and Disease: Insights from Contemporary Genetics
M. Kathryn Liszewski,1 Anuja Java,2
Elizabeth C. Schramm,3 and John P. Atkinson1
1Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110; email: j.p.atkinson@wustl.edu
2Division of Nephrology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110
alternative complement pathway, C3 glomerulopathies, factor H, CD46,
factor I, C3, factor B
Abstract
The vertebrate complement system consists of sequentially interacting proteins that provide for a rapid and powerful host defense. Nearly 60 proteins comprise three activation pathways (classical, alternative, and lectin) and a terminal cytolytic pathway common to all. Attesting to its potency, nearly half of the system’s components are engaged in its regulation. An emerging theme over the past decade is that variations in these inhibitors predispose to two scourges of modern humans. One, occurring most often in childhood, is a rare but deadly thrombomicroangiopathy called atypical hemolytic uremic syndrome. The other, age-related macular degeneration, is the most common form of blindness in the elderly. Their seemingly unrelated clinical presentations and pathologies share the common theme of overactivity of the complement system’s alternative pathway. This review summarizes insights gained from contemporary genetics for understanding how dysregulation of this powerful innate immune system leads to these human diseases.
CONCLUSIONS AND PERSPECTIVES
Over the last decade, a remarkable advance has been the elucidation of the role of mutations in complement regulators and components in aHUS, AMD, and C3G. Next-generation sequencing has led theway to these discoveries, but functional assessments are the critical factors in definitively associating pathogenesis with genetic variants.
Most exciting has been the development and approval by the FDA of the monoclonal antibody, eculizumab, as the new standard of care for treatment of aHUS. Challenges remain, however because eculizumab is costly and the duration of treatment remains uncertain and warrants further prospective studies. The use of eculizumab in C3G should also be prospectively addressed.
Furthermore, given the increasing number of mutations in the complement regulatory proteins identified in aHUS and C3G and the heterogeneity in the mechanisms leading to dysregulation of the AP, there is a need for further assessment of the genetic variants of unknown significance. As yet, no complement inhibitor has been approved to treat AMD.
These analyses coupled with the anticipated new developments of complement therapeutics will help establish patient-tailored therapies based on each patient’s specific alteration. The future holds much promise for the further delineation of complement-disease associations and for novel complement-targeted therapeutic agents.
Patients with coronavirus disease 2019 (COVID-19) present with a range of devastating acute clinical manifestations affecting the lungs, liver, kidneys and gut. The best-characterized entry receptor for the disease-causing virus SARS-CoV2, angiotensin converting enzyme (ACE) 2, is highly expressed in these tissues. However, the pathways that underlie the disease are still poorly understood. Here we show that the complement system is unexpectedly one of the intracellular pathways most highly induced by SARS-CoV2 infection in lung epithelial and liver cells. Within cells of the bronchoalveolar lavage of patients, distinct signatures of complement activation in myeloid, lymphoid and epithelial cells tracked with disease severity. Modelling the regulome of host genes induced by COVID-19 and the drugs that could normalize these genes both implicated the JAK1/2-STAT1 signaling system downstream of type I interferon receptors, and NF-kB.
Ruxolitinib, a JAK1/2 inhibitor and the top predicted pharmaceutical candidate, normalized interferon signature genes, IL-6 (the best characterized severity marker in COVID-19) and all complement genes induced by SARS-CoV2, but did not affect NF-kB-regulated genes. We predict that combination therapy with JAK inhibitors and other agents with the potential to normalize NFkB-signaling, such as anti-viral agents, may serve as an effective clinical strategy.
New Etiology for COVID-19: Death results from Immune-Mediation (virus-independent immunopathology: lung and reticuloendothelial system) vs Pathogen-Mediation causing Organ Dysfunction & Hyper-Inflammation – Immunomodulatory Therapeutic Approaches (dexamethasone)
Curators: Stephen J. Williams and Aviva Lev-Ari, PhD, RN
Corticosteroid, Dexamethasone Improves Survival in COVID-19: Deaths reduction by 1/3 in ventilated patients and by 1/5 in other patients receiving oxygen only
Reporter: Aviva Lev-Ari, PhD, RN – bold face and color fonts added
Sex Differences in Immune Responses that underlie COVID-19 Disease Outcomes
Reporter: Aviva Lev-Ari, PhD, RN and Irina Robu, PhD
COVID-19 is a non-discriminatory virus, it can infect anyone from young to old, but it seems that older men are twice more susceptible to it and most likely to become severely sick and die in comparison to women of the same age.
Researchers from Yale university, published an article suggesting that men, particularly those over the age of 60 may need to depend more on vaccines to protect themselves from infection. According to their research published in Nature in August 2020, known sex differences between men and women pose challenges to the immune system.
Women mount faster and stronger immune responses, possibly because their bodies are equipped to fight pathogens that threaten unborn or newborn children. Over time, an immune system in a constant state of high alert can be harmful. The findings underline the necessity for companies developing coronavirus vaccines to analyze their data by sex and may influence decisions about dosing.
Dr. Iwasaki’s team from Yale analyzed immune responses in 17 men and 22 women who were admitted to the hospital soon after they were infected with the coronavirus. The investigators collected blood, nasopharyngeal swabs, saliva, urine and stool from the patients every three to seven days. The researchers also analyzed data from an additional 59 men and women who did not meet those criteria.
Over all, the scientists found, the women’s bodies produced more T cells, which can kill and stop the infection from spreading. Men on the other hand presented a much weaker activation of T cells and that delay was linked to how sick the men became. The older the men, the weaker their T cell responses.
Even though the study provided some more information about why men become sicker when diagnosed with coronavirus than women, it did not offer a clear reason for the differences between men and women.
SOURCEhttps://www.nature.com/articles/s41586-020-2700-3
This is an unedited manuscript that has been accepted for publication. Nature Research are providing this early version of the manuscript as a service to our authors and readers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.
Sex differences in immune responses that underlie COVID-19 disease outcomes
A growing body of evidence indicates sex differences in the clinical outcomes of coronavirus disease 2019 (COVID-19)1–5. However, whether immune responses against SARS-CoV-2 differ between sexes, and whether such differences explain male susceptibility to COVID-19, is currently unknown. In this study, we examined sex differences in
viral loads,
SARS-CoV-2-specific antibody titers,
plasma cytokines, as well as
blood cell phenotyping in COVID-19 patients.
By focusing our analysis on patients with moderate disease who had not received immunomodulatory medications, our results revealed that
male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. In contrast,
female patients mounted significantly more robust T cell activation than male patients during SARS-CoV-2 infection, which was sustained in old age.
Importantly, we found that a poor T cell response negatively correlated with patients’ age and was associated with worse disease outcome in male patients, but not in female patients.
Conversely, higher innate immune cytokines in female patients associated with worse disease progression, but not in male patients.
These findings reveal a possible explanation underlying observed sex biases in COVID-19, and provide an important basis for the development of
a sex-based approach to the treatment and care of men and women with COVID-19.
Author information
Author notes
These authors contributed equally: Takehiro Takahashi, Mallory K. Ellingson, Patrick Wong, Benjamin Israelow, Carolina Lucas, Jon Klein, Julio Silva, Tianyang Mao.
Affiliations
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06520, USA
Takehiro Takahashi, Patrick Wong, Benjamin Israelow, Carolina Lucas, Jon Klein, Julio Silva, Tianyang Mao, Ji Eun Oh, Maria Tokuyama, Peiwen Lu, Arvind Venkataraman, Annsea Park, Feimei Liu, Eric Y. Wang, Molly L. Bucklin, Yiyun Cao, William Khoury-Hanold, Daniel Kim, Eriko Kudo, Melissa Linehan, Alice Lu-Culligan, Anjelica Martin, Tyler Rice, Eric Song, Nicole Sonnert, Yexin Yang, Aaron M. Ring & Akiko Iwasaki
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, 06520, USA
Mallory K. Ellingson, Arnau Casanovas-Massana, Anne L. Wyllie, Chantal B.F. Vogels, Rebecca Earnest, Sarah Lapidus, Isabel M. Ott, Adam J. Moore, Kristina Brower, Chaney Kalinich, M. Catherine Muenker, Isabel Ott, Mary Petrone, Annie Watkins, Elizabeth B. White, Nathan D. Grubaugh, Albert I. Ko & Saad B. Omer
Department of Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, 06520, USA
Benjamin Israelow, Melissa Campbell, Rupak Datta, Subhasis Mohanty, Haowei Wang, Albert Shaw, John B. Fournier, Camila D. Odio, Shelli Farhadian & Saad B. Omer
Department of Biomedical Engineering, Yale School of Engineering & Applied Science, New Haven, CT, 06511, USA
Feimei Liu
Boyer Center for Molecular Medicine, Department of Microbial Pathogenesis, Yale University, New Haven, CT, 06510, USA
Amit Meir
Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
Jonathan Sun
Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, 06520, USA
Isabel M. Ott
Department of Medicine, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
Giuseppe DeIuliis, Lokesh Sharma & Charles Dela Cruz
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
Wade L. Schulz
Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, 06520, USA
Wade L. Schulz
Yale Institute for Global Health, Yale University, New Haven, CT, 06520, USA
Amyn A. Malik & Saad B. Omer
Yale School of Nursing, Yale University, Orange, CT, 06477, USA
Saad B. Omer
Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA
Akiko Iwasaki
Yale Center for Clinical Investigation, Yale University School of Medicine, New Haven, CT, 06520, USA
Kelly Anastasio, Staci Cahill & Maxine Kuang
Department of Neurology, Yale University School of Medicine, New Haven, CT, 06520, USA
Michael H. Askenase & Sofia Velazquez
Yale School of Medicine, New Haven, CT, 06520, USA
Maria Batsu, Hannah Beatty, Santos Bermejo, Bertie Geng, Laura Glick, Ryan Handoko, Lynda Knaggs, Irene Matos, David McDonald, Maksym Minasyan, Nida Naushad, Allison Nelson, Jessica Nouws, Abeer Obaid, Hong-Jai Park, Xiaohua Peng, Harold Rahming, Kadi-Ann Rose, Lorenzo Sewanan, Denise Shepard, Erin Silva, Michael Simonov, Mikhail Smolgovsky, Yvette Strong, Codruta Todeasa, Jordan Valdez & Pavithra Vijayakumar
Department of Biochemistry and of Molecular Biology, Yale University School of Medicine, New Haven, CT, 06520, USA
Sean Bickerton & Edward Courchaine
Yale Viral Hepatitis Program, Yale University School of Medicine, New Haven, CT, 06520, USA
Joseph Lim
Equity Research and Innovation Center, Yale University, New Haven, CT, 06520, USA
Marcella Nunez-Smith
Department of Molecular, Cellular and Developmental Biology, Yale University School of Medicine, New Haven, CT, 06520, USA
The current COVID-19 pandemic sweeping across developing countries is putting millions at risk of protein-energy malnutrition by pushing them into poverty and disrupting the global food supply chain. COVID-19 disease and protein-energy malnutrition are both known to cause immune dysfunction. The objective of this review is to highlight the known pathogenetic mechanisms underlying immune dysfunction in COVID-19 disease and malnutrition, and thereby identify preventive and therapeutic interventions that would help limit and contain the global health impact of this pandemic. Severe COVID-19 disease is characterized by dysregulation of myeloid compartments and lymphopenia. Lymphopenia is often protracted and outlasts the cytokine storm, suggesting underlying thymic dysfunction or involution. The thymus is considered a barometer of malnutrition, and leptin deficiency induced by protein-energy malnutrition can lead to thymic dysfunction and atrophy. Immune dysfunction in COVID-19 disease and malnutrition may be further increased by comorbidities including zinc and vitamin deficiencies, hyperinflammation, and stress. Thymic dysfunction or involution, especially in children, can potentially slow the recovery from COVID-19 disease and increase the risk of other infections. National governments and international organizations including WHO, World Food Program, and UNICEF should institute measures to ensure provision of food including micronutrients for the poor, thereby mitigating the health impact of the COVID-19 pandemic, especially amongst children in developing countries.
Note: Conflict of Interest: AG has filed provisional patents for use of Ramatroban as an immunotherapy to treat COVID-19 infection. (Gupta, A. Use of Ramatroban as a therapeutic agent for prevention and treatment of viral infections including COVID-Application no. 63/003,286 filed on March 31, 2020; and Gupta A. Use of a DP2 antagonist such as Ramatroban as a therapeutic agent for treatment of adults with viral infection including COVID-19 Provisional Patent Application no. 63/005,205 filed on April 3, 2020). Other authors have not declared conflict of interest.
Division of Nephrology, University of California I
101 City Drive South, City Tower, Suite 400-ZOT;40
Orange, CA California 92868-3217
United States
7144565142 (Phone)
Division of Nephrology, University of California I
101 City Drive South, City Tower, Suite 400-ZOT;40
Orange, CA California 92868-3217
United States
5624197029 (Phone)
92868-3217 (Fax)
As part of the all-of-America approach to fighting the COVID-19 pandemic, the U.S. Food and Drug Administration has been working with partners across the U.S. government, academia and industry to expedite the development and availability of critical medical products to treat this novel virus. Today, we are providing an update on one potential treatment called convalescent plasma and encouraging those who have recovered from COVID-19 to donate plasma to help others fight this disease.
Convalescent plasma is an antibody-rich product made from blood donated by people who have recovered from the disease caused by the virus. Prior experience with respiratory viruses and limited data that have emerged from China suggest that convalescent plasma has the potential to lessen the severity or shorten the length of illness caused by COVID-19. It is important that we evaluate this potential therapy in the context of clinical trials, through expanded access, as well as facilitate emergency access for individual patients, as appropriate.
The response to the agency’s recently announced national efforts to facilitate the development of and access to convalescent plasma has been tremendous. More than 1,040 sites and 950 physician investigators nationwide have signed on to participate in the Mayo Clinic-ledExternal Link Disclaimer expanded access protocol. A number of clinical trials are also taking place to evaluate the safety and efficacy of convalescent plasma and the FDA has granted numerous single patient emergency investigational new drug (eIND) applications as well.
FDA issues guidelines on clinical trials and obtaining emergency enrollment concerning convalescent plasma
FDA has issued guidance to provide recommendations to health care providers and investigators on the administration and study of investigational convalescent plasma collected from individuals who have recovered from COVID-19 (COVID-19 convalescent plasma) during the public health emergency.
The guidance provides recommendations on the following:
Because COVID-19 convalescent plasma has not yet been approved for use by FDA, it is regulated as an investigational product. A health care provider must participate in one of the pathways described below. FDA does not collect COVID-19 convalescent plasma or provide COVID-19 convalescent plasma. Health care providers or acute care facilities should instead obtain COVID-19 convalescent plasma from an FDA-registered blood establishment.
Excerpts from the guidance document are provided below.
Background
The Food and Drug Administration (FDA or Agency) plays a critical role in protecting the United States (U.S.) from threats including emerging infectious diseases, such as the Coronavirus Disease 2019 (COVID-19) pandemic. FDA is committed to providing timely guidance to support response efforts to this pandemic.
One investigational treatment being explored for COVID-19 is the use of convalescent plasma collected from individuals who have recovered from COVID-19. Convalescent plasma that contains antibodies to severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 (the virus that causes COVID-19) is being studied for administration to patients with COVID-19. Use of convalescent plasma has been studied in outbreaks of other respiratory infections, including the 2003 SARS-CoV-1 epidemic, the 2009-2010 H1N1 influenza virus pandemic, and the 2012 MERS-CoV epidemic.
Although promising, convalescent plasma has not yet been shown to be safe and effective as a treatment for COVID-19. Therefore, it is important to study the safety and efficacy of COVID-19 convalescent plasma in clinical trials.
Pathways for Use of Investigational COVID-19 Convalescent Plasma
The following pathways are available for administering or studying the use of COVID-19 convalescent plasma:
Clinical Trials
Investigators wishing to study the use of convalescent plasma in a clinical trial should submit requests to FDA for investigational use under the traditional IND regulatory pathway (21 CFR Part 312). CBER’s Office of Blood Research and Review is committed to engaging with sponsors and reviewing such requests expeditiously. During the COVID-19 pandemic, INDs may be submitted via email to CBERDCC_eMailSub@fda.hhs.gov.
Expanded Access
An IND application for expanded access is an alternative for use of COVID-19 convalescent plasma for patients with serious or immediately life-threatening COVID-19 disease who are not eligible or who are unable to participate in randomized clinical trials (21 CFR 312.305). FDA has worked with multiple federal partners and academia to open an expanded access protocol to facilitate access to COVID-19 convalescent plasma across the nation. Access to this investigational product may be available through participation of acute care facilities in an investigational expanded access protocol under an IND that is already in place.
Although participation in clinical trials or an expanded access program are ways for patients to obtain access to convalescent plasma, for various reasons these may not be readily available to all patients in potential need. Therefore, given the public health emergency that the COVID-19 pandemic presents, and while clinical trials are being conducted and a national expanded access protocol is available, FDA also is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections through the process of the patient’s physician requesting a single patient emergency IND (eIND) for the individual patient under 21 CFR 312.310. This process allows the use of an investigational drug for the treatment of an individual patient by a licensed physician upon FDA authorization, if the applicable regulatory criteria are met. Note, in such case, a licensed physician seeking to administer COVID-19 convalescent plasma to an individual patient must request the eIND (see 21 CFR 312.310(b)).
Today, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for investigational convalescent plasma for the treatment of COVID-19 in hospitalized patients as part of the agency’s ongoing efforts to fight COVID-19. Based on scientific evidence available, the FDA concluded, as outlined in its decision memorandum, this product may be effective in treating COVID-19 and that the known and potential benefits of the product outweigh the known and potential risks of the product.
Today’s action follows the FDA’s extensive review of the science and data generated over the past several months stemming from efforts to facilitate emergency access to convalescent plasma for patients as clinical trials to definitively demonstrate safety and efficacy remain ongoing.
The EUA authorizes the distribution of COVID-19 convalescent plasma in the U.S. and its administration by health care providers, as appropriate, to treat suspected or laboratory-confirmed COVID-19 in hospitalized patients with COVID-19.
Alex Azar, Health and Human Services Secretary:
“The FDA’s emergency authorization for convalescent plasma is a milestone achievement in President Trump’s efforts to save lives from COVID-19,” said Secretary Azar. “The Trump Administration recognized the potential of convalescent plasma early on. Months ago, the FDA, BARDA, and private partners began work on making this product available across the country while continuing to evaluate data through clinical trials. Our work on convalescent plasma has delivered broader access to the product than is available in any other country and reached more than 70,000 American patients so far. We are deeply grateful to Americans who have already donated and encourage individuals who have recovered from COVID-19 to consider donating convalescent plasma.”
Stephen M. Hahn, M.D., FDA Commissioner:
“I am committed to releasing safe and potentially helpful treatments for COVID-19 as quickly as possible in order to save lives. We’re encouraged by the early promising data that we’ve seen about convalescent plasma. The data from studies conducted this year shows that plasma from patients who’ve recovered from COVID-19 has the potential to help treat those who are suffering from the effects of getting this terrible virus,” said Dr. Hahn. “At the same time, we will continue to work with researchers to continue randomized clinical trials to study the safety and effectiveness of convalescent plasma in treating patients infected with the novel coronavirus.”
Scientific Evidence on Convalescent Plasma
Based on an evaluation of the EUA criteria and the totality of the available scientific evidence, the FDA’s Center for Biologics Evaluation and Research determined that the statutory criteria for issuing an EUA criteria were met.
The FDA determined that it is reasonable to believe that COVID-19 convalescent plasma may be effective in lessening the severity or shortening the length of COVID-19 illness in some hospitalized patients. The agency also determined that the known and potential benefits of the product, when used to treat COVID-19, outweigh the known and potential risks of the product and that that there are no adequate, approved, and available alternative treatments.
CLINICAL MEMORANDUM From: , OBRR/DBCD/CRS To: , OBRR Through: , OBRR/DBCD , OBRR/DBCD , OBRR/DBCD/CRS Re: EUA 26382: Emergency Use Authorization (EUA) Request (original request 8/12/20; amended request 8/23/20) Product: COVID-19 Convalescent Plasma Items reviewed: EUA request Fact Sheet for Health Care Providers Fact Sheet for Recipients Sponsor: Robert Kadlec, M.D. Assistant Secretary for Preparedness and Response (ASPR) Office of Assistant Secretary for Preparedness and Response (ASPR) U.S. Department of Health and Human Services (HHS) EXECUTIVE SUMMARY COVID-19 Convalescent Plasma (CCP), an unapproved biological product, is proposed for use under an Emergency Use Authorization (EUA) under section 564 of the Federal Food, Drug, and Cosmetic Act (the Act),(21 USC 360bbb-3) as a passive immune therapy for the treatment of hospitalized patients with COVID-19, a serious or life-threatening disease. There currently is no adequate, approved, and available alternative to CCP for treating COVID-19. The sponsor has pointed to four lines of evidence to support that CCP may be effective in the treatment of hospitalized patients with COVID-19: 1) History of convalescent plasma for respiratory coronaviruses; 2) Evidence of preclinical safety and efficacy in animal models; 3) Published studies of the safety and efficacy of CCP; and 4) Data on safety and efficacy from the National Expanded Access Treatment Protocol (EAP) sponsored by the Mayo Clinic. Considering the totality of the scientific evidence presented in the EUA, I conclude that current data for the use of CCP in adult hospitalized patients with COVID-19 supports the conclusion that CCP meets the “may be effective” criterion for issuance of an EUA from section 564(c)(2)(A) of the Act. It is reasonable to conclude that the known and potential benefits of CCP outweigh the known and potential risks of CCP for the proposed EUA. Current data suggest the largest clinical benefit is associated with high-titer units of CCP administered early course of the disease.
A letter, from Senator Warren, to Commissioner Hahn from Senate Committee asking for documentation for any communication between FDA and White House
August 25, 2020 Dr. Stephen M. Hahn, M.D. Commissioner of Food and Drugs U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993 Dear Commissioner Hahn: We write regarding the U.S. Food and Drug Administration’s (FDA) troubling decision earlier this week to issue an Emergency Use Authorization (EUA) for convalescent plasma as a treatment for coronavirus disease 2019 (COVID-19).1 Reports suggests that the FDA granted the EUA amid intense political pressure from President Trump and other Administration officials, despite limited evidence of convalescent plasma’s effectiveness as a COVID-19 treatment.2 To help us better understand whether the issuance of the blood plasma EUA was motivated by politics, we request copies of any and all communications between FDA and White House officials regarding the blood plasma EUA.
The authorization will allow health-care providers in the U.S. to use the plasma to treat hospitalized patients with Covid-19.
The FDA’s emergency use authorization came a day after President Trump accused the agency of delaying enrollment in clinical trials for vaccines or therapeutics.
The criticism from Trump and action from the FDA led some scientists to believe the authorization, which came on the eve of the GOP national convention, was politically motivated.
FDA Commissioner Dr. Stephen Hahn is walking back comments on the benefits of convalescent plasma, saying he could have done a better job of explaining the data on its effectiveness against the coronavirus after authorizing it for emergency use over the weekend.
In an interview with Bloomberg’s Drew Armstrong, FDA Commissioner Hahn reiterates that his decision was based on hard evidence and scientific fact, not political pressure. The whole interview is at the link below:
Dr. Hahn corrected his initial statement about 35% of people would be cured by convalescent plasma. In the interview he stated:
I was trying to do what I do with patients, because patients often understand things in absolute terms versus relative terms. And I should’ve been more careful, there’s no question about it. What I was trying to get to is that if you look at a hundred patients who receive high titre, and a hundred patients who received low titre, the difference between those two particular subset of patients who had these specific criteria was a 35% reduction in mortality. So I frankly did not do a good job of explaining that.
FDA colleagues had frank discussion after the statement was made. He is not asking for other people in HHS to retract their statements, only is concerned that FDA has correct information for physicians and patients
Hahn is worried that people will not enroll due to chance they may be given placebo
He gave no opinion when asked if FDA should be an independent agency
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Top on the world’s want list right now is a coronavirus vaccine. There is plenty of speculation about how and when this might become a reality, but clear answers are scarce.Science/AAAS, the world’s leading scientific organization and publisher of the Science family of journals, brings together experts in the field of coronavirus vaccine research to answer the public’s most pressing questions: What vaccines are being developed? When are we likely to get them? Are they safe? And most importantly, will they work?
Recent Grim COVID-19 Statistics in U.S. and Explanation from Dr. John Campbell: Why We Need to be More Proactive
Reporter: Stephen J. Williams, Ph.D.
In case you have not been following the excellent daily YouTube sessions on COVID-19 by Dr. John Campbell I am posting his latest video on how grim the statistics have become and the importance of using proactive measures (like consistent use of facial masks, proper social distancing) instead of relying on reactive measures (e.g. lockdowns after infection spikes). In addition, below the video are some notes from his presentation and some links to sites discussed within the video.
Notes from the video:
approaching 5 million confirmed cases in US however is probably an underestimation
295,000 US COVID-19 related deaths estimated by December 1, 2020
however if 95% of people in US consistently and properly wear masks could save 66,000 lives
however this will mean a remaining 228,271 deaths which is a depressing statistic
Dr. John Campbell agrees with Dr. Christopher Murray, director of the Institute for Health Metrics that “people’s inconsistent use of these measures (face masks, social distancing) is a serious problem”
States with increasing transmission like Colorado, Idaho, Kansas, Kentucky, Mississippi, Missouri, Ohio, Oklahoma, Oregon, and Virginia are suggested to have a lockdown when death rate reaches 8 deaths per million population however it seems we should be also focusing on population densities rather than geographic states
Dr. Campbell and Dr. Murray stress more proactive measures than reactive ones like lockdowns
if mask usage were to increase to 95% usage reimposition to shutdown could be delayed 6 to 8 weeks
SEATTLE (August 6, 2020) – America’s COVID-19 death toll is expected to reach nearly 300,000 by December 1; however, consistent mask-wearing beginning today could save about 70,000 lives, according to new data from the Institute for Health Metrics and Evaluation (IHME) at the University of Washington’s School of Medicine.The US forecast totals 295,011 deaths by December. As of today, when, thus far, 158,000 have died, IHME is projecting approximately 137,000 more deaths. However, starting today, if 95% of the people in the US were to wear masks when leaving their homes, that total number would decrease to 228,271 deaths, a drop of 49%. And more than 66,000 lives would be saved.Masks and other protective measures against transmission of the virus are essential to staying COVID-free, but people’s inconsistent use of those measures is a serious problem, said IHME Director Dr. Christopher Murray.
“We’re seeing a rollercoaster in the United States,” Murray said. “It appears that people are wearing masks and socially distancing more frequently as infections increase, then after a while as infections drop, people let their guard down and stop taking these measures to protect themselves and others – which, of course, leads to more infections. And the potentially deadly cycle starts over again.”
Murray noted that there appear to be fewer transmissions of the virus in Arizona, California, Florida, and Texas, but deaths are rising and will continue to rise for the next week or two. The drop in infections appears to be driven by the combination of local mandates for mask use, bar and restaurant closures, and more responsible behavior by the public.
“The public’s behavior had a direct correlation to the transmission of the virus and, in turn, the numbers of deaths,” Murray said. “Such efforts to act more cautiously and responsibly will be an important aspect of COVID-19 forecasting and the up-and-down patterns in individual states throughout the coming months and into next year.”
Murray said that based on cases, hospitalizations, and deaths, several states are seeing increases in the transmission of COVID-19, including Colorado, Idaho, Kansas, Kentucky, Mississippi, Missouri, Ohio, Oklahoma, Oregon, and Virginia.
“These states may experience increasing cases for several weeks and then may see a response toward more responsible behavior,” Murray said.
In addition, since July 15, several states have added mask mandates. IHME’s statistical analysis suggests that mandates with no penalties increase mask wearing by 8 percentage points. But mandates with penalties increase mask wearing by 15 percentage points.
“These efforts, along with media coverage and public information efforts by state and local health agencies and others, have led to an increase in the US rate of mask wearing by about 5 percentage points since mid-July,” Murray said. Mask-wearing increases have been larger in states with larger epidemics, he said.
IHME’s model assumes that states will reimpose a series of mandates, including non-essential business closures and stay-at-home orders, when the daily death rate reaches 8 per million. This threshold is based on data regarding when states and/or communities imposed mandates in March and April, and implies that many states will have to reimpose mandates.
As a result, the model suggests which states will need to reimpose mandates and when:
August – Arizona, Florida, Mississippi, and South Carolina
September – Georgia and Texas
October – Colorado, Kansas, Louisiana, Missouri, Nevada, North Carolina, and Oregon.
November – Alabama, Arkansas, California, Iowa, New Mexico, Oklahoma, Utah, Washington, and Wisconsin.
However, if mask use is increased to 95%, the re-imposition of stricter mandates could be delayed 6 to 8 weeks on average.
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