The Manual is compiling some of the most significant news items regarding COVID-19 to help people stay up to date.
News items compiled by Fred R. Himmelstein, MD, FACEP.
December 21, 2020
In hospitalized patients with COVID-19, combination of anti-inflammatory drug plus remdesivir was superior to remdesivir alone
A double-blind, randomized, placebo-controlled trial published in the New England Journal of Medicine online December 11, 2020, compared the antiviral drug remdesivir to remdesivir plus the anti-inflammatory drug baricitinib (a janus kinase inhibitor) in 1,030 adults hospitalized with COVID-19. The primary endpoint, the median time to recovery, was 7 days for the combination therapy compared to 8 days for remdesivir alone (P = 0.03). In subgroup analysis, patients receiving high-flow oxygen or noninvasive ventilation at enrollment recovered in 10 days with the combination treatment vs 18 days with remdesivir alone. The 28-day mortality was 5.1% in the combination group and 7.8% in the control group, although this difference did not reach statistical significance (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09).
December 18, 2020
COVID-19 transmission among students and staff in educational facilities in Italy
A detailed epidemiological investigation was done to determine the secondary attack rate of COVID-19 cases occurring in school children and staff in 41 classes in 36 schools in the Reggio Emilia province of northern Italy from their reopening on September 1 to October 15, 2020. There were 48 index cases (43 students, 5 staff) among about 1,000 students and 200 staff. During the epidemiological investigations, 1,200 contacts of these index cases were investigated and 38 secondary cases found (3.8%), all resulting from student cases. However, the secondary attack rate varied widely among age groups, with 14 preschool and elementary school cases having a 0.38% secondary attack rate, and 28 middle and high school cases having a 6.46% secondary attack rate. The low secondary attack rate in preschool and elementary schools was in line with other studies published to date. However, secondary schools had a significantly higher rate of transmission than reported in many but not all earlier studies.
December 10, 2020
FDA briefing document for Pfizer-BioNTech COVID-19 vaccine
The FDA made available the full text of the briefing document on the new Pfizer-BioNTech COVID-19 vaccine which is under consideration today for an Emergency Use Authorization (EUA).
December 8, 2020
Health care personnel and residents of long-term care facilities to be offered COVID-19 vaccine in initial phase of vaccination program
The Advisory Committee on Immunization Practices (ACIP) interim recommendations for allocating COVID-19 vaccine was published in the CDC's Morbidity and Mortality Weekly Report on December 3, 2020. The report discusses guidance for the initial phase of the national COVID-19 vaccination program. The committee recommends that health care personnel and residents of long-term care facilities be offered the vaccine in the initial phase. The report acknowledges that even if one or more vaccine candidates receive authorization for emergency use, the demand for the vaccine is expected to exceed supply during the first months of the national vaccination program. The committee noted that health care settings in general, and long-term care settings in particular, can be high-risk locations for SARS-CoV-2 exposure and transmission. The committee believes that protection of health care personnel is critical to preserve capacity to care for patients with COVID-19 or other illnesses. Long-term care facility residents, because of their age, high rates of underlying medical conditions, and congregate living situation, are at high risk of infection and severe illness due to COVID-19. This was underscored by reporting that as of November 15, 2020, approximately 500,000 COVID-19 cases and 70,000 associated deaths had been reported among residents of skilled nursing facilities.
The COVID-19 workgroup was comprised of experts on vaccines and ethics. They held more than 25 meetings to review data regarding vaccine candidates and COVID-19 surveillance and modeling as well as vaccine allocation literature published and in external expert reports. In addition, there were seven public ACIP meetings addressing COVID-19 vaccine topics. The committee was guided by the principles of maximizing benefits, minimizing harms, promoting justice, and mitigating health inequities The interim recommendation might be updated based on additional safety and efficacy data from phase III clinical trials and conditions of FDA Emergency Use Authorization.
December 7, 2020
Variants of SARS-CoV-2 are associated with outcome differences
Multiple studies have found widespread differences in the infection-fatality ratios of SARs-CoV-2 infection. Most authors believe that these differences are due to different age and risk-factor profiles, age-specific prevalence of COVID-19 for various populations, and improvement in treatment since the beginning of the pandemic. A study published in pre-print on the medRxiv server looked at whether different strains of SARS-CoV-2 have different infection-fatality ratios, potentially helping to explain the heterogeneity of the infection-fatality ratios among multiple studies. The authors analyzed data on viral genomes and clinical outcomes of 3,637 patients in the GISAID (Global Initiative on Sharing Avian Influenza Data) database and used logistical regression analysis to determine whether certain variants were associated with disease severity. They found a large number of virus variants were present in the study. Twelve variants were considered common and were present in over 5% of the study population. Of these common variants, only 2 had a twofold or greater association with odds of mild or severe outcome. There were 157 rare variants, of which 84 were associated with a twofold odds of a mild or severe outcome (17 severe [odds ratio > 2] and 67 mild [odds ratio < 0.5]). Adding viral genomic variant information substantially improved the accuracy of a prediction model that used only age, gender, and region.
December 3, 2020
Delirium is common in older patients presenting with COVID-19
Delirium is an acute stage of confusion characterized by disturbances in attention, consciousness, and cognition. Delirium is known to be a common presenting symptom for older adults with severe disease and is associated with adverse outcomes, including prolonged hospitalization and death. A study, published in JAMA Network Online on November 19, 2020, used a cohort of 847 consecutive patients with age ≥ 65 years who presented to the emergency department at 7 sites across the US and subsequently received a diagnosis of COVID-19. Notably, delirium was found in 28% of the 847 patients and was the main presenting symptom in 16% of these patients. Overall, delirium was the sixth most common of all presenting symptoms and signs. What's more, 37% of the patients with delirium had no other typical symptoms of COVID-19 such as cough and fever. Delirium at presentation also was significantly linked to an increased risk for poor hospital outcomes, including intensive care unit stay and death. Factors that contributed to whether a patient would present with delirium included age > 75 years, residing in an assisted living community or skilled nursing facility, prior use of psychoactive drugs, vision or hearing impairment, stroke, and Parkinson's disease. This study emphasizes the importance of delirium as a presenting symptom of COVID-19 in older patients.
December 2, 2020
Admission hyperglycemia is a strong predictor of mortality in hospitalized COVID-19 patients independent of diabetes
Diabetes is a known risk factor for severe COVID-19 and death. Interestingly, a study in the Annals of Medicine showed that high serum glucose levels alone, independent of the diagnosis of diabetes, are correlated with COVID-19 severity and mortality. Researchers in Spain, using a national registry, retrospectively analyzed data from 11,312 COVID-19–positive patients from 109 hospitals in Spain from March 1 to May 31, 2020. The researchers considered patients to have diabetes when their record showed a diagnosis of diabetes or evidence of diabetes medication used upon hospital admission.
Patients were characterized into three groups depending on their blood glucose levels upon hospital admission: Normal (< 140 mg/dL), high (140–180 mg/dL), and very high blood glucose (> 180 mg/dL). Even after controlling for other risk factors (including previous diabetes) in a multivariate Cox regression model, blood glucose levels remained a significant predictor of death with the very high group having a hazard ratio (HR) 1.50, 95% CI: 1.31–1.73, p < 0.001 and the high group HR 1.48, 95% CI: 1.29–1.70, p < 0.001.
November 30, 2020
COVID toes: A manifestation of viral-induced interferonopathy
During the COVID-19 pandemic, there have been reports of pruritic and painful red patches, swelling, and blistering of the toes and rarely of the heels and fingers. This condition is called chilblains, but it has been referred to as “COVID toes” during the pandemic. A case series report in JAMA Dermatology discussed 40 patients who presented with chilblains-like lesions to a COVID clinic in Nice, France within a period of less than two weeks. This presentation was very unusual because the area around Nice is temperate. The manifestations of chilblains-like lesions corresponded with the local spread of SARS-CoV-2. Most patients were young, with a median age of 22 (range 12 to 67), and without additional medical problems. Researchers found these patients all had signs of an overactive immune response. Of note, all patients in the series had negative PCR test results for COVID-19, and only about 30% had antibodies against the virus. Common additional findings included increased D-dimer levels, lymphocytic inflammation, vascular damage detected with skin biopsy, and a significant interferon-alpha response compared with patients with PCR-positive, acute COVID-19 infection. Twenty-four patients (60%) reported contact with possible COVID-19 cases, and 11 (27.5%) met the definition for possible COVID-19 within the 6 weeks preceding the onset of chilblains.
The article examined the potential link between these cutaneous lesions and SARS-CoV-2 infection. The researchers observed a significantly higher interferon-alpha response in patients with chilblains-like lesions compared with those with moderate or severe COVID-19. The production of interferon-alpha is higher in infancy and young adulthood, and then decreases with age. The authors point out that, to the best of their knowledge, chilblains-like lesions were never reported in the literature in any descriptions of moderate or severe forms of COVID-19. They believe the exaggerated type I interferon response may also explain the relatively low rate of seropositivity in patients with chilblains-like lesions because those patients were able to clear SARS-CoV-2 infection before humoral immunity occurs. The article concluded that these lesions are manifestations of a viral-induced interferonopathy and suggested that this was caused by SARS-CoV-2 infection, but they stated that definitive proof of a causal link between COVID-19 and chilblains-like lesions is not demonstrated.
November 24, 2020
FDA issues EUA for first home test kit for COVID-19
Lucira Health received FDA emergency authorization for a COVID-19 self-test kit. This all-in-one test kit is intended to detect the SAR-CoV-2 virus that causes COVID-19. The test uses a technology called loop-mediated isothermal amplification reaction (LAMP). LAMP uses a single-tube technique for amplification of nucleic acid. It can also be used for RNA with an additional step that requires reverse transcription. If the signature SARS-CoV-2 RNA is present in the specimen, LAMP will repeatedly amplify the nucleic acid, changing the turbidity of the specimen, which then can be read by the test unit. The Lucira COVID-19 All-In-One Test Kit test is authorized for prescription home use for individuals age 14 and older who are suspected of having COVID-19 by their health care provider. The test is also authorized for use at point-of-care settings (eg, doctor’s offices, hospitals, urgent care centers, and emergency rooms) and in individuals age 13 and under when thespecimen is collected by a health care provider. The Lucira test was able to accurately detect 94.1% of the infections when compared to other high-sensitivity PCR tests. The sensitivity of the test falls when the viral load is low. Excluding samples with very low levels of virus that possibly no longer reflected active infection, Lucira achieved 100% positive agreement with the other PCR tests. The test has not been evaluated in people who are asymptomatic.
Here's how it works: You place the provided vial into the battery-powered testing unit, swab your nose (as you do in other nasal COVID-19 tests), stir the swab into the vial, and then cap the vial and press down until you hear a click and the "ready" light starts blinking. After the test is completed the results will light up as either positive or negative in about 30 minutes.
November 23, 2020
Vaccine deployment a critical component of success
This study, "Clinical Outcomes Of A COVID-19 Vaccine: Implementation Over Efficacy" by A. David Paltiel, Jason L. Schwartz, Amy Zheng, and Rochelle P. Walensky, modeled the theoretical population outcomes of vaccines with varying degrees of effectiveness on reducing susceptibility to infection, progression of disease, and severity of illness. The population outcomes of interest included cumulative infections, hospitalizations, and deaths. Researchers also looked at how the outcomes would vary with different starting assumptions, including the pace of scale-up, the degree of public acceptance, and changes in disease epidemiology (eg, effective reproductive number, Rt).
They found that the way the vaccine was deployed in a population (ie, pace of manufacturing, delivery and administration, breadth of coverage) had as much effect on outcomes as the actual vaccine biological efficacy. High performance on any one vaccine variable could not overcome low performance in others and achieving and maintaining a low Rt (ie, through public health measures) throughout a vaccination deployment not just at the start was important.
November 10, 2020
A variant of the SARS-CoV-2 virus can evade antibody-mediated immunity
Researchers from the University of Glasgow Centre for Viral Research report on N439K, a variant of the SARS-CoV-2 virus with a mutation in the receptor binding motif that enables it to evade antibody-mediated immunity while maintaining virulence. The N439K variant was first identified in Scotland and subsequently appeared in 12 countries, including the United States, and is the second most commonly observed variant worldwide.
The receptor binding domain (RBD) is the portion of the viral spike protein that allows the virus to enter into cells. The primary target of neutralizing antibody response within the RBD is an area called the receptor binding motif (RBM). The receptor binding motif has been observed to have more plasticity and is less conserved than the RBD or the entire spike protein. The receptor binding variant with the N439K mutation is associated with similar clinical spectrum disease and slightly higher viral loads in vivo compared with the wild type variants without this mutation. Also, the variant was seen to bind better to human cells in cell culture and to multiply a little faster. The researchers evaluated monoclonal antibody isolates from individuals who recovered from SARS-CoV-2 infection early in the pandemic as well as monoclonal antibodies REGN10933, REGN10987, LY-CoV555, and S309. They found that 15.5% of the monoclonal antibodies demonstrated a > 2-fold reduction in binding to the receptor binding domain of the N439K mutation. The report suggests that monitoring the evolution of SARS-CoV-2 will be important. Although SARS-CoV-2 is evolving slowly and, at present, should be controllable by a single vaccine, variation accumulating in the RBM could put this control at risk, especially for individuals with a moderate antibody response to vaccination or infection.
November 4, 2020
Elevated troponin levels predict 30-day mortality in patients with COVID-19
An observational cohort study published in the Journal of the American Heart Association on October 30, 2020, identified 446 patients with COVID-19 that had the following serum biomarkers measured: troponin‐I (TnI), B‐type natriuretic peptide, C‐reactive protein, ferritin, and D‐dimer. The primary endpoint of the study was 30-day in-hospital mortality. Researchers found that elevation of these biomarkers was common in patients with severe COVID-19 but only troponin I elevation was independently predictive of 30-day mortality. With the data collected on the patients in this group, they constructed a risk score for 30-day mortality. Scores were calculated for each patient: 2 points for severe troponin elevation (troponin level ≥ 0.34 ng/mL), 1 point for age 65 to 74 years, 2 points for age older than 75 years, and 1 point for hypoxia upon presentation. Patients with scores of 0 had a 30-day mortality of 0% while patients with a score of 5 had a 30-day mortality of 65.5%. Overall, patients with a score less than 3 had a 30-day in-hospital mortality of 5.9% while patients with a score of 3 or higher had a 30-day mortality of 43.7%. Validation of the risk score was performed using an independent patient cohort (n = 440) from patients in the larger cohort that had serum troponin but not all the other biomarkers measured.
November 2, 2020
Monoclonal antibodies against COVID-19 show promise in ongoing trial
In a news release on October 28, 2020, Regeneron updated results in the ongoing outpatient trial of its monoclonal antibody cocktail, REGN-COV2 (a combination of two monoclonal antibodies). This update added an additional 524 patients, to the 275 patients initially reported in an earlier press release. The trial is a randomized, double-blind study measuring the effects of adding REGN-COV2 vs placebo to the usual standard of care. Regeneron announced that the ongoing phase 2/3 trial of their monoclonal antibody cocktail had positive results and met the primary endpoint and a key secondary endpoint. Notably REGN-COV2 significantly reduced the viral load and patient medical visits for a cohort of patients with mild to moderate COVID-19. Regeneron has shared these results with the U.S. FDA, which is reviewing an Emergency Use Authorization submission for the REGN-COV2 low dose for treatment of adults with mild-to-moderate COVID-19 who are at high risk for poor outcomes.
October 30, 2020
Autoantibody production is common in patients with severe COVID-19
A recent study that is awaiting peer review found that about half of patients with severe COVID-19 had autoantibodies in their serum, primarily antinuclear antibody (ANA) and rheumatoid factor (RF). This retrospective study enrolled 52 patients who had no history of autoimmune disorders. According to the NIH COVID-19 Severity Scale, 50 patients had a designation of critical while 2 had severe disease. Antinuclear antibody was positive (titer ≥ 1:80) in 44% of patients and rheumatoid factor was positive in 24%. It is speculated that these autoantibodies may contribute to the severity of acute COVID-19 illness and, if persistent in the body, may also be responsible for cases of "lingering COVID-19." The study was not designed to show cause and effect, and the authors acknowledge the possibility that the autoantibodies are simply a consequence of COVID-19 (and possibly other severe viral illnesses) rather than a cause. However, this finding may provide more evidence backing the use of immune-modulating drugs in severe COVID-19 infection along with a way to identify candidates for such intervention. One of the authors, Matthew Woodruff, also published a less technical discussion of the study and its findings online in The Conversation on October 23, 2020.
link to the study: https://www.medrxiv.org/content/10.1101/2020.10.21.20216192v2
October 27, 2020
Considerations for an emergency use authorization of COVID-19 vaccines
A perspective, published in the New England Journal of Medicine on October 16, 2020, discussed some of the issues related to making a COVID-19 vaccine available under an emergency use authorization. The authors point out the need to balance the urgency of having a vaccine to respond to a grave public health emergency vs. the need to have sufficient data on safety and efficacy. The authors discuss the reasoning behind their recommendation that clinical trial participants be monitored for two months after vaccine administration to gather adequate data to support an authorization for emergency use. They point out that although most adverse events linked to vaccination start within six weeks after vaccine receipt, full safety and efficacy evaluations require a longer follow-up period. They warn that any curtailment of this minimal follow-up period would undermine the scientific credibility of and public confidence in the decision to authorize any vaccine for use under an emergency use authorization.
October 26, 2020
New co-factor that facilitates SARS-CoV-2 infectivity
Researchers trying to understand why SARS-CoV-2 is highly infectious, and why the virus affects so many organ systems unlike SARS-CoV, compared the structure of their respective viral spike proteins using genomic sequencing. They discovered that the former has acquired a small sequence of amino acids that appears to mimic a protein sequence found in human proteins that interact with neuropilin-1 (NRP1). This sequence is also found in the S proteins of many devastating human viruses, including Ebola, HIV-1, and highly pathogenic strains of avian influenza. The researchers believe that NRP1 is a cofactor involved with viral entry into the cells and enhances the ability of the virus to infect cells that have low angiotensin-converting enzyme 2 (ACE2) receptor expression. NRP1 is localized in the respiratory and olfactory epithelia. One reason SARS-CoV-2 has a high rate of transmission, in contrast to SARS-CoV, is that the virus that causes COVID-19 infects both the upper and lower respiratory tract. Consequently, SARS-CoV-2 is present in the nasal mucosa and is more easily shed and dispersed with coughing, sneezing, and breathing. The research team was able to demonstrate that this extra piece of viral spike protein on the SARS-CoV-2 virus binds to NRP1 receptor on the surface of human cells and this binding significantly potentiates viral entry into cells via the ACE2 receptor. The authors explained that while the focus to date has almost been entirely of the role of ACE2 receptors in SARS-CoV-2 entry into cells, this new knowledge reveals how the virus can exploit the NRP1 receptor to gain access into cells. This may explain why the pattern of the expression of the ACE2 receptors does not match with the tissue tropism of SARS-CoV-2. This discovery, published in Science on October 20, 2020, was made by a German-Finnish team of investigators and importantly provides a previously unrecognized avenue for antiviral therapies.
October 21, 2020
Neurologic manifestations are common in hospitalized patients with COVID-19
A retrospective study of 509 consecutive patients with COVID-19 hospitalized from March 5 to April 6 in 10 hospitals of the Northwestern Medicine Healthcare System in the Chicago area looked for the presence of neurological symptoms on admission and while in the hospital. In this study, published in the Annals of Clinical and Translational Neurology, the neurologic manifestations were myalgias (44.8%), headaches (37.7%), encephalopathy (31.8%), dizziness (29.7%), dysgeusia (15.9%), and anosmia (11.4%). Strokes, movement disorders, motor and sensory deficits, ataxia, and seizures were uncommon (0.2 to 1.4% of patients each). Encephalopathy was associated with triple the hospital length of stay and worse clinical outcomes after leaving the hospital. When looking at the range of neurologic symptoms, including headaches, myalgias, encephalopathy, dizziness, dysgeusia, and anosmia, 82% of the patients presented with or manifested some type of neurologic symptom. The study showed that neurologic manifestations occur in most patients hospitalized with COVID-19 and encephalopathy was independently associated with increased morbidity and mortality.
October 20, 2020
Likelihood of pregnant women infected with SARS-CoV-2 transmitting the virus to their newborns is low
A study published in JAMA Pediatrics online on October 12, 2020 finds that separating mothers who are positive for COVID-19 from their newborns may not be warranted and direct breastfeeding appears to be safe. A retrospective cohort analysis of the first 101 neonates born to 100 mothers with perinatal SARS-CoV-2 infections at two large hospitals affiliated with the Columbia University Irving Medical Center from March 13 to April 24, 2020, found the overall incidence of transmission was 2.0% (95% CI, 0.2%–7.0%—2 newborns), and no evidence of clinical infection among the cohort of infants. In addition, 55 infants were followed up in the first 2 weeks of life in a new COVID-19 Newborn Follow-up Clinic, all of whom remained healthy. To the author's knowledge this was the largest series of newborns born to mothers positive for or with suspected SARS-CoV-2 infection to date. Overall, there was no clinical evidence for neonatal COVID-19 infection. The study endorses retaining evidence-based newborn care practices such as rooming in, establishing breastfeeding, and delaying bathing and suggests that separating mothers positive for SARS-CoV-2 from their newborns and avoiding direct breastfeeding may not be warranted.
October 19, 2020
World Health Organization study finds remdesivir and other repurposed drugs ineffective in COVID-19
The World Health Organization (WHO) recently conducted a large-scale randomized, but not blinded or placebo-controlled, trial to evaluate the efficacy of four repurposed antiviral medications in the treatment of COVID-19. The antiviral medications included remdesivir, hydroxychloroquine, lopinavir (fixed-dose combination with ritonavir), and interferon. The trial involved 11,266 adult patients with COVID-19 admitted to 405 hospitals in 30 countries. Patients were randomly divided into different drug groups and received whichever study drugs were locally available or open control. In this study, 2,750 patients received remdesivir, 954 received hydroxychloroquine, 1,411 received lopinavir, 651 received interferon and lopinavir, 1,412 received only interferon, and 4,088, the control group, did not receive any study drug. The study found that none of these medications reduced the initiation of ventilation, mortality, or duration of hospital stay when compared to the control group. The non-peer-reviewed data has been posted to the medRxiv preprint server by the SOLIDARITY investigators.
October 15, 2020
Excess deaths and effects of the COVID-19 pandemic
An editorial in the October 12, 2020, issue of the Journal of the American Medical Association summarized and commented on several reports published in that issue of the Journal regarding the mortality, economic, and emotional costs of the COVID-19 pandemic in the United States. From March 1 through August 1, 2020, a total of 1,336,561 deaths occurred in the United States, a 20% increase over expected, representing 225,530 excess deaths, 67% of which were attributable directly to COVID-19. The other excess deaths are reasonably attributable to other factors related to the pandemic. Projecting this 5-month period through the remainder of 2020 suggests that more than 400,000 excess deaths will have occurred this year—approaching the number of US deaths from World War II. Another article draws attention to other consequences of the pandemic, suggesting that for every death an estimated nine family members are affected by prolonged grief or symptoms of posttraumatic stress disorder. And another article estimates the financial costs of the pandemic.
October 13, 2020
SARS-CoV-2 takes the brakes off the body's immune system, resulting in damage to healthy tissue by the alternative pathway complement cascade
The SARS-CoV-2 virus has the ability to turn the immune system against healthy cells. Researchers at John Hopkins University School of Medicine have identified a mechanism by which the virus allows a cascading series of biological reactions called the alternative pathway complement (APC) to attack and damage healthy organs. The role of complement activation and its contribution to disease severity is increasingly recognized in COVID-19, but the mechanism of complement activation was not known. From previous research, it was discovered that the virus binds with heparan sulfate, a complex carbohydrate on the cell surface, in order then to bind with the ACE2 receptor, allowing it to enter the cell. Apart from virus interaction, heparan sulfate on cell surfaces is also important for binding factor H, a negative regulator of the APC. When the SARS-CoV-2 virus binds to cell surface heparan sulfate, the virus blocks factor H from binding and regulating the alternative pathway complement system. This loss of inhibitory regulation releases the APC, resulting in immune system damage to healthy tissues and organs. The research team found that by blocking another protein known as factor D, which works upstream in the pathway from factor H, they were able to stop the destructive chain of events triggered by SARS-CoV-2. The finding that SARS-CoV-2 spike proteins activate the APC has profound implications for understanding the multiorgan dysfunction, coagulopathy, and endothelial injury characteristic of COVID-19. The findings have therapeutic implications for COVID-19 and raise the prospect for targeted therapy using complement inhibitors that bind upstream of factor H, which may be effective in stopping the activation of the complement cascade by SARS-CoV-2.
October 9, 2020
COVID-19 antibodies in convalescent plasma donations wane by 3 to 4 months
A longitudinal study done in Quebec, Canada, reported by Healio News, and published as a letter in the journal Blood on October 1, 2020, reported on 15 convalescent plasma donors who donated their plasma multiple times. Their first donation was 33 to 77 days after symptom onset and their last donation was 66 to 114 days after. Anti-receptor-binding domain (RBD) antibodies were present at the first donation for all donors, and the level decreased between first and last donation for all donors. The researchers divided the timing of donations into four quartile ranges (33-53, 54-69, 70-84, and 85-114 days). Antibody levels remained stable between the first, second, and third quartiles with a small but not statistically significant decline. In contrast, between the 3rd and 4th quartiles, there was a marked decreased (36.8%; p = 0.0052) in antibody levels. This finding informs people recovering from COVID-19 who want to donate blood plasma that they should not wait too long once they become eligible, and informs clinicians that they should check donated plasma for the presence of antibodies before giving to patients.
October 8, 2020
Study shows high-risk contact plays an important role in COVID-19 transmission in India
In one of the largest studies to date on transmission of COVID-19, contact tracing efforts reached 3,084,885 individuals exposed to 84,965 test-positive coronavirus patients in two states in India. Researchers looked at 575,071 contacts who had individual epidemiological data as well as laboratory test results available. The study was published in Science on September 30, 2020. Researchers from Princeton Environmental Institute, John Hopkins University, and University California Berkeley collaborated with public health officials in the South East Indian states of Tamil Nadu and Andra Pradesh. The data showed that infected patients came into contact with about 7 people, on average, and that 71% of positive patients did not infect any contacts. For high-risks contacts (who had close social contact or direct physical contact with index cases without protective measures), the transmission rate (from an index case to an exposed contact) was about 10.7%. For low-risk contacts (proximity of index cases but did not meet these criteria for high-risk exposure), the transmission rate was about 4.7%. In the study, children and young adults were the key demographics spreading the virus, and most often they spread the virus to someone their own age. This demographic is potentially more important in transmitting the virus then has been identified in previous studies. The study highlights the role of transmission by high-risk contact.
October 2, 2020
Immunological abnormalities may explain why some otherwise healthy patients develop severe COVID-19
Two studies recently published in the journal Science shed some light on why people may develop severe COVID-19. What researchers found is that some patients have antibodies against interferon proteins and others have inborn errors or genetic mutations that impede interferon production and function. In looking for interferon antibodies in patients with severe COVID-19 pneumonia, they found that among the 987 patients they tested with severe COVID-19, 101 of the patients had neutralizing auto-antibodies against type 1 interferons. In comparison, among 663 people who developed asymptomatic or mild COVID-19, none had the anti-interferon antibodies. Researchers also found that patients over age 65 were more likely to develop interferon antibodies. Interferons are a set of 17 crucial proteins that protect cells in the body from viruses. People who lack type I interferons cannot mount an effective immune response. The researchers have previously shown that a significant number of patients with severe COVID-19 carried a rare genetic variant in 13 genes critical for the body's immune defense against influenza, and in this study, they found similar mutations in (3.5%) 23 of 659 patients with severe COVID-19 pneumonia. This finding may provide a better understanding of why some people develop severe disease while others do not. The patients who developed severe COVID-19 pneumonia were completely missing a functioning gene and did not produce any detectable type I interferons in response to SARS-CoV-2 infection. Overall, inborn errors and immunological anomalies causing an absence of type 1 interferons might play a role in up to 14% of the most serious cases of COVID-19 infection. These two publications highlight the crucial role of type I interferons in protective immunity against SARS-CoV-2.
September 28, 2020
Extracorporeal membrane oxygenation on COVID-19 patients
A study published online in the Lancet on September 25, 2020, on the use of extracorporeal membrane oxygenation (ECMO) in 1,035 patients with acute hypoxic respiratory failure due to COVID-19, found that the death rate was less than 40%. Data were obtained from an international registry of 230 hospitals in 36 countries. Patients diagnosed with COVID-19, aged 16 years or older, who had ECMO support initiated as recorded in the ELSO registry between January 16 and May 1, 2020, were included in the analysis. The study used 90 day in-hospital mortality as the primary outcome in their analysis. ECMO is used in the final step of the algorithm for managing life-threatening respiratory failure in patients who face a staggeringly high risk of death when ventilators and other care failed to support their lungs. These results are consistent with previously reported survival rates with ECMO in acute hypoxemic respiratory failure, supporting current recommendations that centers experienced in ECMO should consider its use in refractory COVID-19–related respiratory failure.
September 23, 2020
Differing immune responses to SARS-CoV-2 infection in hospitalized pediatric and adult patients
A study done at Albert Einstein College of Medicine Children's Hospital Montefiore and Yale University compared the immune responses of adults and younger patients with COVID-19 in attempt to study why children typically have milder disease than adults. The study compared cytokine, humoral, and cellular immune responses in young (age < 24 years, n = 65) and adult (n = 60) patients with COVID-19. As expected, the study found children fared clinically much better than the adults.
The data also showed that younger patients exhibited more robust innate immunity than adults as demonstrated by higher levels of the cytokine interleukin-17 (IL-17), which is associated with the innate immune system. On the other hand, adults mounted a more robust T-cell response to the viral spike protein, had higher serum neutralizing antibody titers, and had more robust antibody-dependent cellular phagocytosis compared to younger patients. Researchers also found that neutralizing antibody levels were higher in adult COVID-19 patients who died or required mechanical ventilation than in those who recovered, and significantly higher than the levels detected in the younger patients.
These findings suggest that perhaps young peoples’ more robust innate response helps protect them from developing severe disease and often fatal outcomes, and, as a corollary, that boosting the T-cell and antibody response, particularly late in the course of disease, may not be helpful.
September 22, 2020
Researchers at the University of Connecticut report on CRISPR-based point-of-care COVID-19 testing
Current PCR/RT–PCR-based methods are considered the most accurate method of diagnosing SARS-CoV-2 infection but are complicated and do not lend themselves to point-of-care diagnostic applications. Researchers at the University of Connecticut Health Center have developed a CRISPR-based nucleic acid detection test to detect viral RNAs extracted from SARS-CoV-2 virus. The new CRISPR-based test, unlike PCR-based methods, allows all components to be incubated in one pot, eliminating the need for separate and complex manual operations. Also, the results of the AIOD-CRISPR assay are indicated by fluorescence of the sample that can be directly seen by the naked eye, although instrumentation, such as in a microfluidic diagnostic chip, may eventually allow automation and possibly semiquantitative resulting.
The CRISPR-based assay was tested on 28 clinical COVID-19 swab samples, which included eight COVID-19 positive samples. Each sample was assessed with the new assay and standard RT-PCR methodology. All eight of the COVID-19 positive samples were identified as positive within 40 minutes. The new assay did not react with SARS-CoV or MERS-CoV samples. This proof of concept will, of course, require significant development before it is clinically or commercially applicable.
September 18, 2020
Cellular heparan sulfate enables SARS-CoV-2 cell entry
A team of researchers discovered that cellular heparan sulfate acts as a co-receptor for SARS-CoV-2, letting it to bind the angiotensin-converting enzyme (ACE) receptor and allowing the virus to enter the cell. Cellular heparan sulfate is found on cell surfaces, and this knowledge leads to a potential new approach in preventing and treating COVID-19. The study, which was ,published September 14, 2020, in Cell, describes how the SARS-CoV-2 entry into cells is facilitated when cellular heparan sulfate binds to and results in a conformational change in the spike protein of the coronavirus, enhancing the attachment of the virus to ACE2 and subsequent binding to human cells. They found that the virus must bind both heparan sulfate on the cell surface and ACE2 protein in order to get inside the human lung cells. Further work by the investigators found that using enzymes that remove heparan sulfate from cell surfaces prevented SARS-CoV-2 from gaining entry. Likewise, treatment with heparin and non-anticoagulant derivatives also blocks infection by competitively binding the coronavirus away from human cells.
September 17, 2020
Novel synthetic nanobody neutralizes SARS-CoV-2 and can be aerosolized for administration by inhalation
Inspired by tiny antibody-like immune mediators called nanobodies that are found in camels, alpacas, and llamas, researchers at the University of California San Francisco engineered a molecule that tightly binds the spike protein of the SARS-CoV-2 coronavirus. They are functional antibodies devoid of light chains of which the single N-terminal domain is fully capable of antigen binding. These single-domain antibody fragments (VHHs or Nanobodies®) have several advantages for biotechnological applications. These "nanobodies" are less structurally complex and smaller than antibodies found in humans. These features make the nanobody highly stable and easily modified in the laboratory. Screening their large library of nanobodies, researchers identified those with binding to the spike protein of SARS-CoV-2. Experiments conducted on the three most potent nanobodies showed they were effective in preventing SARS-CoV-2 virus from infecting human cells. Efficacy was found even in very low doses. The researchers were able to improve the potency of one select nanobody by sequentially mutating all its amino acids that were responsible for binding the spike protein. Incorporating two of these mutations improved the affinity to bind the spike protein by 500-fold. Scientists then linked three of these antibodies together to form a molecular chain. They observed that this triplet had 200,000 times more binding affinity to the spike protein than a single antibody alone. The researchers were able to make a dry powder of the triplet nanobody and demonstrated retention of its antiviral potency. These antibodies have significant advantages in terms of production and deliverability. They can be inexpensively produced at scale in bacteria or yeast, are very stable, and can be made into a powder for aerosol delivery. The goal is to use an aerosolized preparation as a therapeutic or prophylactic agent in treating COVID-19. Only a small fraction of systemically circulating antibodies cross epithelial cells that line the airways; however, aerosolized nanobodies can be delivered directly to the nasal and lung epithelial by self-administered inhalation.
September 16, 2020
Assessing the risk of attending an event during the pandemic
In the mist of the pandemic, knowing the risk of encountering a COVID-19–positive patient while attending an event would be important information in deciding whether to attend that event. As many parts of the country begin to open up, being able estimate the risks involved in resuming nonessential activities is crucial. There is a tool, COVID-19 Event Risk Assessment Planning Tool, developed by Georgia Tech that incorporates data from The New York Times case count and the Covidtracking.com dashboard and is updated daily. This interactive map will show you down to the county level how likely you are to come across someone with COVID-19 at an event of a certain size. The tool expresses the risk level in percentage of there being at least one person with COVID-19 present an event in a given county based on the size of the gathering. The calculator assumes that every person attending an event is as likely to be infected as anyone else in a given area. The calculator can be adjusted for ascertainment bias, which takes into account a multiple of how many more cases there are than are being reported. Based on these assumptions, results of the calculation can be regarded as an approximation. For example if you were to attend a wedding in Los Angeles County with 100 people in attendance, using an ascertainment bias of 10, there is a 74% chance that at least one person would be infected with COVID-19. The risk would be 61% in Philadelphia but less than 1% in Wetzel County West Virginia.
September 15, 2020
Study disputes "cytokine storm" being responsible for severe outcomes in COVID-19
New research suggests that disease severity in patients with COVID-19 may not be due to cytokine storm. In a study published in JAMA, researchers from Radboud University Medical Center in the Netherlands measured the concentration of three proinflammatory cytokines (tumor necrosis factor [TNF], interleukin 6 [IL-6], and interleukin 8 [IL-8]) in the blood of patients admitted to the intensive care unit with COVID-19 with acute respiratory distress syndrome (ARDS), patients with bacterial septic shock (with or without ARDS), and patients admitted to intensive care after cardiac arrest or severe trauma. Patients were excluded if they had immunological insufficiencies such as use of immunosuppressive drugs or cancer. They found that the level of all three cytokines were significantly lower in COVID-19 patients then in patients with bacterial septic shock and ARDS. Cytokine concentrations in COVID-19 patients were similar to those in ICU patients with trauma or cardiac arrest. The results of this study showed that COVID-19 is not characterized by cytokine storm, challenging previous reports and assumptions that cytokine storm plays a major role in more severe COVID-19 patient outcomes. Whether anticytokine therapies will benefit patients with COVID-19 remains to be determined.
September 10, 2020
COVID-19 can mimic acute cholecystitis
SARS-CoV-2 is known to affect multiple organ systems and can present initially with clinical manifestations not involving the respiratory system. Clinicians need to be aware of the potential of COVID-19 to mimic other disease entities and not overlook the possibility of COVID-19 infection when evaluating patients with non-respiratory symptoms involving other organ systems. A letter to the editor in the Journal of Hepatology on September 2, 2020, reported a case series of two patients with COVID-19 who presented with acute acalculus cholecystitis. The first case was an 84-yea-old female patient presenting to the emergency department with signs and symptoms of a urinary tract infection and fever for 24 hours. The patient was treated for sepsis due to pyelonephritis. On day three, the patient developed right upper quadrant pain and was subsequently found to have thickening of the gallbladder wall and perivesicular fluid. CT scan of the chest and abdomen ruled out gallbladder perforation and showed normal pulmonary parenchyma. Metronidazole was added to the patient's treatment, and the patient underwent laparoscopic cholecystectomy. After extubation, the patient developed respiratory symptoms and acute respiratory distress syndrome. Nasopharyngeal swabs confirmed the presence of SARS-CoV-2 RNA. The patient died on postoperative day five of multiorgan failure. Histological analysis of the gallbladder did not demonstrate any inflammation, but the tissue from the gallbladder wall was positive for the presence of SARS-CoV-2 RNA in all three areas that were sampled. The second case was an 83-year-old man who was on dialysis with end-stage renal failure. The patient was admitted to the hospital with fever. At the time of presentation, no abdominal or respiratory symptoms were identified, and the patient’s chest x-ray was normal. On day five, the patient developed right upper quadrant pain and a positive Murphy sign. Abdominal ultrasound revealed thickening of the gallbladder wall, the presence of perivesicular fluid, and the absence of gallstones. Patient was treated with conservative management of ceftriaxone and metronidazole and slowly recovered. On day six, the patient developed respiratory symptoms and COVID-19 infection was confirmed. These cases demonstrate that SARS-CoV-2 infection can mimic acute acalculous cholecystitis.
link to the study: https://www.journal-of-hepatology.eu/article/S0168-8278(20)30550-X/fulltext
September 8, 2020
Systemic corticosteroids and mortality in critically ill patients with COVID-19
Corticosteroids are clearly shown to reduce mortality for critically ill patients with COVID-19. These are the findings in a meta-analysis of seven prospective, randomized trials including 1,703 patients published in JAMA on September 2, 2020. The meta-analysis was based on a relatively large number of critically ill patients with COVID-19 from geographically diverse sites. Of the 1,703 patients in the trial, 647 died by 28 days after randomization. Mortality rate among patients receiving standard care was 40%, this dropped to 32% in those treated with corticosteroids. This was a highly statistically significant difference (p < 0.001). This finding was true for patients requiring mechanical ventilation as well as for those who required supplemental oxygen but not a ventilator. The meta-analysis also revealed little difference in serious adverse events for patients who received corticosteroids versus those who did not. Based on the clear benefit that corticosteroids showed for critically ill patients, the World Health Organization released updated guidance recommending use of systemic corticosteroids for the treatment of patients with severe and critical COVID-19.
link to the study: https://jamanetwork.com/journals/jama/fullarticle/2770279
September 4, 2020
Newly discovered cellular pathway protects cells from infection by the Ebola virus and SARS-CoV-2
Scientists studying mechanisms by which cells protect themselves against viral infections have discovered a novel pathway which could lead to new therapies against a variety of viruses. Findings were published in the journal Science on August 27, 2020. The researchers used an innovative screening technique, transposon-mediated gene-activation screen, to look for genes that can prevent infection of human cells by the Ebola virus. They found that the genes MHC class II transactivator (CIITA) and CD74 have antiviral activity and can inhibit the Ebola virus by blocking cathepsin-mediated cleavage of viral glycoproteins, preventing viral fusion. Many viruses, including coronaviruses and filoviruses (Ebola and Marburg viruses), use cathepsin proteases to help them infect cells. Researchers showed that these genes can block the endosomal entry pathway of coronaviruses, including SARS-CoV-2. This newly discovered cellular protection mechanism may be efficacious against multiple viruses, including those that may emerge in the future.
August 28, 2020
Novel intranasal COVID-19 vaccine elicits strong, widespread immune response and prevents infection in mice
Washington University School of Medicine announced the development of a novel COVID-19 vaccine. Unlike other vaccines in development for COVID-19, this vaccine is administered intranasally. Mice given this vaccine developed a strong immune response, particularly in the lining of the nose and upper respiratory tract. The senior author of the paper, Michael S. Diamond, MD, PhD, said "these mice were well protected from disease, and in some of the mice, we saw evidence of sterilizing immunity, where there is no sign of infection whatsoever after the mouse is challenged with the virus." The vaccine uses as a vector an adenovirus that has been rendered harmless and has the spike protein from the coronavirus inserted. The new vaccine also incorporates two mutations into the spike protein. These mutations stabilize it into a specific shape that is most conductive for forming antibodies against it. Comparing nasal administration to intramuscular injection, the researchers found intranasal delivery prevented infection in both the upper and lower respiratory tracts. Although intramuscular injection induced an immune response that prevented pneumonia, it did not prevent infection in the nose or lungs. One promising finding was that a single intranasal dose produced such a robust immune response that a second dose should not be needed. Researchers will soon begin studying the intranasal vaccine in nonhuman primates and plan to move into clinical trials in humans as quickly as possible. This study was published online in Cell on August 19, 2020.
link to press release: https://medicine.wustl.edu/news/nasal-vaccine-against-covid-19-prevents-infection-in-mice/
August 20, 2020
Virologists identify potential COVID-19 treatments
Scientists developing inhibitors of a critical viral enzyme called C3-like protease have engineered and studied compounds that inhibit this viral enzyme. C3-like protease is an enzyme that is essential for coronaviruses to replicate and crucial to their survival. Researchers tested the antiviral compounds' effect on SARS-CoV-2 in cultured human airway cells and tested them in a mouse model for MERS. The findings appeared in the journal Science Translational Medicine, August 3, 2020. Researchers found two of the 22 compounds they tested of interest. Cultured human airway epithelial cells from 3 people infected with SARS-CoV-2 were treated with 2 of the antiviral compounds, 6e and 6j, and the results showed lower viral loads than cells treated with vehicle, indicating that the viruses’ ability to replicate was suppressed by the compounds. They further tested 6j using a mouse model for MERS because a relevant mouse model for SARS-CoV-2 has not yet been developed. In testing with this model researchers found that mice treated on day one after they had been infected all survived while all those in the untreated group died. With the ongoing COVID-19 pandemic and few therapeutic options available, there is an urgent need for effective treatments. This study is important because it identifies both an therapeutic target to inhibit viral replication and compounds to use against it.
August 19, 2020
Timing of symptoms can help differentiate COVID-19 from other respiratory illnesses
Researchers at the USC Michelson Center for Convergent Bioscience analyzed thousands of COVID-19 cases and figured out the likeliest order of COVID-19 symptoms. According to the study published in the medical journal Frontier Public Health, the most likely order of symptoms is as follows: fever, followed by cough, followed by muscle pain, followed by nausea and vomiting, and then diarrhea. The researchers analyzed data sets for more than 55,000 COVID-19 cases in China that were collected in mid-February by the World Health Organization, as well as data from nearly 1,100 cases from December 11 to January 29 collected by China Medical Treatment Expert Group. Comparing the progression of symptoms in COVID-19 patients with influenza, SARS (severe acute respiratory syndrome), and MERS (Middle East respiratory syndrome), the researchers found that the presenting order of symptoms can help differentiate COVID-19 from the other respiratory illnesses. COVID-19 is most likely first heralded with fever and then cough, as opposed to influenza whose first symptom is most likely cough followed by fever. In COVID-19, upper gastrointestinal tract symptoms of nausea and vomiting most likely precede diarrhea, differentiating it from both SARS and MERS, in which diarrhea most likely precedes nausea and vomiting. The analysis also suggested that if diarrhea was a presenting symptom of COVID-19, the patient may experience a more severe case. This information may be useful to healthcare workers to help distinguish COVID-19 patients from others. Patients who are educated about the progression of COVID-19 symptoms may seek medical care earlier than they might have otherwise and can quarantine earlier to avoid spreading the disease.
August 18, 2020
The association of large vessel occlusion stroke and COVID-19 in New York City
Published online in Stroke, a retrospective, observational study was conducted in New York City across the Mount Sinai Health System on emergent large vessel occlusive stroke (ELVO) during the pandemic period from March 21 to April 12, 2020, compared to historical data from the previous year. Researchers looked at the 45 consecutive patients hospitalized during a 3-week peak of COVID-19 surge. Among those patients, 24 (53%) tested positive for the virus. This was significantly higher than the 19.9% infection rate in the general population in New York City. Patients with COVID-19 were younger than those not infected (mean 59 vs 74 years; P = 0.004), more apt to be male (75% vs 43%; P = 0.032), and less likely to be white (8% vs 38%; P = 0.027). Also, the absence of cardiovascular risk factors was noted in 46% of the COVID-19 ELVO patients versus 24% of the ELVO patients who did not have COVID-19. Of the COVID-19 cohort, only 50% had typical COVID-19 related symptoms on presentation; however, during the hospital stay, 60% of the previously asymptomatic patients developed typical COVID-19 symptoms, showing that for some patients, stroke may be the first manifestation of COVID-19. Compared to historical data, there was approximately a 2-fold increase in the number of emergent large vessel ischemic strokes during the study period. The authors concluded that there is an association between large vessel ischemic stroke and COVID-19 and clinicians should consider COVID-19 in the workup of acute ischemic stroke, particularly in patients without typical cardiovascular risk factors.
August 12, 2020
Cardiovascular MRI shows residual cardiac effects in patients recently recovered from COVID-19
A study published in JAMA Cardiology, online July 27, 2020, by researchers at the University Hospital Frankfurt Germany studied the cardiovascular effects of COVID-19 on 100 patients with documented infection.
In a prospective, observational cohort study of 100 patients who recently recovered from COVID-19, 78 % were found to have cardiac involvement revealed by cardiac magnetic resonance imaging, (CMR) and high-sensitivity troponin levels. The results were compared to those of a similar number of age and sex-matched controls. Testing was done in clinically recovered patients a median of 71 days following initial diagnosis. Of the cohort, 67% had recovered at home, while 33% required hospitalization. Sixty percent of the COVID-19 patients had evidence of ongoing myocardial inflammation, which was independent of pre-existing conditions, severity, and overall course of the illness. At the time of CMR, high-sensitivity troponin was detectable in 71% of the recently recovered patients and was significantly elevated in 5%. The most prevalent abnormality on CMR was myocardial inflammation. Compared with controls, COVID-19 patients had lower left ventricular ejection fraction and higher left ventricular volumes.
This is the first study to document significant cardiac involvement occurring independently of the severity of the disease and persistent beyond the period of acute illness. The long-term cardiovascular consequences of COVID-19 infections need to be investigated further.
August 10, 2020
Number of newly identified cancer cases decreased by 46.4% during the pandemic
In a research letter published in JAMA network August 4, 2020, analysis of the number of new cancer diagnoses fell 46.4% during the pandemic period from March 1 to April 18, 2020, compared to baseline historical data. The study included patients across the US who received testing for any cause by Quest Diagnostics in which the ordering physician assigned an ICD–10 code associated with any of the six types of common cancers (breast, colorectal, lung, pancreatic, gastric, and esophageal). Most of the decrease in new cancer diagnoses was in breast and colorectal cancers, which are diagnoses most often made by screening. Results mirror findings from other countries, which have also seen as much of as a 40% decline in weekly cancer incidence and a 75% decline in referrals for suspected cancer since COVID-19 restrictions were implemented. The letter makes the point that cancer does not take a pause, and the delay in diagnosis will likely lead to presentation of the cancers at more advanced stages with possibly poorer clinical outcomes. The article referenced a study that suggested a potential increase of 33,890 excessive cancer deaths in the United States and call for urgent planning to address the consequences of the delayed diagnoses.
August 7, 2020
NIH to launch a new clinical trial to determine if monoclonal antibodies can shorten symptomatic period in COVID-19 outpatients
The NIH announced on August 4, 2020, a clinical trial (ACTIV-2) to determine whether monoclonal antibodies can shorten the symptomatic period of COVID-19 in outpatients. This phase 2 clinical trial will evaluate the efficacy and safety of an investigational therapy based on monoclonal antibodies to treat the disease. Volunteers currently infected with SARS-CoV-2 with mild to moderate disease, and not requiring hospitalization, will be randomly assigned to receive the experimental therapy or placebo. The therapy being tested is an intravenous infusion of LY– CoV555, an investigational monoclonal antibody made by Eli Lilly Company. The initial stage of trial will enroll approximately 220 volunteers. Researchers will track each participant’s COVID-19 symptoms and check for the presence of RNA from SARS-CoV-2 in the participant’s nose and saliva. The primary goal of the trial is to determine whether the investigational therapy can safely reduce the duration of symptoms through study day 28. Researchers also want to determine whether the investigational therapy can increase the proportion of participants with undetectable virus in nasopharyngeal swabs and saliva at specific time points.
August 4, 2020
Prior exposure to the coronaviruses that cause the common cold may affect the severity of SARS-CoV-2 symptoms
An article in Science Magazine online July 29, 2020, reported on a study published as a preprint in the journal Nature which showed that healthy individuals possessed immune cells capable of recognizing novel coronavirus SARS-CoV-2. Researchers suggested this cross-reactivity is due to prior exposure to "common cold" coronaviruses and may play a part in the spectrum of symptom severity in the pandemic. Helper T cells of healthy individuals with no known exposure to COVID-19 were exposed to fragments of the spike of protein of SARS-CoV-2. In 35% of healthy individuals, helper T cells were capable recognizing the fragments of SARS-CoV-2. The article discusses general information on the body's immune response, implications of the study results, and future plans by the researchers to further study how range of immunological factors correlate with symptoms.
link to Nature: https://www.nature.com/articles/s41586-020-2598-9
July 30, 2020
Rapid decay of anti-SARS-CoV-2 antibodies
In a correspondence published in The New England Journal of Medicine, researchers from the David Geffen School of Medicine at the University of California reported on a small study done on 31 participants who recovered from mild COVID-19 and had their antibody levels to the SARS CoV-2 virus quantified. Measurements showed a rapid decay of anti-SARS-CoV-2 antibodies. The authors noted that a recent study had suggested a rapid decay of these antibodies but the rate was not described in detail. In the current study, the first antibody level was obtained at 37 days after the onset of symptoms (range, 18 to 65) and last measurement was obtained 86 days after the onset of symptoms (range, 44 to 119). The mean decrease in the level of antibodies suggested a half-life of approximately 36 days over the observation period. The authors concluded that the early antibody decay after acute viral exposures raises the concern that humoral immunity against SARS-CoV-2 may not be long-lasting in persons with mild illness. They raised concerns regarding antibody-based immunity passports, herd immunity, and perhaps vaccine durability in light of their findings and what is already known about common human coronaviruses.
July 29, 2020
FDA warns consumers and health care professionals not to use certain alcohol-based hand sanitizers
In a press release, July 27, 2020, the US Food and Drug Administration (FDA) reiterated its warning not to use certain hand sanitizers containing methanol. There have been an increasing number of adverse events including blindness, cardiac effects, effects on the central nervous system, and hospitalizations and deaths. The news release also reported the FDA's latest enforcement efforts to prevent certain hand sanitizers from entering the country. The FDA stresses that consumers must be vigilant about which hand sanitizers they use and urges consumers to immediately stop using all hand sanitizers on the FDA's list of dangerous hand sanitizer products. Methanol, commonly known as wood alcohol, is a dangerous substance. Exposure can result in nausea, vomiting, headache, blurred vision, permanent blindness, seizures, coma, permanent damage to the nervous system, or death. People using these products on their hands are at risk for methanol poisoning; however, young children who ingest these products or adolescents and adults who drink these products as an alcohol substitute are at most risk.
July 27, 2020
Aging-associated inflammation and COVID-19
In a though-provoking perspective published in the journal Science, Professors of Immunology at University College of London suggest that age-associated increases in baseline inflammation, called inflammaging, may be implicated in the overwhelming inflammation which is often responsible for fatalities due to COVID-19 infection. In older people, inflammaging is thought to be caused, at least partially, by deterioration of aged cells (senescence) in tissues of the body that release inflammatory molecules. The authors point out that studies have shown that excessive inflammation due to the phenomenon of inflammaging, combined with an aged immune system, can inhibit overall immunity. According to the authors, reducing the number of senescent cells with senolytic drugs or reducing inflammation with anti-inflammatory drugs may be a beneficial strategy for improving COVID-19 outcomes in older patients.
July 23, 2020
Making the case for aerosol transmission of SARS-CoV-2
Making the case that SARS-CoV-2 can be transmitted by aerosols, Kimberly Prather, Chair of Atmospheric Chemistry at the Scripps Institute of Oceanography, University of California San Diego, and colleagues authored an article published in Science that explained the science and reasoning why aerosol transmission can and does occur. Dr. Prather notes that, given how little is known about the production and airborne behavior of infectious respiratory droplets, it is difficult to define a safe distance for social distancing. She states that assuming the SARS-CoV-2 virions are contained in submicron aerosols, as is the case for influenza viruses, a good comparison is exhaled cigarette smoke, which also contains submicron particles and will likely follow comparable flows and dilution patterns. “The distance from a smoker at which one smells cigarette smoke indicates the distance in those surroundings at which one could inhale infectious aerosols.” She believes masks are effective and that it is important to wear a properly fitted mask indoors even when 6 feet apart.
July 22, 2020
Recurrent SARS-CoV-2 positivity after COVID-19
A meta-analysis of studies that reported recurrent SARS-CoV-2 RNA positivity was published in preprint on the med RX IV server on July 21, 2020. The meta-analysis included 14 studies of which 13 were conducted in China and one study was conducted in Brunei. There was a total of 2,568 participants from the 14 studies combined, of which 318 experienced recurrent SARS-CoV-2 positivity. The pooled estimate of recurrent SARS CoV-2 RNA positivity was 14.8%, confirming that recurrent positivity among patients who have recovered and been discharged from hospital is relatively common. The mean time of recurrence was 35.44 days from disease onset and 9.76 days from the last that negative test. The authors noted this is the first systematic review of recurrent SARS-CoV-2 RNA positivity among individuals who have recovered from COVID-19. The meta-analysis characterized the features and risk factors related to the recurrent SARS-CoV-2 positivity in patients who had recovered from COVID-19.
July 20, 2020
Transmission of SARS-CoV-2: A brief by the World Health Organization
The World Health Organization published a scientific brief, July 9, 2020, updating the current knowledge concerning COVID-19 transmission. The brief was undertaken by World Health Organization and their partners to consolidate information from reviews and publications in peer-reviewed journals and non peer-reviewed manuscripts in preprint servers. The document discusses the different modes in which the virus may be transmitted and when people infected with SARS-CoV-2 can infect others. The brief also explores the question of whether asymptomatic or pre-symptomatic transmission occurs. The World Health Organization brief underscores that understanding how the infection is spread, and when and in which settings the virus is transmitted, have important implications for strategies in preventing the disease.
July 17, 2020
Transplacental transmission of SARS-CoV-2 infection
Some cases of perinatal transmission of SARS-CoV-2 infection have been described, but it is unclear if these occurred via the transplacental or the transcervical route or through environmental exposure. A case report published in the July 14, 2020, edition of Nature Communications shared comprehensive evidence of a transplacental transmission of the SARS-CoV-2 virus. Maternal viremia was confirmed. Placental infection and inflammation was demonstrated by histological examination and immunohistochemistry and high viral loads. Neonatal viremia was detected following placental infection. Importantly, in this case report there were clinical manifestations in the neonate including neurological signs and symptoms that the authors felts were consistent cerebral vasculitis due to COVID-19.
July 15, 2020
Italian study finds 81.9% of individuals aged 20 years or younger have no symptoms following infection with the coronavirus
Age-specific estimates on the probability of developing symptoms upon infection with SARS-CoV-2 are sparse. Strategies for controlling the spread of the infection that rely on testing close contacts of individuals with the infection and isolating those who test positive are hampered by asymptomatic infections, which are easily missed by surveillance teams. Of particular relevance is transmission of infection by children given they are much less likely to experience symptoms. In a study done in Lombardy, Italy, clinical observations were made of the close contacts of 64,252 people with laboratory-confirmed SARS-CoV-2 infection. In the study, a cluster of 3,420 infected individuals were identified where all close contacts were tested for COVID-19 either by nasal swabs or serological testing, yielding overall sample size of 5,484 close contacts. Among the selected 5,484 close contacts, 51.5% or 2,824 tested positive. Of the 2,824 confirmed SARS-CoV-2 infections, 876 or 31% were symptomatic. Symptomatic cases were defined as showing upper or lower respiratory tract symptoms (eg, cough, shortness of breath) or fever ≥ 37.5 °C. The data were stratified by age, and researchers found that the probability of developing symptoms increased with age:
- Age < 20 years: 18.1% developed symptoms
- Age 20–39 years: 22.4% developed symptoms
- Age 40–59 years: 30.5% developed symptoms
- Age 60–79 years: 35.5% developed symptoms
- Age > 80 years: 64.6% developed symptoms
The authors noted that the contribution of asymptomatic infections to transmission of SARS-CoV-2 is poorly quantified and the estimates of the proportion of SARS-CoV-2 infections which are asymptomatic range from 17 to 87%, depending on what symptoms were included in the definition and when they were ascertained. This study shows that the likelihood of experiencing symptoms of SARS-Cov-2 infection increases with age. This study represents a useful piece of information that may lead us to better understand the role of children and young adults in the epidemiology of COVID-19. This preliminary study does not yet appear in a peer-reviewed journal, but its authors have made their findings available online, on the preprint platform arXiv.
July 14, 2020
A large proportion of COVID-19 patients had persistent symptoms after recovery from acute infection
A study done by Italian researchers and published in in the Journal of the American Medical Association found that a large number of COVID-19 patients had lingering symptoms. The study included 143 patients who were discharged from the hospital after recovery from COVID-19. All patients had met criteria for discontinuation of quarantine (no fever for 3 consecutive days, improvement in other symptoms, and 2 negative tests results for COVID-19, 24 hours apart). Patients enrolled in the study an average 36 days after discharge and had another negative PCR test for COVID-19 at the time of enrollment. The majority of patients reported fatigue and shortness of breath as persisting symptoms. At the time of evaluation, only 12.6% were completely free of any COVID-19 related symptoms, while 30% had one or two symptoms, and 55% had three or more symptoms. None the patients had a fever or any signs of acute illness. Worse quality-of-life was observed among 44.1% patients. A high proportion of individuals reported fatigue (53.1%), dyspnea (43.4%), joint pain (27.3%), and chest pain (21.7%). The researchers point out that while much attention has been focused on the acute phase of COVID-19, continued monitoring after discharge for long-lasting effects is needed. The authors note that the study has limitations, including being a single-center study, and information about symptoms the patient had prior to the infection were not available. Furthermore, there was no control group for comparison.
July 8, 2020
Understanding respiratory physiology demystifies silent (happy) hypoxemia
A new paper published in the American Journal of Respiratory and Clinical Care Medicine addresses the puzzling condition of silent (happy) hypoxemia in COVID-19 patients. Silent hypoxia refers to patients with low oxygen levels (PaO2) without dyspnea. The authors present information on 16 COVID-19 patients with silent hypoxia and explain that several pathophysiologic mechanisms can account for most, if not all of this phenomenon. They also highlight confounding factors which impact on the phenomenon.
Mechanisms that may account for silent hypoxia include:
- Ventilation responds more quickly to changes in PaCO2 than PaO2 and PaCO2 is often low or within normal range
- Patients with diabetes and older people (a significant portion of seriously ill patients) have a decreased ventilatory response to hypoxia
- Carotid bodies have angiotensin-converting enzyme-2 (ACE2) receptors and may be directly affected by the virus
Confounding factors include
- Pulse oximetry is accurate with high levels of oxygenation but can exaggerate the severity of low oxygen saturation
- Fever shifts the oxygen-hemoglobin dissociation curve to the right, causing desaturation, but carotid body chemoreceptors respond only to PaO2 rather than oxygen saturation
- The response to hypercapnia or hypoxia can vary dramatically among individuals
July 6, 2020
A review of COVID-19 and the digestive system
A review published in the American Journal of Gastroenterology (AJG) July 4, 2020 on the relationship between COVID-19 and the digestive system focused both on the clinical findings and potential underlying mechanisms of COVID-19 gastrointestinal (GI) pathogenesis. An earlier study of the incidence of GI symptoms during the outbreak of COVID-19 in Wuhan, China (AJG May 2020) reported that although COVID-19 was predominately characterized by respiratory symptoms, 18.6% of patients had GI symptoms of nausea, vomiting, and diarrhea on presentation. Occasionally, these GI symptoms were the initial presenting symptoms without respiratory symptoms. Also, the presence of GI symptoms was closely associated with more severe illness. The current review also stated that SARS-CoV-2 infection can lead to liver injury and abnormal liver enzymes are associated with COVID-19 severity.
The authors point out that angiotensin-converting enzyme-2, which is the functional receptor of SARS-CoV-2, is widely distributed in various human organs but note that the expression of the receptor is approximately 100 times higher in the GI tract then in the respiratory system. The review discusses the clinical and pathological evidence for COVID-19 involving digestive system, the mechanisms of interstitial damage and liver injury. The authors of this review article conclude that digestive symptoms should be treated with caution in the early stage of COVID-19 and monitoring of liver function and cytokines is important during clinical practice.
July 2, 2020
CDC says pregnant women at greater risk for severe COVID-19
According to a new report published online in the Morbidity and Mortality Weekly Report (MMWR) on June 26, 2020, pregnant women may be at increased risk for severe COVID-19 illness. In women of reproductive age (15 to 44 years) who were infected with SARS-CoV-2 (the virus that causes COVID-19), pregnancy was associated with a greater likelihood of hospitalization, admission to the intensive care unit, and needing mechanical ventilation. However, pregnancy was not associated with increased risk of death. There were 8207 cases of pregnant women who tested positive for COVID-19 reported to the CDC as of June 7. These women were compared with the 83,205 women of reproductive age who were known not to be pregnant and who tested positive for COVID-19. There was a substantially greater proportion of hospital admissions among pregnant women (31.5%) compared with non-pregnant women (5.8%). ICU admissions were reported for 1.5% of pregnant women compared with 0.9% of their non-pregnant counterparts, and mechanical ventilation was required for 0.5% of pregnant women compared with 0.3% of their non-pregnant counterparts. Hispanic and African-American women appear more likely to be infected by SARS-CoV-2 during pregnancy. The authors point out that during pregnancy women experience physiologic and immunologic changes that could increase the risk for more severe illness resulting from respiratory infections. Although the study has several limitations, the authors of this CDC report state that “…pregnant women should be made aware of their potential risk for severe illness from COVID-19. Pregnant women and their families should take measures to ensure their health and prevent the spread of SARS-CoV-2 infection. Specific actions pregnant women can take include not skipping prenatal care appointments, limiting interactions with other people as much as possible, taking precautions to prevent getting COVID-19 when interacting with others, having at least a 30-day supply of medicines, and talking to their health care provider about how to stay healthy during the COVID-19 pandemic. To reduce severe outcomes from COVID-19 among pregnant women, measures to prevent SARS-CoV-2 infection should be emphasized, and potential barriers to the ability to adhere to these measures need to be addressed.”
June 30, 2020
Five techniques to reduce depression and anxiety
Healthcare providers, especially emergency teams, are at high risk of mental health consequences during the COVID-19 pandemic. In response, the Department of Emergency Medicine, University of Ottawa, Canada has provided to its members information on 5 evidence-based techniques shown to decrease symptoms of depression and anxiety. These techniques have been described in detail in a paper accepted for publication in the Canadian Journal of Emergency Medicine (see link below). The 5 techniques are:
- Mindfulness meditation: A broad term for a variety of meditative practices to assist in grounding individuals in the present. One example: During stressful situations use box breathing: inhale for 4 sec, hold for 4 sec, exhale for 4 sec, and then hold for 4 sec.
- Exercise: Gradually increase to 150 min of moderate to vigorous physical activity per week.
- Set a limit on social media (< 30 min per day): Instead, video chat or call a loved one.
- Eat a healthy diet such as the Mediterranean diet: Engage in cooking.
- Therapy and counseling: Engage in mental health resources through peer support or through a mental health professional.
The article ends with an engaging graphic highlighting the above techniques.
June 29, 2020
The reduction in daily CO2 emissions during the COVID-19 confinement
The amount of carbon dioxide (CO2) being released by human activity each day fell as much as 17% during the height of the coronavirus crisis in early April according to a study published on May 17, 2020 in the journal Nature Climate Change. Government policies of confinement (quarantine or stay at home) to reduce transmission of the virus during the COVID-19 pandemic have drastically altered patterns of energy demand around the world. Daily emissions temporarily fell to levels last seen in 2006. The analysis was carried out by an international team of researchers working on a future Earth's global carbon project, an initiative to trace the impacts of human-generated greenhouse gases on the planet. The 17% decline in CO2 emissions came in early April when confinement measures around the world were at the peak. The overall impact on 2020 annual emissions depends on the duration of the confinement with a low estimate of a decrease of about 4% if pre-pandemic conditions return by June and high estimate of a decrease of about 7% if some restrictions remain worldwide until the end the 2020. The authors point out that the annual decrease of CO2 emissions of between 4.2 to 7.5% is comparable to the rate of decrease needed year on year over the next decade to limit climate change to 1.5°C, highlighting the challenge faced to limit climate change in line with the Paris climate agreement.
June 25, 2020
Clinical guidances from the American College of Rheumatology for pediatric rheumatologic disease during the COVID-19 pandemic and for patients with multisystem inflammatory syndrome
The American College of Rheumatology has issued two new clinical guidance documents with evidence-based recommendations (see links below for these recommendations). The first guidance on management of children with rheumatologic disease during the COVID-19 pandemic provides recommendations for prevention of COVID-19 in children with rheumatologic disease as well as recommendations for treatment of pediatric rheumatologic disease in various situations related to COVID-19, including no exposure, close/household exposure, asymptomatic and symptomatic COVID-19 infections.
The second guidance provides detailed diagnosis and treatment recommendations for multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. The draft summaries were approved by the ACR Board of Directors on June 17, 2020 and published online.
June 24, 2020
Prone positioning in non-intubated patients with respiratory failure due to COVID-19
Prone positioning of intubated patients has been shown to reduce mortality in moderate to severe acute respiratory distress syndrome. In a study investigating the feasibility and effects on gas exchange of prone positioning in non-intubated patients with COVID-19, a prospective study on 56 hospitalized patients with confirmed COVID-19 pneumonia was done between March 20 and April 9, 2020, in Monza, Italy. Patients were receiving supplemental oxygen or non-invasive continuous positive airway pressure. After baseline data were collected, patients were placed in the prone position and kept prone for a minimum 3 hours. Data were re-collected at baseline while supine, 10 minutes after prone positioning, and 1 hour after returning to the supine position in the 49 patients who successfully did the prone positioning. Study found that oxygenation substantially improved from the supine to prone positioning (PaO2/FiO2 ratio 180·5 mm Hg [SD 76·6] in supine position vs 285·5 mm Hg [112·9] in prone position; p < 0·0001). After resuming the supine position, improved oxygenation was maintained in half of the patients. Overall, the improvement 1 hour after returning to supine position was not statistically significant. The study supports previous reports of the benefit of prone positioning in awake patients with respiratory failure due to interstitial pneumonia. The study demonstrated the feasibility of this technique in patients affected by COVID-19. Further studies need to be done to assess the safety and medium- and long-term outcomes of prone positioning on respiratory parameters and survival.
June 23, 2020
Blood type is associated with the severity of COVID-19
A study published in the New England Journal of Medicine June 17, 2020, reported on genetic analysis done on samples from more than 1900 severely ill patients in Spain and Italy. Patients had respiratory failure due to COVID-19 that was confirmed with RNA testing. Samples from these severely ill patients were compared to those from more than 2000 healthy controls, some of whom may have had COVID-19 but had only mild or no symptoms. Researchers found that genetic locus 3p21.31 and locus 9q34.2 were significantly associated with respiratory failure due to COVID-19. At locus 9q34.2 the association coincided with the blood group locus. Further study found that patients with type A blood had a significantly higher risk of respiratory failure as a result of COVID-19 compared to people with other blood types, and type O blood was protective. In summary, the study identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with COVID-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. Previously, non-genetic studies have implicated the involvement of ABO blood groups in COVID-19 susceptibility. While the findings do not prove a blood type connection, it appears to be a significant signal for a group that is of higher risk.
June 22, 2020
Nanoparticle decoys soak up SARS-CoV-2
In a novel approach to fighting infection, instead of targeting the virus, researchers at the University of California San Diego used nanoparticles coated with cell membranes extracted from lung epithelial cells and macrophages. The research was published in the peer-reviewed journal Nano Letters on June 17, 2020. These nanoparticles, or nanosponges, act as biological mimics or decoys to which the virus would attach instead of the host cell. The nanosponges are a thousand times smaller than the width of a human hair and covered with cell membranes with the same protein receptors as the cells they impersonate. Researchers found that following incubation with the nanosponges, SARS-CoV-2 virus infectivity in cell culture was reduced by 90% in a dose-dependent manner. One significant advantage of this strategy is that it is unrelated to the virus’ ability to mutate. By presenting a nanoparticle decoy, this platform would be effective against any mutation or any virus that targets the same host cell. Researchers plan to evaluate the efficacy of these nanosponges in animal platforms in the upcoming months. The efficacy and safety in humans of this futuristic therapy have not been demonstrated.
June 19, 2020
Antibody cocktail to SARS-CoV-2 to prevent rapid mutational escape
Monoclonal antibodies to treat COVID-19 are being developed. However, there is a concern that resistance could develop quickly because of the virus's ability to mutate. A report published in Science, June 15, 2020, studied the problem of resistance. The authors showed in a live-virus model that resistance developed to a single antibody within a few generations. They then identified several pairs of antibodies, one pair to overlapping regions of the receptor binding domain (RBD) and a pair that bound distinct and non-overlapping regions of the RBD. They found resistance developed when there was overlap between the areas bound by the antibody. However, resistance did not develop when the antibodies targeted distinct regions, presumably because this would require the unlikely occurrence of simultaneous viral mutations at two distinct genetic sites. These results suggest that an antibody cocktail targeting non-overlapping regions of the viral RBD, rather than a single antibody may be superior.
June 18, 2020
Comorbidities increase death by a factor of 12 in COVID-19 cases
The June 15 early release issue of the US Centers for Disease Control, Morbidity and Mortality Weekly Report, describes demographic characteristics, underlying health conditions, symptoms, and outcomes among 1,320,488 laboratory-confirmed COVID-19 cases as of May 30, 2020. Overall, 184,673 (14%) patients were hospitalized, 29,837 (2%) were admitted to an intensive care unit (ICU), and 71,116 (5%) died. Among 287,320 (22%) of cases with data on individual underlying health conditions, the most common underlying health conditions were: cardiovascular disease 32%, diabetes 30%, and chronic lung disease 18%. Hospitalizations were 6 times higher and deaths 12 times higher among those with reported underlying conditions compared to those who reported no underlying conditions. The CDC feels that the findings highlight the need for continued community mitigation strategies, especially for the vulnerable populations.
June 17, 2020
Dexamethasone reduced deaths among patients with severe COVID-19
An Oxford University news release dated June 16, 2020, reported positive results of a clinical trial of 6425 patients with severe COVID-19. Patients were randomly assigned to receive either dexamethasone 6 mg once per day either by mouth or intravenous injection for 10 days (n = 2104) or usual care alone (n = 4321). Dexamethasone reduced the deaths by 1/3 in ventilated patients and by 1/5 in patients receiving oxygen only. Both results were highly statistically significant. Based on these results, one death would be prevented by treatment of 8 ventilated patients or about 25 patients requiring oxygen alone. There was no benefit among those patients who did not require respiratory support. In the news release, Peter Hornby, professor of emerging infectious disease Nuffield Department Population Health, University of Oxford, and one of the chief investigators for the trial said “dexamethasone is the first drug to show improved survival and COVID-19.” It is important to note that the full data from the study have not yet been published or subjected to peer review, but outside experts immediately embraced the results. Patrick Vallance, the U.K. government’s chief scientific adviser, called the result “tremendous news” and “a ground-breaking development in our fight against the disease.” Scott Gottlieb, a former commissioner of the U.S. Food and Drug Administration, called it “a very positive finding.”
June 16, 2020
New-onset diabetes and COVID-19
A letter published in the New England Journal of Medicine and signed by an international group of 17 leading diabetes experts involved in the CoviDiab Registry project warned that COVID-19 may trigger new-onset diabetes. The goal of the registry is to establish the extent and characteristics of new-onset diabetes in patients with COVID-19. Clinical observations so far have shown a bidirectional relationship between COVID-19 and diabetes. Of patients who died with COVID-19, 20 to 30% have been reported to have diabetes. On the other hand, new-onset diabetes and atypical metabolic complications of pre-existing diabetes have been observed in people with COVID-19. It's not clear how SARS-CoV-2 impacts diabetes. One possible mechanism involves the angiotensin-converting enzyme 2 (ACE2) protein that binds SARS-CoV-2, allowing the virus to enter human cells. ACE2 is located in many organs involved in glucose metabolism such as the pancreatic beta cells, small intestine, adipose tissue, and kidneys.
June 15, 2020
FDA encourages physicians to use CURE ID program and app to report novel uses of existing drugs in the fight against COVID-19
Health care professionals have long been able to prescribe a legally marketed drug for an unapproved use if they judge the drug is medically appropriate for a given patient. However, unless this prescribing is done within the context of a formal drug trial, the success or failure of such use rarely becomes known to the medical and scientific communities. Thus, in 2013, the FDA and the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH), implemented the voluntary CURE ID program, which created a straightforward way for clinicians to report the results of unapproved use in individual patients.The deidentified data are aggregated by disease and are available for users to browse.The program is intended to streamline the identification of drug candidates for research studies, rather than being part of the formal drug approval process. Recently, the CURE ID program, including its free app, was updated to make it easier to report COVID-19 data and hopefully identify potentially effective new therapies.
June 12, 2020
Striking decline in emergency department visits during the early parts of the pandemic
The COVID-19 pandemic has had a significant impact on the number of visits to the emergency room in the United States. A report published by the CDC in the Morbidity and Mortality Weekly Report on June 3, 2020, showed there was a decline in emergency visits by 42% during the early COVID-19 pandemic. The mean number of visits per week during the time frame from March 29 to April 25, 2020, was 1.2 million. Over the comparable time frame the previous year, March 31 to April 27, 2019, there were 2.2 million visits per week. The proportion of infectious disease related visits, however, was four times higher during this time period. The decreases were especially pronounced for children and females, and also in the Northeast part of the country. Visits for many conditions, including abdominal pain and other gastrointestinal symptoms, nonspecific chest pain and acute myocardial infarction, and high blood pressure decreased during the pandemic, raising the concern that some individuals may be delaying care for conditions that might result in additional mortality if left untreated.
link to the study: https://www.cdc.gov/mmwr/volumes/69/wr/mm6923e1.htm?s_cid=mm6923e1_w
June 10, 2020
COVID-19 deaths rates put in perspectives
The New York Times reviewed the numbers of deaths in 25 cities and regions around the world during their most devastating months of the outbreak, setting those figures against their normal mortality levels, and then compared the increases to other natural disasters in history.
Increase in deaths during peak month compared to normal years:
- 7.3x 1918 Spanish flu in Philadelphia
- 6.7x COVID-19 in Bergamo, Italy
- 5.8x COVID-19 in New York City
- 4.0x COVID-19 in Lima, Peru
- 2.4x Hurricane Katrina in New Orleans
- 1.05x bad flu season in New York City
June 5, 2020
Hydroxychloroquine study retracted
Several authors of a study recently published in The Lancet retracted their article from the publication. The data sources of the study, which appeared to show ineffectiveness of hydroxychloroquine or chloroquine for treatment of COVID-19, were called into question following publication. Three authors of the paper then attempted to have an independent 3rd party review the data and analysis, but these peer reviewers were not given access to the full dataset, leading the authors to retract the paper.
June 5, 2020
A case of COVID-19 with long duration of viral shedding
A May 23 letter to the editor of the Journal of Microbiology, Immunology and Infection describes a case of COVID-19 with the longest reported duration of viral shedding. The median duration of viral shedding for COVID-19 has been reported to be 11 to 20 days and the longest period previously reported was 49 days. This case report was of a 59-year-old woman, diagnosed with COVID-19 in Wuhan, who has been found to have an intermittently positive SARS-CoV-2 RNA PCR test for 72 days after disease onset. The patient had been symptom-free since the first week of her hospital stay and shown to have antibodies to SARS-CoV-2 from 38 days after disease onset. However, multiple RNA PCR tests were intermittently positive out to 72 days. The case report did not contain evidence on whether the positive PCR tests were due to the presence of transmissible virus or simply residual viral fragments.
June 4, 2020
First Phase 1 Trial of COVID-19 Antibody Drug
Eli Lilly this week began the first phase-1 trial of a monoclonal antibody drug specific for the SARS-CoV-2 virus. The antibody duplicates one of 550 different antibodies found using a new screening technique in the blood of a patient who recovered from COVID-19.
link to the announcement: https://www.biopharmadive.com/news/eli-lilly-abcellera-coronavirus-antibody-drug-first-trial/578980/
June 3, 2020
Timing of the COVID-19 test and the variability of false-negative results
In a study published in the Annals of Internal Medicine, May 13,2020, researchers at Johns Hopkins University analyzed the results from seven previously published studies on RT-PCR test performance and found that the probability of a false-negative result varied significantly with the timing of the test. Dates of testing ranged from the date of infection (the date of exposure), to the onset of symptoms (typically on day 5), and then dates after symptom onset. They discovered that the average probability of a false-negative result was 100% on day 1 of being infected, 67% on day 4, 38% on the day of symptom onset, and 20% (the lowest false-negative rate) on day 8. After day 8, the probability of a false-negative result started to increase again. Therefore, the lowest false-negative rate was 8 days after exposure and 3 days after the typical onset of symptoms. The authors concluded that this may be the optimal time for testing if the goal is to minimize false-negative results. They emphasized that care must be taken in interpreting RT-PCR test results for SARS-CoV-2 infection, particularly early in the course of the infection. If clinical suspicion is high, infection should not be ruled out on the basis of test results alone. Researchers advised doctors to consider the timing of the testing when interpreting negative results, especially for individuals likely to have been exposed and who have symptoms consistent with COVID-19. They concluded that when the pretest probability of infection is high the post-test probability remains high, even with a negative test result. Furthermore, if testing is done immediately after exposure, the test result provides no additional information about the likelihood of infection. The authors stated that research into higher sensitivity approaches is critical.
link to the study: https://www.acpjournals.org/doi/10.7326/M20-1495
June 2, 2020
What sewage can tell us about the spread of COVID-19
Researchers have found large amounts of SARS-CoV-2 RNA, the genetic material for COVID-19, are excreted in the stool. Finding the viral signature of COVID-19 in sewage has allowed scientists to correlate the presence and amount of virus with disease spread and severity. Analysis of sewage can be a tool for disease surveillance and offers an easier way to gain a broader perspective of the pandemic without having to sample and test every person. In an article published in Smithsonian Magazine on May 14, 2020, Catherine J. Wu, a Boston-based science journalist and PhD in microbiology and immunology from Harvard University, discusses the recent research on how waste water can help track the spread of the COVID-19 virus, and the possible health implications of viral shedding in the feces, which then makes its way into the waste water system.
June 1, 2020
In New York City, household size may be a more important determinant of COVID-19 infection rate than population density
Throughout the United States and even within the same city, the number of confirmed COVID-19 cases relative to population size has varied greatly. It is important to know which factors drive this variation because this has important policy implications on how to contain the epidemic. A statistical study (published in preprint in medRxiv on May 20, 2020; not yet peer reviewed) of this variation across New York City used available data to investigate these factors by ZIP code.The study found that when taking into account important factors such as population density, average household size, percentage of population below poverty line, and percentage above age 65, it was average household size that emerged as the most important variable correlating with rate of confirmed cases. The percentage of population above age 65 as well as the population below the poverty line were additional indicators that impacted the case incidence rate. Interestingly, contrary to common belief, population density itself did not have a significant impact on the case rate in a given ZIP code. In fact, when the other factors were taken into account, the study found that population density and case incidence were negatively correlated. However, the study used 2018 statistical data that did not take into account any changes in population during the outbreak. It also was not clear how nursing homes and their residents were classified for the purposes of this study, which could have affected study results.
link to the study: https://www.medrxiv.org/content/10.1101/2020.05.25.20112797v1.full.pdf+html
May 29, 2020
Article was retracted June 4, 2020.
No benefit of hydroxychloroquine or chloroquine alone or with macrolides in large multinational retrospective database study
A large, multinational study that analyzed the hospital outcomes for patients with COVID-19 treated with chloroquine or hydroxychloroquine alone or in combination with macrolides was published in the journal Lancet on May 22, 2020. A multinational registry comprising data from 671 hospitals on six continents was was analyzed. Data included patients hospitalized between December 20, 2019 and April 14, 2020, with a positive laboratory finding of SARS-CoV-2. The registry yielded the data from 96,032 patients for inclusion in the study; 14,888 patients received one of the treatments of interest within 48 hours of diagnosis and 81,114 patients were in the control group who did not receive chloroquine or hydroxychloroquine alone or in combination with macrolides. Outcomes yielded no evidence confirming benefit of hydroxychloroquine or chloroquine when used alone or with a macrolide in terms of in-hospital outcomes for COVID-19. The study showed an association of each of these drug regimens with reduced in-hospital survival and increased frequency of ventricular arrhythmias when compared to the control group. Due to the retrospective observational study design, the possibility of unmeasured confounding factors cannot be excluded. One such possibility is that clinicians treated sicker patients with the drugs. The authors concluded that "randomized clinical trials will be required before any conclusion can be reached regarding benefit or harm of these agents in COVID-19 patients." The authors also stated that "these findings suggest that these drug regimens should not be used outside of clinical trials."
May 27, 2020
Autopsy study of lungs from patients that died from COVID-19
An autopsy study on the lungs of COVID-19 patients found that the coronavirus that causes COVID-19 invades the endothelial lining of the blood vessels, promoting blood clots. The study published online in The New England Journal of Medicine on May 21, 2020, examined the morphologic and molecular features of lungs obtained during autopsy from patients who died from COVID-19 and compared them to lungs from patients who died from influenza and with lungs from age-matched uninfected controls. The lungs from patients with COVID-19 showed distinctive vascular features and severe endothelial injury. Histologic analysis of pulmonary vessels in patients with COVID-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times more prevalent in patients with COVID-19 than in patients with influenza. Also, the study found the lungs from patients with COVID-19 had significant new vessel growth through a mechanism of intussusceptive angiogenesis. The study also examined and found significant differences in the expression of inflammation and angiogenesis related genes in the the lung tissue from patients who died from COVID-19 and influenza A (H1N1).
link to the study: https://www.nejm.org/doi/full/10.1056/NEJMoa2015432
May 22, 2020
The airborne lifetime of small speech droplets and their potential importance in SARS-CoV-2 transmission
A study published on May 13, 2020, by the Proceedings of the National Academy of Sciences of the United States of America (PNAS) demonstrated that normal human speech emits droplets capable of lingering in the air. Researchers used lasers to emit an intense sheet of light to visualize bursts of speech droplets produced when subjects spoke the words "stay healthy." This light-scattering method provides visual evidence for speech droplet emission and also assesses their airborne lifetime. This method is particularly sensitive in measuring speech droplets with diameters less than 30 micrometers, which could remain airborne for longer than the larger droplets that have typically been the subject of research. They estimated that 1 minute of loud speaking generates at least 1000 virion-containing droplet nuclei that remain airborne for more than 8 minutes. Speech droplets generated by asymptomatic carriers are increasingly considered a likely mode of disease transmission. This direct visualization demonstrates how normal speech generates airborne droplets that can remain suspended for tens of minutes or longer and are eminently capable of transmitting disease in confined environments.However, it should be noted that this study does not address actual COVID-19 transmission.
link to the study: https://www.pnas.org/content/early/2020/05/12/2006874117
May 21, 2020
The CDC's advice for caring for someone sick at home
The Centers for Disease Control and Prevention (CDC) has recently published guidelines on caring for someone with COVID-19 at home or in a non-healthcare setting. The advice pertains to caring for people who are symptomatic with COVID-19 and for people who are asymptomatic but have tested positive. The recommendations are extensive and detailed. CDC provides helpful strategies on how to meet the basic needs of a person who is sick. CDC also identifies symptoms that may require emergency medical attention. CDC details ways caregivers can protect themselves.In the document, instructions can be found on how to limit contact with the sick person, how to handle meals, and when a sick person or caregiver is to wear face coverings or use gloves. Advice on handwashing, bathroom use, cleaning and disinfecting around the house, and doing the laundry is given. CDC also provides guidance on how to discontinue home isolation.
link to CDC guidance: https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/care-for-someone.html
May 20, 2020
Understanding immunity to SARS-CoV-2
To better understand the body's immune response to SARS-CoV-2, researchers at La Jolla University studied the cellular immune response in a group of 20 adults who had recovered from COVID-19. In the study that was published online in Cell on May 14, 2020, the researchers found there was a robust cellular immune response to the virus. The researchers chose to study people who had a mild to moderate disease course that didn't require hospitalization to provide a benchmark for what a normal immune response looks like. The immune system recognized the virus in many ways with both humoral (antibody) and cellular (T-cell) immunity. This helped dispel fears that the virus may elude efforts to create an effective vaccine. They found robust T-cell response to not only the spike protein but to other proteins as well, speculating that it might be good to have multiple epitopes in a vaccine candidate rather than just spike protein. Interestingly, they detected SARS-CoV-2−reactive CD4+ T cells in ~40-60% of unexposed individuals (testing samples taken prior to the current pandemic), suggesting cross-reactive T cell recognition between circulating ‘common cold’ coronaviruses and SARS-CoV-2 although it is unknown whether and to what extent these may be protective.
link to the study: https://www.cell.com/cell/fulltext/S0092-8674(20)30610-3
May 19, 2020
COVID-19: Transmission explained
In a recent blog post, "The Risks-Know Them-Avoid Them," Erin S. Bromage, PhD, Associate Professor of Biology at the University of Massachusetts Dartmouth, explains the science of a contagious dose, where and how the virus spreads, and which environments are the riskiest. Dr. Bromage does an excellent job of translating data and findings into prose that non-scientists can more readily understand. Hopefully, a better understanding of how the COVID-19 virus spreads will help individuals make decisions about how to avoid becoming infected with the virus.
link to the blog post: https://www.erinbromage.com/post/the-risks-know-them-avoid-them
May 18, 2020
Promising COVID-19 vaccine using inactivated virus
Purified inactivated viruses have been traditionally used in vaccine development, providing safe and effective vaccines to prevent diseases caused by viruses such as poliovirus and influenza virus. In a paper published in Science on May 6, 2020, a group of researchers in China reported on a purified, inactivated SARS-CoV-2 vaccine (PiCoVacc) that produced neutralizing antibodies in mice, rats, and non-human primates. Antibodies were shown to neutralize 10 representative strains of the virus. When later infected with SARS-CoV-2, the rhesus macaques (a non-human primate species that shows a COVID-19–like disease caused by SARS-CoV-2 infection) who received a 6-microgram dose showed complete protection. The vaccine did not elicit any observable or biochemical adverse effects. Notably, there was no evidence of a phenomenon known as antibody-dependent infection enhancement, which previous reports have raised as a concern.
The authors said, "These results suggest a path forward for clinical development of SARS-CoV-2 vaccines for use in humans." Clinical trials with PiCoVacc are expected to begin later this year.
link to the study :https://science.sciencemag.org/content/early/2020/05/06/science.abc1932
May 15, 2020
Higher concentrations of angiotensin-converting enzyme 2 (ACE2) in men
Men are more vulnerable to COVID-19 than women.There is a preponderance of men compared with women testing positive for COVID-19. A report from Italy found that 70% of patients that died of COVID-19 were men.
A study done on several thousand patients with heart failure in 11 European countries found significantly higher concentrations of angiotensin-converting enzyme 2 (ACE2) in the blood of men than women ACE2 is a receptor on the surface of healthy cells. Coronavirus binds to this receptor, allowing the virus to infect healthy cells.The strongest predictor of elevated concentrations of ACE2 was male sex.The study also found that patients receiving ACE inhibitors or angiotensin receptor blockers (ARBs) did not have higher plasma concentrations of ACE2. This finding of higher concentrations of ACE2 may explain why men are more vulnerable to COVID-19 than women. The study was published online in the European Heart Journal on May 10, 2020.
link to the study :https://academic.oup.com/eurheartj/article/41/19/1810/5834647
May 13, 2020
Pediatric multisystem inflammatory syndrome potentially associated withCOVID-19
Boston Children’s Hospital has published a brief overview of a recently reported pediatric syndrome that may be related to COVID-19. In recent weeks, reports have come in from Europe and the Eastern US of a small number of seriously ill children with a multisystem inflammatory illness termed Pediatric Multisystem Inflammatory Syndrome (PMIS). Reports are still fragmentary and the syndrome is variably described, but patients seem to have fever, varying degrees of organ dysfunction, and multiple laboratory markers of severe inflammation. The syndrome sometimes progresses to significant shock, requiring vasoactive drugs and mechanical ventilation.
There seems to be a connection to the current COVID-19 pandemic in that a number of the affected children have a positive PCR test for SARS-CoV-2, and a similar number of children who are antigen-negative have positive antibody test results. However, a significant number of cases have neither. The connection remains unclear.
The syndrome also bears some relationship to Kawasaki disease, with some children fulfilling all or some criteria for Kawasaki. However, although myocarditis is common in children with PMIS, coronary artery involvement (including coronary artery aneurysms), a hallmark of Kawasaki, does not seem to be reported.
Although rare, the cases are quite severe and seem to respond to treatments, such as anticoagulation, IV immunoglobulin, IL-1 or IL-6 blockade, and corticosteroids. Clinicians should be alert for these manifestations and refer potentially affected children to a specialty center.
link to the overview: https://discoveries.childrenshospital.org/covid-19-inflammatory-syndrome-children/
May 12, 2020
Genetic variability may affect susceptibility to COVID-19
Analysis of the known genetic variations within the human immune system suggests there are differences that could influence the ability to respond to SARS-CoV-2 infection. Immune variability may explain why some people have severe symptoms while others have only mild symptoms or are asymptomatic.
HLA proteins bind to peptides that are foreign to the body, marking the foreign peptide and activating the immune system to kill the infected cell. The more peptides that a virus has that can be detected by the HLA system, the stronger the immune response. Some HLA proteins may be better tailored to SARS-CoV-2 and therefore be a factor in how effectively the immune system can fight the virus.
Researchers analyzed the human leukocyte antigen (HLA) system to determine which HLA alleles most effectively bound coronavirus peptides. The paper is posted online in the Journal of Virology as an accepted manuscript. The authors used computer modeling with a known database of the proteins that make up SARS-CoV-2 and then used algorithms to predict how well different HLAs bind to these coronavirus proteins. Of the 145 different HLA alleles, researchers identified the 3 best (A*02:02, B*15:03, C*12:03) and the 3 worst (A*25:01, B*46:01, C*01:02) at presenting viral antigen. The model predicted that one HLA allele, B*46:01, was particularly bad in presenting antigen of both SARS-CoV-2 and SARS-CoV. The results were then compared to those of previous studies. The comparison revealed that people with this allele (B*46:01) tended to have more severe SARS infections and higher viral loads. The results may help explain the wide disparity in clinical presentations of COVID-19, identify high-risk individuals, and prioritize those individuals for vaccination.
link to the study: https://jvi.asm.org/content/early/2020/04/16/JVI.00510-20
May 11, 2020
A combination of antiviral drugs improves outcome in COVID-19 patients
A study published in online in The Lancet, May 8, 2020, enrolled 124 hospitalized patients in Hong Kong with a SARS-CoV-2–positive baseline nasopharyngeal swab. The multicenter, randomized (2:1), open-label study compared the combination of lopinavir and ritonavir, ribavirin, and three doses of 8 million international units of interferon beta-1b to a control group given lopinavir and ritonavir alone. The median time from symptom onset to enrollment in the study was 5 days. The primary endpoint of the study was the time to a nasopharyngeal swab that was negative for SARS-CoV-2 virus by reverse transcription-PCR. The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days) than the control group (12 days; p = 0.001). There was also a significant improvement in symptoms and reduction in length of hospital stay. Adverse events were not different between the 2 groups and were generally mild and self-limiting. Very few patients required ICU care and only 1 patient (control group) required intubation and ventilation support. There were no deaths. This study found that treatment with a combination of antiviral therapies was effective in shortening the duration of virus shedding in patients with mild to moderate COVID-19. The authors discussed the benefit of rendering viral loads negative, thereby reducing infectiousness of the patient. They recommended a subsequent placebo-controlled study to establish the efficacy and safety of this combination therapy.
May 8, 2020
SARS-CoV-2 was already spreading in France in late December 2019
RT-PCR testing on a stored sputum sample of a patient hospitalized in France in late December with severe acute respiratory syndrome was found to be positive for coronavirus. This result revealed that the epidemic in France started much earlier than originally believed. This finding was published online in the International Journal of Antimicrobial Agents on May 3, 2020. The researchers examined the medical records of all patients admitted to their ICU with influenza-like illness between December 2, 2019, and January 16, 2020 (n = 124). They excluded patients with a positive PCR assay for other respiratory viruses and excluded patients with non-typical–COVID medical records. Nasopharyngeal samples of the remaining 12 patients were tested. One sample was positive for COVID-19. The positive sample belonged to a 42-year-old Algerian immigrant with no history of travel or link to China. He presented to the emergency ward on December 27, 2019, with haemoptysis, cough, chest pain, headache, and fever, evolving for 4 days. It is notable that one of his children had an influenza-like illness prior to the onset of his symptoms. The paper includes the medical history, clinical presentation, laboratory findings, radiological findings, and clinical course of his illness. Researchers concluded the disease was already spreading among the French population at the end of December 2019.
link to the study: https://www.sciencedirect.com/science/article/pii/S0924857920301643
May 7, 2020
Epidemiological study of the transmission of SARS-CoV-2 in close contacts
An epidemiological study of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China published in The Lancet, provides information on the natural history and transmissibility of the SARS-CoV-2 virus. Using a large primary data set, researchers were able to shed light on the incubation times, time to recovery, and transmissibility of the virus. Interestingly, they found the secondary attack rate in close contacts to average around 7%. Transmission between very close contacts, such as individuals sharing a household, was less than one in six contacts (ie, secondary attack rate of 11 to 15%).
The study highlighted the finding that children were as likely to become infected as adults. Although children frequently do not get sick, they should not be overlooked as a significant source of transmission. The study also demonstrated the value of contact-based surveillance in reducing the spread of the SARS-CoV-2 virus in the community.
link to the study: https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(20)30287-5.pdf
May 6, 2020
Do ACE inhibitors or ARBs worsen outcome in COVID-19?
Concern whether angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) worsen the outcomes in patients with COVID-19 has led to much research into this question. The coronavirus that causes COVID-19 infects lung cells by binding to the membrane-bound form of angiotensin-converting enzyme 2 (ACE2). This knowledge led to speculation that these drugs could be harmful in patients with COVID-19. An editorial in The New England Journal of Medicine on May 1, 2020, discusses the results of three recent database studies that found no adverse outcomes in patients taking ACE inhibitors or ARBs.
link to the editorial: https://www.nejm.org/doi/full/10.1056/NEJMe2012924
May 5, 2020
Large-vessel strokes in young and middle-aged patients with COVID-19
The New England Journal of Medicine reported on April 28, 2020, on five cases of large-vessel stroke in patients 50 years of age or younger infected with COVID-19. The youngest was a 33-year-old woman.The report included allstroke patients younger than 50 at the Mount Sinai health system in New York City during a two-week period in late March and early April. The rate was nearly seven times the number of stroke patients in that age group during any average two-week period over the previous year and indicates a very strong correlation with COVID-19.
link to the article:https://www.nejm.org/doi/full/10.1056/NEJMc2009787
May 4, 2020
COVID-19, a disease of the nicotine cholinergic system?
In China, it is estimated the prevalence of smoking is 31.3 %, yet data from case series analysis in China reveals that only 6.5 percent of the patients hospitalized with COVID-19 were smokers. Interestingly, this finding suggests there are potentially beneficial effects of nicotine. An editorial published in Toxicology Reports, available online 30 April 2020, discusses the relationship between the cholinergic and immune systems and how nicotine can influence the dynamics and potentially be a treatment for COVID-19.
April 30, 2020
Hypoxemia without dyspnea, new phenomenon described in COVID-19 patients
Alarming hypoxia without the expected symptom of dyspnea was discussed in an online article written by Jennifer Couzin-Frankel in April 28, 2020, Science news. In the article, she reported on this phenomenon, current research, and thinking about its cause and treatment. She drew attention to one small but thought-provoking study done in Brazil by Elnara Marcia Negri and colleagues (see below link to medrxiv preprint posted April 20, 2020). That study was a series of 27 consecutive patients with respiratory failure due to COVID-19 who were treated with heparin and had a better rate of positive outcomes then reported elsewhere. Dr Negri, a pulmonologist, proposed that disseminated intravascular coagulation (DIC) or microemboli in small blood vessels in the lungs leads to perfusion mismatch, or shunting, causing hypoxemia. Pulmonary compliance appears to be preserved and patients are able to expel carbon dioxide. Respiratory drive is affected by the carbon dioxide levels in the blood stream, not the levels of oxygen.This explains why these patients do not feel short of breath with low oxygen levels alone.
link to the Science article: https://www.sciencemag.org/news/2020/04/why-don-t-some-coronavirus-patients-sense-their-alarmingly-low-oxygen-levels
April 29, 2020
Yale University School of Public Health finds saliva samples promising alternative to nasopharyngeal swab
Yale University School of Public Health conducted a study comparing saliva and nasopharyngeal samples in 44 patients hospitalized with COVID-19 and 98 health care workers with occupational exposure to COVID-19 patients.The study was reported by Michael Greenwood on April 24, 2020, in Yale News. Although the study was small and limited, it showed great promise for using saliva samples in place of the current standard of using nasopharyngeal swabs.The study found that saliva yielded greater detection sensitivity and consistency throughout the course of infection when compared with patient-matched nasopharyngeal samples.There was also less variability in self-sample collection.This can be transformative in testing for COVID-19. Saliva testing is noninvasive, does not rely on nasopharyngeal swabs, and can be easily self-administered and therefore negates the risks, bottlenecks, and use of resources such as swabs and personal protective equipment (PPE), that direct patient contact and current testing practices use. The study has not been subject to peer review. The research results are currently available on the pre-print server medRxiv.
link to the study: https://www.medrxiv.org/content/10.1101/2020.04.16.20067835v1.full.pdf+html
April 28, 2020
WHO issues guidance on "immunity passports"
The World Health Organization (WHO) issued a brief warning (April 24, 2020) that there is no evidence that the presence of antibodies to the SARS-CoV-2 virus protects against reinfection and development of COVID-19 disease. The WHO cautions governments against using antibody testing to guide them on relaxing social measures and issuing “immunity passports” or “risk free certificates” that enable individuals to assume they are protected against re-infection. There are no guarantees that individuals who have had COVID-19, or have tested positive for antibodies, can return to work or travel risk-free. “At this point in the pandemic, there is not enough evidence about the effectiveness of antibody-mediated immunity to guarantee the accuracy of an 'immunity passport' or 'risk-free certificate,’ ” WHO said.
The WHO also emphasized that laboratory tests that detect antibodies to SARS-CoV-2 in people, including rapid immunodiagnostic tests, need further validation to determine their accuracy and reliability. Immunodiagnostic tests may falsely categorize people in two ways. The first is that they may falsely label people who have been infected as negative (false-negative) and the second is that people who have not been infected are falsely labelled as positive (false-positive). Each antibody test will need to have its accuracy (false-negative and false-positive rates) determined. Both errors have serious consequences and will affect control efforts.link to the WHO announcement: https://www.who.int/news-room/commentaries/detail/immunity-passports-in-the-context-of-covid-19
April 27, 2020
Characteristics of patients hospitalized with COVID-19
A large case series of 5700 sequential patients admitted to New York City area hospitals between March 1 and April 4, 2020 with confirmed COVID-19 was published in JAMA Network online April 22, 2020. The study provides a comprehensive description of their presenting characteristics, comorbidities, and outcomes. Most notable is that many patients also had other medical problems such as high blood pressure (57%), obesity (42%) and diabetes (34%). At triage, only 31% had a fever. The study focused on the 2643 patients who were either discharged (2090) or died (553) during the study period. In this group of patients who reached these outcomes, 320 had received mechanical ventilation of whom 88% died, of those over age 65 who received mechanical ventilation 97% died. It should be noted that 3066 patients remained hospitalized at the time the outcome data was collected, and this certainly includes a number of patients over the age of 65 who required mechanical ventilation and had survived to that time.link to the study: https://jamanetwork.com/journals/jama/fullarticle/2765184
April 24, 2020
Additional data on antimalarials for COVID-19
The initial enthusiasm and early embrace of hydroxychloroquine has been tempered by concerns about efficacy and potential adverse effects.Several recent studies and reports are summarized (and mentioned below) in an April 21st online review article in Science (1), which highlights reasons for these concerns:
A retrospective analysis (2) posted on April 21 of 368 hospitalized veterans treated with hydroxychloroquine (HCQ), HCQ + azithromycin (AZ), or no HCQ, showed no benefit in terms of reduced mortality or need for mechanical ventilation in the groups receiving HCQ alone or in combination with AZ. Rates of death in the HCQ, HCQ + AZ, and no HCQ groups were 27.8%, 22.1%, and 11.4%, respectively. The group receiving only HCQ had an increase in all-cause mortality.
A Mayo Clinic Proceedings publication on April 7 (3) discussed the mechanism of QTc prolongation by chloroquine and hydroxychloroquine and provided guidance on monitoring for and avoiding this potentially lethal complication. The paper details the pharmacology of chloroquine and hydroxychloroquine, pointing out that both drugs block KCNH2-encoded HERG/Kv11.1 potassium channel, which can prolong the QTc interval, increasing the risk of dangerous arrhythmias (eg, torsades de pointes) and sudden cardiac death. The authors list risk factors and recommend screening for these before treatment, correcting modifiable risk factors, and monitoring for QTc prolongation during treatment.
A study at the New York University School of Medicine (4) looked at the change in the QT interval in 84 adult patients with SARS-CoV-2 infection treated with hydroxychloroquine + azithromycin. In 30% of patients, QTc increased by > 40ms. In 11% of patients, QTc increased to > 500 ms, representing high risk for arrhythmia.
In Brazil, a blinded, randomized clinical trial (5) of high- and low-dose chloroquine (given with ceftriaxone and azithromycin) in people hospitalized for COVID-19 was halted early after only 81 patients were enrolled when investigators found more deaths in the group getting the higher of the two doses.
1. Servick K: Antimalarials widely used against COVID-19 heighten risk of cardiac arrest. How can doctors minimize the danger? Science April 21, 2020. https://www.sciencemag.org/news/2020/04/antimalarials-widely-used-against-covid-19-heighten-risk-cardiac-arrest-how-can-doctors
2. Magagnoli J, Siddharth N, Pereira F, et al: Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. April 23, 2020. PREPRINT medRxiv available at https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v2. doi: https://doi.org/10.1101/2020.04.16.20065920
3. Giudicessi JR, Noseworthy PA, Friedman PA, et al: Urgent guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19). Mayo Clin Proc 2020 Apr 7 doi: 10.1016/j.mayocp.2020.03.024 [Epub ahead of print]
4. Chorin E, Dai M, Schulman E, et al: The QT interval in patients with SARS-CoV-2 infection treated with hydroxychloroquine/azithromycin. April 3, 2020. PREPRINT medRxiv available at https://www.medrxiv.org/content/10.1101/2020.04.02.20047050v1. doi: https://doi.org/10.1101/2020.04.02.20047050
5. Silva Borba MG, de Almeida Val F, Sampaio VS, et al: Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study). April 16, 2020. PREPRINT medRxiv available at https://www.medrxiv.org/content/10.1101/2020.04.07.20056424v2 https://doi.org/10.1101/2020.04.07.20056424
April 23, 2020
Proposed national COVID-19 testing action plan
The Rockefeller Foundation has provided a comprehensive plan (dated 4/21/2020-see link below) to reopen workplaces and communities based on testing for COVID-19 and close follow-up of positive test results. The goal of the plan is to build a state-led national program of COVID-19 testing that supports reopening the economy through the goals of workforce monitoring, early detection of recurrent outbreaks, and diagnostic and home testing. The plan has 3 major components:
- Dramatically expand COVID-19 testing from the current 1 million tests per week to 3 million per week over the next 8 weeks and then to 30 million tests per week over the next 6 months. This will require investing in and bolstering test capacity at national, university, and thousands of small local labs across the country.
- Train and launch an army of healthcare workers to administer the tests and to do contact tracing for those with positive tests.They suggest this be organized around the state public health departments. They propose hiring 100,000 to 300,000 workers who will need to be supported by computer networks linked to many electronic health records.
- Integrate and expand federal, state, and private data platforms to facilitate real-time analyses and disease tracing. This will identify recurrent COVID-19 outbreaks and direct surges in testing volumes and follow-up.
This white-paper provided by the Rockefeller Foundation has many good ideas and is a must read. The massive plan will require integration of many scattered computerized data platforms. All this will need to balance privacy with the need for infection control.
April 22, 2020
Highlighting the importance of coagulation disorders in COVID-19
Thrombotic complications are an emerging issue in patients with COVID-19. It is important to be aware of the significant complications arising from and contributing to the morbidity and mortality of the disease. Dysregulation of the coagulation cascade by the infection creates a prothrombotic state.This can result in disseminated intravascular coagulation, thromboembolism, hemorrhage, or overt clot formation. A paper published online (see below link) for the Journal of Clinical Virology (June 2020), highlights the importance of coagulation disorders in patients with COVID-19 and reviews past experience with severe acute respiratory syndrome coronavirus 1 (Sars-CoV-1) and the Middle East respiratory syndrome coronavirus (MERS-CoV).
link to the study: https://www.sciencedirect.com/science/article/pii/S1386653220301049
April 21, 2020
28,000 missing deaths: tracking the true toll of the coronavirus crisis
A review of mortality data in 11 countries showing that far more people died in these countries than in previous years was reported by Jin Wu and Allison McCann in the New York Times on April 21, 2020. They estimated the excess mortality for each country by comparing the number of people who died from all causes this year with the historical average during the same period. The finding was that at least 28,000 more people have died during the coronavirus pandemic over the last month than the official COVID-19 death counts report. Since most countries report only those COVID-19 deaths that occur in hospitals there are many COVID-19 deaths that are unreported. The 28,000 excess deaths found in this study include deaths from COVID-19 as well as those from other causes, likely including people with other disorders who were not treated as hospitals became overwhelmed. This article suggests that the overall global death toll from COVID-19 will be much higher than the reports of deaths due to COVID-19 confirmed by testing. For impressive graphic presentation of these trends in each country please use the following link to the article.
link to the news article: https://www.nytimes.com/interactive/2020/04/21/world/coronavirus-missing-deaths.html?smid=em-share
April 20, 2020
60 Percent of Sailors That Tested Positive Are Asymptomatic
A story reported by Idress Ali and Phil Stewart of Reuters on April 16, 2020, reveals a clue about the pandemic. While it is known that patients can be infected and be asymptomatic, posing a risk of transmission, the extent of asymptomatic infection is unknown and may be underappreciated. The Navy’s testing of the entire 4,800 member crew of the carrier Theodore Roosevelt, was 94 % complete. Of the over 600 sailors who tested positive, 60 % were asymptomatic. This figure was presented to reporters in a call with Vice Admiral Phillip Sawyer, deputy chief of naval operations at the center of the Navy’s coronavirus efforts, and commented on in a television interview by Defense Secretary Mark Esper. The article comments that the figure is higher than the 25% to 50% range offered by Dr. Anthony Fauci on April 5. The findings are of marked interest and provide insight to the possible scope of asymptomatic infection.
link to the news article: https://taskandpurpose.com/news/uss-theodore-roosevelt-sailors-coronavirus-asymptomatic
April 17, 2020
Scoring model predicts progression risk in COVID-19
Researchers in China developed a four-factor model based on comorbidity, age, lymphocyte count, and LDH (lactate dehydrogenase) level that predicted which patients did and did not progress with confirmed COVID-19 infections. The model aims to help clinicians identify the optimal therapeutic strategy for a particular patient. The risk model was developed By Dr. Enqiang Qin and colleagues and published online in the journal Clinical Infectious Diseases on April 9, 2020.
Data from 208 consecutive patients was collected retrospectively and analyzed using a multivariate COX regression that identified four factors at presentation, comorbidity, age > 60 years, low lymphocyte count, and high LDH, that were independently associated with progression of COVID-19 illness. Based on these factors, a scoring model was developed to classify individuals in one of three categories:
- Low risk with a 10% chance of progression
- Intermediate risk with a 10 to 40 % risk of progression
- High risk with > 50 % chance of progression
This model will need to be validated in prospective studies to confirm the ability of these risk factors to predict progression of COVID-19.
link to the study: https://academic.oup.com/cid/article/doi/10.1093/cid/ciaa414/5818317
April 16, 2020
Serosurvey by NIH requesting volunteers
To get a clearer picture of the magnitude of the COVID-19 pandemic in the United States, the NIH is enrolling as many as 10,000 volunteers. Individuals with a confirmed history of COVID-19 or current symptoms of COVID-19 are not eligible to participate. “This study will…tell us how many people in different communities have been infected without knowing it, because they had a very mild, undocumented illness or did not access testing while they were sick,” said Anthony S. Fauci, MD, NIAID Director. Researchers will collect and analyze blood samples for antibodies to Sar-CoV-2 S protein. Results will help illuminate the extent to which the virus has spread undetected in the population. Participants will be shipped at-home blood collection kits and provided detailed instructions on collecting a microsample of blood and mailing it back for analysis. People interested in joining the study should contact:firstname.lastname@example.org
April 14, 2020
Why coronavirus death rates can't be summed up in one simple number
Johnathan Fuller, MD, PHD, provides a clear article in which he explains the wider perspective on the ever-shifting COVID-19 statistics. In an April 10, 2020, article in the on-line journal, The Conversation, Dr. Fuller explains why statistics and models differ. His scholarship provides the reader with a framework and perspective to help interpret the large volume of epidemiological information being reported about the COVID-19 pandemic. Making the best decisions on public health policy and individual cases requires deeper understanding of the models than just the numbers alone.
link to the article: Why coronavirus death rates cant be summed up in one simple number
April 10, 2020
Can smart phone apps help beat pandemics?
An interesting article was posted April 9, 2020 by Dr, Francis Collins, Director of the National Institutes of Health (NIH). On the NIH Director's Blog, he discusses enlisting the use of smart phones for contact tracing and notification in fighting the COVID-19 pandemic. Traditional methods involving teams of public health workers speaking to people via phone or in face-to-face meetings is very time consuming. Lost time allows for infection to spread more widely because there is a delay in finding and notifying individuals exposed to the virus. By taking advantage of smart phones' wireless Bluetooth technology, digital tracing can improve the chances of keeping COVID-19 under control. In China, research showed a correlation between the use of contact-tracing apps and what appears to be sustained suppression of COVID-19 infection. Dr. Collins touches on major ethical, legal, and social issues.
link to the blog post: https://directorsblog.nih.gov/author/collinsfs/
April 9, 2020
COVID-19 can affect the heart and present with cardiovascular symptoms. Four very interesting cases
Patients with COVID-19 frequently present with respiratory symptoms that can progress to pneumonia and in severe cases acute respiratory distress syndrome (ARDS) and shock. It is now apparent that COVID-19 infection can affect the heart. Dyspnea is a common presenting symptom with both pulmonary and cardiac involvement and discriminating between cardiac and respiratory etiology can be challenging. Its critical to recognize when cardiac and pulmonary involvement coexist and there are a variety of cardiovascular presentations of COVID-19 infection. Paper published online in Circulation April 3 discusses four cases illustrating this point.
link to the study: https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.120.047164
April 9, 2020
A new antiviral drug heading into clinical trials offers hope for COVID-19 treatment
A new drug called EIDD-2801 shows promise in treating lung damage caused by the novel coronavirus Sars-CoV -2. EIDD-2801, a ribonucleoside analog with antiviral activity on the RNA-dependent RNA polymerase, was developed by researchers at UNC-Chapel Hill Gillings School of Global Public Health. Results from the most recent study were published April 6, 2020 online by the journal Science Translational Medicine. The published study found EIDD-2801 can protect cultured human lung cells infected with SARS-Cov-2. The drug also appears effective in treating other serious coronavirus infections. Experiments with mice found when EIDD-2801 is given 12 to 24 hours after onset of infection with viruses related to COVID-19 lung damage and weight loss were significantly reduced. An added advantage is that the drug can be given orally as opposed to other treatments that must be given intravenously. The ease of treatment offers the potential for treating less ill patients, or for prophylaxis.
link to the study: https://stm.sciencemag.org/content/early/2020/04/03/scitranslmed.abb5883
April 8, 2020
COVID-19 vaccine candidate shows promise, research shows
Interesting news from a story published in ScienceDaily
Scientists at the University of Pittsburgh School of Medicine announced a potential vaccine against COVID-19. The vaccine when tested in mice produced antibodies specific to Sars-CoV-2 at quantities sufficient for neutralizing the virus. The paper detailing the research appeared April 2, 2020 in EBioMedicine, which is published by Lancet. Using groundwork laid during earlier coronavirus epidemics, the vaccine targets the spike protein of the coronavirus. The vaccine is produced using lab-made pieces of viral protein to build immunity. It's the same way the current flu shots work. Researchers use a novel approach to deliver the drug, called a microneedle array, to increase potency. The co-senior author of the study stated that "testing in patients would typically require at least a year and probably longer."
link to news article: https://www.sciencedaily.com/releases/2020/04/200402144508.htm
April 6, 2020
New report finds no benefit from the combination of Hydroxychloroquine and Azithromycin in patients severely ill with COVID-19
A small trial looking at the drug hydroxychloroquine, in combination with azithromycin on patients with severe symptoms found no evidence of strong antiviral activity or clinical benefit from the combination of drugs. There were only eleven patients in the study, eight of the patients had underlying conditions that placed them at poor risk. This trial is too small to allow meaningful statistical analysis or conclusions regarding efficacy or safety of the drugs. However, this report cast doubts about the antiviral efficacy of this combination in patients severely ill with COVID-19 as had been suggested by an earlier French study.
April 6, 2020
CDC recommends the Use of Cloth Face Coverings, Especially in Areas of Significant Community-Based Transmission
A significant portion of people who are infected with coronavirus lack symptoms and even those who eventually develop symptoms can transmit the virus to others before showing symptoms. This means that the virus can spread between people interacting in close proximity—for example, speaking, coughing, or sneezing—even if those people are not exhibiting symptoms. In light of this, the CDC recommends wearing cloth face coverings in public settings where other social distancing measures are difficult to maintain (e.g., grocery stores and pharmacies) especially in areas of significant community-based transmission. Use of simple cloth face coverings will slow the spread of the virus and help people who may have the virus and do not know it from transmitting it to others. Cloth face coverings fashioned from household items or made at home from common materials at low cost can be used as an additional, voluntary public health measure.
It is critical to emphasize that maintaining 6-feet social distancing remains important to slowing the spread of the virus.
The cloth face coverings recommended are not surgical masks or N-95 respirators. Those are critical supplies that must continue to be reserved for healthcare workers and other medical first responders, as recommended by current CDC guidance.
For the full CDC recommendations see: https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/cloth-face-cover.html