Week of August 18th through August 25th
This week we have new information on remdesivir, information on the use of shields as an adjunct to masks, an FDA statement on convalescent serum, and an AMA suggestion on how to apportion testing since demand is expected to out strip resources for the remainder of 2020.
Remdesivir yields statistically, but perhaps not clinically, significant benefit to those with moderate COVID-19
596 patients were randomized to remdesivir 200mg IV on day 1 and then 100mg IV per day for a total of 5 or 10 days. Patients were included if they had a positive PCR within 4 days of randomization and had infiltrates but with an oxygen saturation of >94% on room air. Patients also had to have transaminases of <5X upper limit of normal and a creatinine clearance of >50ml/min. Outcomes included the number of patients discharged by day 14 (original outcome); clinical assessment on a 7 point scale by day 11 was added as the primary outcome during the trial.
The 10-day course did not seem to yield any improvement in clinical status (p=0.18) whereas the 5-day course did (p=0.02). The difference was an odds ratio of 1.65 (CI 95% 1.09-2.48) for improvement.
The authors conclude that “Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance.” The full text can be found here.
A couple of points: 1) This doesn’t mean that remdesivir doesn’t work in more severe disease. We would expect people with more mild disease to benefit less from an intervention since they may have done well anyway. 2) As nicely pointed out by the authors, statistical significance isn’t the same as clinical significance. One can have a statistical difference between two groups that is clinically meaningless. 3) Finally, it doesn't make sense that a 10 day course would be worse than a 5 day course unless remdesivir is doing something untoward. So likely this is likely due to chance, especially since those in the 10 day group got an average of only 6 days of treatment. See the BMJ remdesivir guideline here.
Spinner, CD et al. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients with Moderate COVID-19A Randomized Clinical Trial JAMA. Published online August 21, 2020. doi:10.1001/jama.2020.16349
Shields are additive to masks when it comes to protecting healthcare workers from COVID-19. This is an Indian observational study of 62 community health workers who visited 5880 homes to explain social distancing, quarantine, etc. By report, workers wore masks and maintained social distancing. All workers were also housed in separate rooms in hostels to prevent them from getting infected by contact with the community (so theoretically they only place they would be exposed to SARS-CoV-2 was during their visits to homes). In a 10 day period 12 of these workers (19%) tested positive for SARS-CoV-2. Thereafter, the remaining 50 workers wore both face shields and masks and visited a total of 18,228 homes over a one month period. No community health workers became infected with SARS-CoV-2 during this phase of the study. The full text is available here.
This study suggests that face shields are additive to masks in preventing the spread of COVID-19.
Bhaskar E, Arun S. SARS-CoV-2 Infection Among Community Health Workers in India Before and After Use of Face Shields JAMA. Published online August 17, 2020. doi:10.1001/jama.2020.15586
The FDA has approved the emergency use of COVID-19 convalescent plasma (CCP) for treatment. The salient points are:
The two randomized, controlled studies of CCP were stopped early, therefore did not have the power to prove the effectiveness of CCP. However, both hint at benefit.
Some non-randomized, controlled trials showed benefit and some not.
Retrospective matched cohort studies have been positive but have limitations.
CCP is safe based on a study of 20,000 patients coordinated by the Mayo Clinic (<1% transfusion reaction, <1% thromboembolic events but 3% cardiac events). None of the cardiac or thromboembolic events were deemed to be caused by CCP.
CCP should be tested for SARS-CoV-2 antibodies and should meet a certain level of antibody to be deemed “high titer CCP”. Other units should be labeled as “CCP of low titer”.
The initial dose should be 200 ml but we have no firm experience and dosing should be based on “the prescribing physician’s medical judgement and the patient’s clinical response.”
The complete statement can be found here.
FDA Clinical Memorandum, Emergency Use Authorization for COVID-19 convalescent plasma 23 August 2020. https://www.fda.gov/media/141480/download
The American Medical Association (AMA) has released testing recommendations since testing is likely going to be limited at least through the end of 2020. They point out that the supply of swabs is finally adequate but that reagents, viral transport media, pipette tips and other testing paraphernalia are still in short supply.
They recommend prioritizing testing for high risk individuals:
Patients exhibiting signs/symptoms of COVID-19
Those with a known exposure to COVID-19 (e.g. as in contact tracing).
Those required to have a negative COVID-19 test in order to get needed medical care such as elective surgery, chemotherapy, etc.
Health care workers.
A second tier would be those not at immediate risk of infection including:
Those wishing to travel
Those wishing to attend social engagements
Those returning to work or school.
They emphasize counseling those being tested to stay quarantined until the results are reported, and a negative test is confirmed. The full statement can be found here.
AMA Public Health, Considerations for physicians ordering SARS-CoV-2 PCR diagnostic testing. https://www.ama-assn.org/delivering-care/public-health/considerations-physicians-ordering-sars-cov-2-pcr-diagnostic-testing
Week of August 11th through August 17th
Welcome to the weekly COVID-19 update. This week we have information on two studies about the efficacy of different types of masks in preventing aerosolization of particles, the increase of disease among children, an MMWR article about the mental health effects of COVID-19 and American Academy of Pediatrics guidelines on the reopening of schools. Finally, we are including a link to the CDC website listing the sanitizers that contain methanol and which should be avoided.
Tests of masks: Behind the ear-loop masks are not particularly useful for preventing the aerosolization of particles; data on “neck gaiters” inconsistent.
The first study looked at the effectiveness of different styles of masks at preventing the aerosolization of particles. They had an individual wearing each mask say, “Stay healthy people” and measured the particles produced. There was a control using no mask and each mask was tested 10 times. They found in order of effectiveness:
- N95 masks were the most effective followed by: Surgical masks, 3 layer polypropylene/cotton/polypropylene masks, 2 layer polypropylene/polypropylene, followed by two layer cotton masks.
- Bandanas were the least effective.
- “Neck Gaiters” didn't perform well. This data has been questioned in an unpublished small study using a different methodology.
- A full list can be found here.
A separate trial used the traditional Occupational Safety and Health Administration’s (OSHA) Quantitative Fit Testing Protocol for Filtering Facepiece Respirator to test 29 different “hospital” masks. They found that reused N95 masks treated with ethylene oxide or hydrogen peroxide maintained their effectiveness. The same held true for “expired” masks from 2009 and 2011. However, they also found that surgical masks with “behind the ear” straps were the least effective type of surgical masks (38% filtration efficacy) when compared to masks that tie or use “over-the-head” elastic. Additionally, imported, non-NIOSH approved N95 masks did not perform to the N95 standard (filtering as little as 80% of particles).
Both studies have significant limitations including small numbers. And, the first study was designed as a proof-of-concept of the procedure to measure aerosolization. The takeaway message is that tie masks/over the head masks are better than behind the ear loops; neck gaiters may be counterproductive. If our patients are wondering what masks they should buy, this will provide some guidance.
Fischer, EP et al. Low-cost measurement of facemask efficacy for filtering expelled droplets during speech Science Advances 07 Aug 2020:
eabd3083 DOI: 10.1126/sciadv.abd3083 (from AAAS)
Sickbert-Bennett EE et al. Filtration Efficiency of Hospital Face Mask Alternatives Available for Use During the COVID-19 Pandemic JAMA Intern Med. Published online August 11, 2020. doi:10.1001/jamainternmed.2020.422-1
Mental health disorders including suicidality are increasingly common during the COVID-19 pandemic. This is a study from the CDC that invited 9900 adults to complete a web-based survey of whom 5400 (55%) chose to participate. Of these, 1,729 had completed a prior survey. Forty-one percent of respondents noted some mental health issue, including 31% who reported anxiety or depression, 13% reported starting or increasing substance abuse and 11% had contemplated suicide in the last 30 days. Suicidal thoughts were most common in minority communities (Hispanic, Black) but also among unpaid caregivers and essential workers.
There are some limitations to this study, including possible selection bias: Those who had mental health issues may have felt it more important that they be heard and may have been more likely to participate. Still, it is a stark reminder of the social and mental health aspects of COVID-19 and a signal to all healthcare providers to stay attuned to the mental health needs of patients during the pandemic.
Czeisler MÉ et al. Mental Health, Substance Use, and Suicidal Ideation During the COVID-19 Pandemic — United States, June 24–30, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1049–1057. DOI: http://dx.doi.org/10.15585/mmwr.mm6932a1external icon.
COVID-19 infection rates are increasing in the pediatric population. The American Academy of Pediatrics has compiled COVID-19 data from 49 states, the District of Columbia, New York City, Puerto Rico and Guam. The data is incomplete from Texas and New York. The bottom line is that 9% of COVID-19 cases in the US are in pediatric patients under age 18 with a cumulative case count of 380,174. The percent of positive tests range from 3.7%-18.6% depending on the state.
While transmission from young children 0-9 years of age seems to be less likely than in other age groups, transmission from those 10-17 seems to be higher. This has implications for schools reopening.
American Academy of Pediatrics. Children and COVID-19: State Data Report https://downloads.aap.org/AAP/PDF/AAP%20and%20CHA%20-%20Children%20and%20COVID-19%20State%20Data%20Report%208.6.20%20FINAL.pdf
Park YJ et al. Contact tracing during coronavirus disease outbreak, South Korea, 2020. Emerg Infect Dis. 2020 Oct (early release) https://doi.org/10.3201/eid2610.201315
Finally, the American Academy of Pediatrics has released a detailed set of guidelines on the safe return to classroom teaching. The key points are:
- Classroom teaching is ideal but needs to be done in a safe manner.
- Flexibility is key; if transmission rates go up there should be a rethinking of policy.
- Physical distancing measures for students should be in place including maintaining 6 feet between students; students over 2 years of age should wear masks. Three feet may be adequate if masks are worn and students are asymptomatic. There are specific mask recommendations for those hard of hearing, etc. See the link below.
- Adults should maintain a 6-foot distance between students and other school personnel.
- Physical barriers (e.g. plexiglass) should be in place where appropriate.
- Staggered drop-off and pickup times should be implemented to prevent crowding.
- Classes should not be multi-period/multi-classroom; cohorts should stay together as much as possible.
- Meals should be taken at the desk and not in a cafeteria setting.
This is a detailed guideline with suggestions based on student age, physical ability, etc. The full guideline can be found here.
American Academy of Pediatrics: COVID-19 Planning Considerations: Guidance for School Re-entry https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/covid-19-planning-considerations-return-to-in-person-education-in-schools/
Finally, the FDA is keeping a current list of dangerous hand sanitizers that contain methanol and 1-propanol. There have been reports of systemic toxicity secondary to ingestion of these products. And, the FDA warns of the risk of toxicity if used topically. A full list of these products can be found here at the bottom of the linked page.
Week of August 4th through August 10th
This week we have a practice guideline from the United Kingdom for the use of remdesivir, a relaxing of travel restrictions issued by the State Department, a report on confusion as a presenting symptom of COVID-19, a negative study on convalescent serum for treatment and a positive study of IL-6 inhibitors, both of which have major caveats. We also have data on PPI use and COVID-19 risk.
The British Medical Journal (BMJ) has released a treatment guideline for the use of remdesivir in the United Kingdom based on randomized trials with a total 1300 patients. This guideline applies to patients with one of the following:
- A respiratory rate of >30 or
- Respiratory distress or
- An SpO2 <94% on room air or
- Who require intensive care admission.
For this population they suggest remdesivir 100mg IV QD for 5-10 days. It is a weak recommendation because of the low quality of the data.
Following this guideline will (at best) reduce mortality by 85 patients out of 1000. It has little or no effect on the duration of hospitalization but may reduce the duration of ventilation.
The recommendations are weak based on the limited number and quality of studies. However, this can help advise practice.
Remdesivir for severe COVID-19: a clinical practice guideline BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m2924 (Published 30 July 2020)
The State Department has relaxed international travel rules. Individual states within the United States have strengthened theirs and the CDC has made no change. Twenty-four states now have some sort of travel restrictions for visitors with some states requiring a 14 day quarantine before engaging in any activities (a reasonably up to date list can be found here).
At the same time, the State Department has relaxed limits on international travel. The Global Level 4 Health Advisory was lifted on August 6th, 2020. However, many areas are still considered problematic. What this means is that each country needs to be assessed individually when determining the risk of travel. A list can be found here.
The CDC has not changed their recommendations which can be found here.
Note that some of the links on the CDC website pointing to their travel recommendations are broken but this direct link works.
State Department: https://travel.state.gov/content/travel/en/traveladvisories/traveladvisories.html/
Studdert,DM et al. Partitioning the Curve — Interstate Travel Restrictions During the Covid-19 Pandemic5 August 2020 DOI: 11056/NEJMp2024274
Interleukin-6 inhibitors may (or may not) be of benefit when used early, although the study methodology is not the best. This is an observational study of the use of sarilumab or tocilizumab in 255 patients with COVID-19. The drugs were initially used in critically ill patients but later on less ill patients were included. The first group included those requiring >45% FiO2 and elevated markers of inflammation. This was liberalized to an Fi02 requirement of 27%-33% or an A-A gradient of >50mmHg plus elevated inflammatory markers. 86% of patients were discharge alive.
After adjusting for age, obesity, period of care, CRP, and the need for mechanical ventilation, there was no difference in outcome for the severe group (compared to a mixed group of historical controls from a different institution). The less severe group had a mortality rate of 2.7% which was lower than historical controls.
This study suffers from the same problems found in many other COVID-19 trials: No randomization of patients to treatment or placebo. We don’t know how many in the lower risk group would have gone on to die without treatment. What can we take from this study? We need more and better trials. In fact, the authors state that “the medical community awaits more definitive results from randomized controlled trials.”
Sinha P. et al. Early administration of Interleukin-6 inhibitors for patients with severe Covid-19 disease is associated with decreased intubation, reduced mortality, and increased discharge Internantional Jornal of Infectious Disease July 25, 2020 DOI:https://doi.org/10.1016/j.ijid.2020.07.023
Convalescent plasma may not be effective in patients with severe and life threatening COVID-19. This was an open-label, placebo control study of 103 patients with severe COVID-19 defined as “severe (respiratory distress and/or hypoxemia)” or “life-threatening (shock, organ failure, or requiring mechanical ventilation).” Patients were randomized to convalescent plasma (n=52) or standard care (n=51). Outcome included time to clinical improvement, reduced severity of disease and mortality at 28 days (among others). There was no outcome difference between the two groups.
This study was planned for 200 patients and was stopped early which may have led to a type II error (not enough patients to see a difference if one is present). For example, clinical improvement was seen 52% of those getting convalescent plasma versus 43% in the control group. Likewise, mortality at 28 days was 16% versus 24%. These were not statistically different, but the study may have been underpowered. As in most COVID-19 studies, we need more and better data.
Ling L. et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19 A Randomized Clinical Trial JAMA. 2020;324(5):460-470. doi:10.1001/jama.2020.10044 (initially published in June, now updated with corrections).
An online survey suggests an association between PPI use and COVID-19 infection. This is an online survey of 264,058 individuals. Of these 86,602 (22%) chose to participate of whom 61% noted a prior history of abdominal pain, heartburn or GERD. 6% of these patients were COVID-19 positive.
There was an association between PPI use and rate of COVID-19 (OR 3.8 with BID use for > 6 months). This association was not found with H-2 blockers.
This is an association and does not necessarily mean causality. There were a similar associations between PPIs and dementia, pneumonia and chronic kidney disease reported which was found to be not true in a randomized study. Additionally, there is no doubt selection bias: only 22% of individuals chose to participate.
What should we take from this? Don’t use PPIs unless they are necessary and use the lowest dose possible to achieve your goal. The same is true of all medications, of course.
Almario CV et al. Increased risk of COVID-19 among users of proton-pump inhibitors. Am J Gastroenterol 2020. Preprint at: https://journals.lww.com/ajg/Documents/AJG-20-1811_R1(PUBLISH%20AS%20WEBPART).pdf
Moayyedi P et al. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology 2019 May 29; [e-pub]. (https://doi.org/10.1053/j.gastro.2019.05.056)
Finally, isolated mental status changes can be the initial presenting symptom of COVID-19. This is a report of 4 elderly patients with dementia who presented with mental status changes before the onset of fever, cough, etc. It just reminds us to be aware of atypical presentations of COVID-19.
Ward CF et al. Altered mental status as a novel initial clinical presentation for COVID-19 infection in the elderly. Am J Geriatr Psychiatry 2020 Aug; 28:808. (https://doi.org/10.1016/j.jagp.2020.05.013)
Week of July 28th through August 3rd
This week we have more information on the intermediate sequelae of COVID-19, information on school closures and transmission, not-very-helpful information on antibody titers post-COVID-19 infection and useful information on antibody titers to confirm COVID-19 in those suspected cases where a PCR is negative.
Antibody testing at 2 weeks seems to accurately reflect a patient’s COVID-19 status. There has been quite a bit of confusion regarding diagnosing COVID-19 via antibody test and the CDC currently does not recommend antibody testing to diagnose the presence or absence of COVID-19. This study sheds some additional light on the subject.
This is a study of 115 individuals hospitalized for COVID-19, some of whom were diagnosed clinically despite the absence of a positive PCR. The control group consisted of 513 samples of patients not known to have COVID-19 (one of whom had a presumed false positive antibody test). At 14 days post symptom onset, IgG to SARS-CoV-2 spike protein was of 0.976 (95% CI, 0.928 to 0.995) sensitive and 0.988 specific (CI, 0.974 to 0.995). Several of the patients clinically classified as COVID-19 but with negative PCR proved to have COVID-19 by IgG levels. Sensitivity and specificity fell off rapidly if the test was done <14 days prior to PCR/clinical diagnosis. Alternatively, antibody levels remained positive for at least 58 days.
Current CDC criteria do not recommend antibody testing to determine the presence or absence of COVD-19. This study suggests that in patients whose condition is uncertain, antibody testing at least 14 days after the onset of symptoms might be helpful. There is at least one caveat: this was done at a single center using a single manufacturer’s test (Euroimmun Anti-SARS-CoV-2 ELISA). The results may have been different using a different test and different test operators.
- Caturegli G, Materi J, Howard BM, Caturegli P. Clinical Validity of Serum Antibodies to SARS-CoV-2: A Case-Control Study [published online ahead of print, 2020 Jul 6]. Ann Intern Med. 2020;M20-2889. doi:10.7326/M20-2889
Antibody levels do drop off over time, but the clinical significance is unknown. This is a study of serial IgG antibody levels in 34 COVID-19 patients who had at least two IgG antibody levels. They found that the half-life of antibodies to COVID-19 is 36 days (95% CI 26-60 days).
There has been much made in the news of the rapid decay in COVID-19 antibody levels. This has been raised as a reason that a vaccine may not be viable. However, we expect serum antibody levels to wane over time. This is the nature of the world. It does not mean that we won’t have an anamnestic response similar to our response to other diseases (e.g. tetanus) after immunization. We may not know this answer for a while; it is ethically suspect to expose recovered COVID-19 patients and those who participate in vaccine trials to SARS-CoV-2 to test their response. Time will provide us with an appropriate natural history experiment.
- Ibarrondo FJ et al. Rapid Decay of Anti–SARS-CoV-2 Antibodies in Persons with Mild Covid-19, NEJM July 21, 2020 DOI: 10.1056/NEJMc2025179
More data on cardiac sequelae. This is a prospective study of 100 patients with a history of COVID-19 diagnosed by PCR; the median age was 49 (45-53 range). Fifty-three percent were men. Importantly, 57% were treated as outpatients (e.g. didn’t have severe COVID-19). A cardiac MRI was done between 64-92 days after initial COVID-19 diagnosis. These patients were compared to 50 health patients and 57 risk factor matched patients. Exclusion criteria included referral for cardiac MRI (CMR) for active symptoms. Of those with a history of COVID19 tested, 78% had evidence of cardiac involvement with 60% showing current involvement. The mean left ventricular ejection (LVEF) fraction was 56% in those with a history of COVID-19 compared to 61% in risk-factor matched controls and 60% in healthy controls. Residual symptoms included atypical chest pain (17%), palpitations (20%, shortness of breath (36%) and a decrease in daily activities (25%). There were no differences in patients who were treated at home versus those needing hospitalization.
It is still not clear what to do with this data. Longer term follow-up of symptoms and LVEF would be helpful. It does remind us that not all patients are asymptomatic after discharge from hospital and that even “mild”, non-hospitalized cases can have long term consequences.
- Puntmann, VO et al. Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19) JAMA Cardiol. Published online July 27, 2020. doi:10.1001/jamacardio.2020.3557
We now have data on school closures and the associated decrease in risk for COVID-19 infections. This can help inform return-to-school decisions. All 50 states in the U.S. closed schools in March 2020 before data on the effectiveness of this intervention was known. This study was done between March 9th and May 7th 2020 and looked at mortality and cases per 100,000 before and after school closure. Before school closures, the incidence of infection was going up by 265% per week. After school closure it dropped by 62% per week (with a lag period to allow for COVID-19 incubation). Mortality also dropped by 58% per week. The authors tried to adjust for stay-at-home/shelter-in-place orders, business closures and limits on the size of gatherings in their results.
Unfortunately, it is difficult to tease out exactly what the role of school transmission is since other control efforts (e.g. stay-at-home orders) often occurred concomitantly. It may be that parents staying at home to take care of their children was the driver of lower transmission rates; we need to remember that association doesn’t necessarily mean causation. Nevertheless, there is an association between school closure and both transmission and mortality even if this is secondary to other social distancing measures taken at the same time.
Auger KA et al. Association Between Statewide School Closure and COVID-19 Incidence and Mortality in the US JAMA. Published online July 29, 2020. doi:10.1001/jama.2020.14348
Last week we reported about intermediate term clinical sequelae of COVID-19 from a study out of Italy. This week we have similar, shorter term data, from the CDC (14-21 days after positive a PCR).
This is a phone interview of 292 randomly selected individuals done 14-21 days after having a positive test for COVID-19 who were treated as outpatients (e.g. did not have severe disease). Of these 94% reported one or more symptom at the time of testing (6% were asymptomatic). Thirty-five percent still reported one or more symptoms at follow-up (a median 16 days from the positive test) including 47% of those over age 50. Of those with cough, fatigue or dyspnea at the time of testing, 43%, 35% and 29% reported these symptoms at follow-up. There were no differences in symptom persistence based on gender, insurance status or ethnicity. However, hypertension, obesity and immunosuppression were all associate with continued symptoms.
These results aren’t surprising since the symptom documentation was within three weeks of first testing positive. But we need to view the numbers with a jaundiced eye. The researchers started with a database of 583 patients of whom only 292 were interviewed; it could be that those unable to be reached were sicker and less likely to answer the phone or perhaps even hospitalized. Nonetheless, while the data is incomplete, this study still provides a window into what symptoms remain two weeks after PCR positivity.
- Tenforde MW, Kim SS, Lindsell CJ, et al. Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network — United States, March–June 2020. MMWR Morb Mortal Wkly Rep 2020;69:993-998. DOI: http://dx.doi.org/10.15585/mmwr.mm6930e1
Week of July 13th through July 20th
In COVID-19 news this week, the CDC has revised the quarantine duration for patients with the disease, inhaled interferon shows promise, but data is very limited, transmission from older children is not uncommon and myocarditis is common among those with COVID-19 but the long term sequelae in survivors seem minor. Finally, hydroxychloroquine still doesn’t work.
Based on testing data, the CDC has determined that, except in rare cases (severe disease, immunosuppressed), the SARS-CoV-2 virus is no longer infectious 10 days after the onset of symptoms in patients with mild illness. Accordingly, the duration of quarantine for symptomatic individuals has been reduced to 10 days after symptom onset from the current 14 days as long as the patient is afebrile for 24 hours without the use of fever reducing drugs. Note that this does not change the length of quarantine for exposed individuals. Isolation is still 14 days after exposure.
Other points of note:
- A test-based strategy for leaving quarantine is no longer recommended (though can be used if needed to end quarantine in less than 10 days).
- Serologic testing should not be used to determine the presence or absence of SARS-CoV-2.
- PCR should not be done within the first 90 days of a previous positive. It likely represents viral RNA shedding and not new infection.
Inhaled interferon shows promise in reducing the severity of COVID-19 but we do not yet have published data. This randomized, controlled trial of a proprietary inhaled interferon with a planned 400 patients was stopped early after 101 patients were enrolled. The combined endpoint of death and need for mechanical ventilation was lower in those getting inhaled interferon. It isn’t clear from the press release that mortality was statistically better in the treatment group. The limited press release is not enough to push us to change our current practice.
Household transmission of SARS-CoV-2 from those aged 10-19 is more likely than from other age groups (although household transmission is less likely from those 0-9 years of age).
This is a study from Korea of 59,000 contacts of 5700 COVID-19 patients looking at positivity rates among contacts. Within households, there was an 11.8% COVID-19 positive rate overall (somewhat reassuring itself). The authors broke down household contacts by age. The index patient was 10-19 years old (124 individuals) in 18.6% (95% CI 14.0%–24.0%) of the families. Positive rate in families with an index case age 0-9 (29 individuals) was only 5.3% (95% CI 1 1.3%–13.7.0%). They do note that as more children are exposed when returning to school, their role in transmission will likely increase simply because of the increased number of exposures and positives in children. And, the numbers are still small in the 0-9 year age group.
Park YJ et al. Contact tracing during coronavirus disease outbreak, South Korea, 2020. Emerg Infect Dis. 2020 Oct (early release) https://doi.org/10.3201/eid2610.201315
The majority of hospitalized patients with COVID-19 have an elevated high sensitivity troponin T. Some patients have myocarditis but a preserved ejection fraction after discharge.
This is a series of 828 patients discharged from a single hospital in Britain. Seventy-one percent had an elevate high-sensitivity troponin-T (hsTnT) of which 41% died (compared to 8% of those without an elevated hsTnT). They excluded patients with PE or a history of ACS or another reason for an elevated troponin. A complete evaluation including cardiac MRI was only done on 29 patients (4%). Of these 29, 69% had “residual lung parenchymal changes”. Findings suggestive of myocarditis were seen in 45% of the 29. The mean left ventricular ejection fraction was normal, however (68%).
Unfortunately, even though they started with 828 patients in their series, only 4% had a complete workup after excluding known causes of an elevated hsTnT (which is clearly a marker for overall higher mortality). In those with presumed COVID-19 related myocarditis, the ejection fraction and wall motion were normal. There were some residual lung parenchymal changes but the clinical significance is not clear. It is hard to know what to do with this data at this point. Longer term follow-up will tell if there is any clinical significance to these findings.
Knight DS et al. COVID-19: Myocardial injury in survivors. Circulation 2020 Jul 14; [e-pub]. (https://doi.org/10.1161/CIRCULATIONAHA.120.049252)
Finally, hydroxychloroquine still doesn’t work.
This is a randomized, multicenter open label study of consecutive patients admitted for presumed COVID-19 less than 14 days after symptom onset (667 patients were enrolled but only 504 patients were found to be COVID-19 positive. Exclusion criteria included the need for > 4L of oxygen or use of study drug/macrolide for >24 hours before enrollment. Five-hundred and four patients were randomized 1:1:1 to get standard care alone, or plus hydroxychloroquine, or hydroxychloroquine + azithromycin. Treatment was continued for 7 days.
There was no difference in any outcome between the groups including death, discharge, need for oxygen, continued limits on activities after discharge, etc.
We already have data that hydroxychloroquine does not work for severe COVID-19 disease. We now have data that it does not work for mild-moderate disease requiring hospitalization. This also tells us that if it walks like a duck and quacks like a duck it is a house wren. A significant percentage of the patients enrolled for presumed COVID-19 did not test positive. Remember the “normal” diseases when seeing a patient with symptoms and signs that may be attributable to COVID-19.
Cavlacanti, AB et al. J Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. NEJM July 23, 2020 DOI: 10.1056/NEJMoa2019014
Week of July 12th through July 19th
A lot of new and useful information about COVID-19 this week. We will cover neuropsychiatric manifestations of COVID-19, sequelae of COVID-19, how children fit (or don’t fit) into the epidemiology of transmission and some new information on mortality. Finally, we have additional data on COVID-19 in pregnancy.
Neurologic and psychiatric manifestations of COVID-19. The first study is a report of 153 patients collected online by several British neurological and psychological professional associations from April 1st -April 26th 2020; complete data was available for 125.
The neurologic manifestations of COVID-19 were protean including 62% of the 125 patients having a cerebrovascular event, (mostly ischemic but some hemorrhagic and a single vasculitis). Mental status changes were seen in 31%. Of this 31%, 23% were encephalopathic, 18% had encephalitis and 59% had a new neuropsychiatric diagnosis, such as psychosis, neurocognitive syndrome/dementia, or affective disorders. The great majority of diagnoses were confirmed or “probable”. About 50% of those with mental status changes were under 60. The great majority with CVA (82%) were over 60.
Likely, the psychiatric/neurologic diagnosis was dependent at least to some degree on the qualifications of the reporter (psychiatrist versus neurologist). Additionally, this does not give us a good denominator: these may be relatively rare events since reporting was selective. However, it does give us an idea of what we might think about when we see a COVID-19 patient with neurological or psychiatric manifestation.
- Varatharaj A et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: A UK-wide surveillance study. Lancet Psychiatry 2020 Jun 25; [e-pub]. (https://doi.org/10.1016/S2215-0366(20)30287-X)
When COVID-19 “gets better” they don't become asymptomatic. This is a report of 143 patients who were followed up as outpatients after their acute COVID-19 hospitalization. Individuals ranged from 19-84 years of age with a mean of 57. 37% were women and all of the patients tested negative for COVID-19 at follow-up. Patients were evaluated a mean of 60 days after the onset of COVID-19 symptoms.
Only 13% reported no symptoms; 32% had one or two symptoms while 55% had 3 or more symptoms. Specifically, 53% reported fatigue, 43% continued dyspnea, 27% reported arthralgias and 22% reported “chest pain”. Less common symptoms included cough, anosmia, SICCA syndrome, headache, vertigo and others. About 45% reported a diminished quality of life.
This reminds us that COVID-19 symptomatology does not end when the patient is discharged from the hospital. It doesn’t give us information about interventions that might help or overall incidence (there were over 81,000 cases in the region) but does help us understand some of the medium-term sequelae of COVID-19.
- Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent Symptoms in Patients After Acute COVID-19 JAMA. Published online July 9, 2020. doi:10.1001/jama.2020.12603
Children may (or may not) be a source of contagion. One of the critical questions regarding COVID-19 in the Northern Hemisphere is whether to send children back to school after the summer break. We now have some data about infectivity among children.
This is a study of all children with COVID-19 infection < 16 years of age identified by the Geneva University Hospital in Switzerland. They tried to determine how often children were the index case in the family; 39 patients were followed. The great majority of pediatric patients presented with couth (82%), fever (67%) or nasal discharge (64%) followed by headache, sore throat and dyspnea. Almost all had mild symptoms They found that 8% of the time the child was the index case in the family.
This study has been cited to suggest that children are unlikely to represent a large source of infection. Not so fast. The numbers are limited. And, we don’t’ know how many children were exposed to COVID-19 outside of the home. It is possible that children were quarantined more frequently than adults (who may have had to go to work, etc.). For that reason, we cannot really draw firm conclusions about the infectivity of children with COVID-19.
- Posfay-Barbe KM, Wagner N, Gauthey M, et al. COVID-19 in Children and the Dynamics of Infection in Families. Pediatrics. 2020;146(2):e20201576
Mortality due to COVID-19 seems to be higher than is reported. Between March 1st and May 30th there were 780,975 reported deaths in the United States. This is 122,300 more deaths than predicted based on historical data. Of these excess deaths, about 95,500 were reportedly due to COVID-19. This leaves about 26,800 unexplained deaths suggesting about an undercount of approximately 22% of deahs do to COVID-19. Likely, this reflects inadequate testing: Patients are dying of COVID-19 but there is no documentation because of a dearth of testing.
- Weinberger DM et al. Estimation of excess deaths associated with the COVID-19 pandemic in the United States, March to May 2020. JAMA Intern Med 2020 Jul 1; [e-pub]. (https://doi.org/10.1001/jamainternmed.2020.3391
Finally, some additional data about COVID-19 and pregnancy. This study reports surveillance data of 91,000 US women age 14-11 with COVID-19 of whom 8200 were pregnant. Unfortunately, only 62% of pregnant women had symptom status reported versus 90% of those not pregnant. And, 75% of women did not report pregnancy status at all. Of those supplying data, about 97% of both groups were symptomatic. Cough and dyspnea were equally common in those pregnant and those not. Fever was less common during pregnancy, as were myalgias, chills, and diarrhea. Women who were pregnant were more likely to be admitted to the hospital (32% versus 6%), perhaps reflecting an abundance of caution. There were more ICU admissions and intubations in the pregnant group, however mortality was the same in both groups despite more diabetes, chronic lung disease and cardiovascular disease in the pregnant cohort.
A second study in of 241 pregnancies in New York found that a maternal BMI ≥30 kg/m2 was the sole factor associated with the severity of maternal disease (not underlaying illness, ethnicity, etc.) and that the severity of maternal disease was associated with preterm delivery. 6 of 236 (3%) of neonates tested positive for COVID-19.
This reminds us to be vigilant during pregnancy. While it is reassuring that COVID-19 related mortality is no worse in pregnancy, the need for inpatient intervention seems to be higher. Maternal BMI ≥30 seems to be one of the most important maternal factors in predicting the severity of disease. Both studies were consistent in finding that underlaying illness was not a predictor of severity (perhaps because immune changes in pregnancy trump underlaying illness). As in most things COVID-19, we need more and better data.
- Ellington S et al. Characteristics of women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status — United States, January 22–June 7, 2020. MMWR Morb Mortal Wkly Rep 2020 Jun 26; 69:769. (https://doi.org/10.15585/mmwr .mm6925a1)
- Khoury R et al. Characteristics and outcomes of 241 births to women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection at five New York City medical centers. Obstet Gynecol 2020 Jun 16; [e-pub]. (https://doi.org/10.1097/aog.0000000000004025)
Week of July 4th through July 11th
This has been a week in which we are seeing the rapid spread of COVID-19 in the US population. Below we will discuss COVID-19 transmission amongst meat packing workers, the seropositive rate in Spain and New York and the increase of abusive head trauma in children.
Reports of suspected abusive pediatric head trauma increased exponentially during the first month that the COVID-19 lockdown was in force in Britain.
This group looked at suspected abusive pediatric head trauma at one institution in Britain during the first month of COVID-19 lockdown. They compared this rate to the rate in the same months (23 March-23 April) in the 3 years preceding. All patients had a complete workup for abuse including MRI and/or CT. They found 10 cases in one month during lockdown compared to 0.67 cases/month at baseline. Of the abused children, 50% had colic. Unfortunately, 40% were found to be apneic with a decreased level of consciousness.
They point out that all of the families were had stressors including financial, mental health, and a history of criminal behavior. However, this may be a reflection of the area in which the hospital is located and doesn’t absolve other populations of similar problems with child abuse during lockdown.
This reminds us that the lockdown has been stressful leading to increased child abuse. It is also a reminder to discuss alternative caretakers with all families and identify alternate care givers ahead of time should the stress at home become so great that there is a risk of child abuse. This discussion seems to be particularly important in families with a colicky child, which can be trying in the best of times.
Sidpra J, Abomeli D, Hameed B, et al. Arch Dis Child doi:10.1136/archdischild-2020-319872Accepted 24 June 2020
Herd immunity may (or may not) be possibility against SARS-CoV-2
Spain is one of the countries that has been most impacted by COVID-19. This study elucidates the seropositive rate in the country. 36,000 households were contacted of which 75% agreed to have a point-of-care antibody test which, if a blood draw was allowed, was confirmed by chemiluminescent microparticle assay. A total of 61,000 individuals agreed to participate. The overall seropositive was 5% (95% CI 4.7-5.4) with higher rates around Madrid (10%) and lower results elsewhere in the country. There are several concerns about this study including the validity of a point of care antibody testing. However, if these results are confirmed, it speaks against the possibility of rapid herd immunity: it is estimated that at least 60% of the population need to be immune in order to have herd immunity.
Alternatively, in a predominately minority neighborhood up to 68% of patients seen at one clinic in Queens, New York were seropositive vs. 13% in a more affluent, White, area. This likely overestimates the positivity rate because of selection bias; those symptomatic were probably more likely to get the test. But it also speaks to the disproportionate burden of disease in people of color. As with most of COVID-19, we need more, and better, data.
Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study Published:July 06, 2020DOI:https://doi.org/10.1016/S0140-6736(20)31483-5
Meat processing plants seem to be particularly prone to outbreaks of COVID-19 infection amongst workers.
The CDC has tried to quantify the toll of COVID-19 on workers in the 3,5000 US meat processing plants. This data was collected in April and May of 2020. Only 28 of 50 states responded of which 23 states reported COVID-19 outbreaks in meat processing plants. Of those states reporting, there were 16,233 cases with 86 deaths. Minorities represented 87% of the cases, reflecting the burden of COVIED-19 illness in minority populations. The report notes that social distancing is difficult in this environment. Only 111 (of 3500 plants nationally) reported what steps they had taken to protect workers. 22% closed operations. Only 37% offered COVID-19 testing to employees. At least in Iowa (where I live) there is no requirement to report workplace outbreaks. Without mandatory reporting, it will be difficult to get a handle on the impact of COVID-19 on workplaces.
Wlaltenburg MA, Victoroff T, Rose CE, et al. Update: COVID-19 Among Workers in Meat and Poultry Processing Facilities ― United States, April–May 2020. MMWR Morb Mortal Wkly Rep. ePub: 7 July 2020. DOI: http://dx.doi.org/10.15585/mmwr.mm6927e2external icon.
Week of June 28th through July 3rd
Welcome to the weekly update. This week we have an updated guideline for the use of masks issued by the CDC, more information about Multisystem Inflammatory Syndrome in Children, a quantification of the stroke risk in COVID-19 patients admitted/ED, as well as a quick report on the effect of the pandemic on exercise.
The CDC has released guidelines calling for the use of cloth masks in public.They point out that masks should be used except in “children under the age of 2 or anyone who as trouble breathing, is unconscious, incapacitated or cannot remove the mask without assistance.”
The information at both sites is appropriate for all audiences, however.
We have new information on Multisystem Inflammatory Syndrome in Children (MIS-C)
As a quick review, the case definition of MIS-C is (verbatim from the CDC):
- An individual aged <21 years presenting with fever*, laboratory evidence of inflammation**, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND
- No alternative plausible diagnoses; AND
- Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of sym
*Fever >38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours
**Including, but not limited to, one or more of the following: an elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and low albumin.
The first report is of a series of 95 confirmed and 4 suspected cases in the State of New York. The second case series of 186 individuals confirms the findings of the first (albeit with slightly different percentages). Overall, the presentation of MIS-C occurred 10-31 days after the onset of COVID-19 symptoms with a median of 21 days.
Patients of color were over-represented in the group with MIS-C; 40% were Black and 36% Hispanic. About ½ were male and “children” of all ages were represented: age 0-5 (31%), 6-12 (42%) with the remainder being 13-20 years of age. Many had underlaying conditions (36% overall, primarily obesity but also chronic lung disease). All patients had fever or chills with 97% having tachycardia, 80% with GI symptoms, 60% with rash, 56% had conjunctival injection and 27% showed mucosal changes. 53% had evidence of myocarditis and 2 died.
In both series, a diagnosis of Kawasaki’s disease or incomplete Kawasaki’s disease was given in about 39% with approximately 9% having coronary artery aneurysms. Treatments varied so cannot be commented on. This reminds us to be on the lookout for MIS-C and not to assume that it will be present at the first encounter for COVID-19.
Dufort, EM. et al. Multisystem Inflammatory Syndrome in Children in New York State. NEJM 29 June 2020 DOI: 10.1056/NEJMoa2021756
Feldstein, LR. et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents NEJM June 29, 2020 DOI: 10.1056/NEJMoa2021680
Stroke risk is elevated in those with COVID-19 who are seen in an ED or admitted compared to those who have influenza.
We have had anecdotal evidence of an elevated stroke risk with COVID-19. We now have some data about 1961 COVID-19 patients and 1486 control patients with influenza seen in the ED or admitted to an inpatient unit. Stroke was determined by a panel of neurologists reviewing the chart; not all stroke patients had imaging which is one weakness of this study. Of those with COVID-19, 1.3% (CI 95 % 1.1%-2.3%) were diagnosed with a stroke compared to 0.2% (CI 95% 0.0%-0.6%.) of those with influenza. This difference remained after adjusting for age, gender and, vascular risk factors and “race” with an odds ratio of 7.6 (CI 95% 2.3-25.2). It is likely that some confounders remain such as smoking. What we do with this information in terms of prophylaxis is yet undetermined.
Merkler, AE et al. Risk of Ischemic Stroke in Patients with COVID-19 versus Patients with Influenza. JAMA Neurol. Published online July 2, 2020. doi:10.1001/jamaneurol.2020.2730
In a brilliant little study documenting step counts, it was found that exercise (as measured by step counts) was reduced by 7% in Sweden and 49% in Italy 30 days into the pandemic.
This study tracked step counts based on smartphone fitness app Argus (a product of Azumio corporation). It tracked 455,404 unique users from 187 unique countries. The mean decrease of steps was 27% per day at 30 days after the announcement of the pandemic with regional variation as noted above.
Of course this is not a randomized study and only looked at people owning a cell phone who use the Argus app. It is a good reminder to clinicians, however, to help patients come up with alternative ways to maintain exercise and fitness during the pandemic.
Tison, GH et al. Worldwide Effect of COVID-19 on Physical Activity: A Descriptive Study 29 June 2020 Annals of Internal Medicine, https://www.acpjournals.org/doi/10.7326/M20-2665
Week of June 21st through June 27th
There have been several notable developments regarding COVD-19 over this past week. These include:
- The expansion of the “at risk” criteria by the CDC
- A warning from the FDA about the accuracy of multiple brands of antibody tests.
- The usefulness of even good antibody tests.
- New information about the survival of SARS-CoV-19 in aerosols.
- Finally, there were two unique ideas were published this week about 1) how to go about testing in low resource areas and 2) how to create an N-95 mask out of a regular surgical mask.
The CDC released a new list of individuals at-risk for severe illness with COVID-19. The high-risk criteria include:
- Advanced age
- Chronic kidney disease
- Immunocompromised state
- Obesity (BMI of >30); This is changed from the prior cutoff of a BMI of 40
- “Serious conditions” such as heart failure, CAD, cardiomyopathy
- Diabetes Mellitus type 2
- Sickle cell disease
- Children with congenital heart disease or neurologic or genetic diseases, including inborn errors of metabolism.
A second list of individuals who “might be at increased risk” for severe illness with COVID-19 per the CDC include those with:
- Cerebrovascular disease
- Cystic fibrosis
- Neurologic conditions such as dementia
- Liver disease
- Pulmonary fibrosis
- A significant history of smoking
- Diabetes Mellitus type 1
Pregnancy is a reversal from the previous dictum that COVID-19 risk was not elevated in pregnancy. Additional data on pregnancy now classifies it as a high-risk condition. A CDC study of 8207 patients found that 1) presenting symptoms are the same as in the non-pregnant population, 2) Risk of admission and ventilation is increased in those who are pregnant, but mortality rate is not. In this study, 32% of pregnant women were admitted to the hospital compared to 5.2% of non-pregnant women. Part of this may be because of an abundance of caution in treating women who are pregnant, especially since mortality doesn’t differ. None-the-less we know that pregnancy is a relatively immunodeficient state with reduced T4 cells, among other changes.
Ellington S, et.al. Strid P, Tong VT, et al. Characteristics of Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status — United States, January 22–June 7, 2020. MMWR Morb Mortal Wkly Rep 2020;69:769–775. DOI: http://dx.doi.org/10.15585/mmwr.mm6925a1external icon.
The FDA sent out a warning about the accuracy of multiple brands of antibody tests for COVID. The list is extensive and can be found here under the heading “What Tests Should No Longer Be Distributed for COVID-19?”
We also have additional information from an analysis by the Cochrane group about the clinical usefulness of IgG/IgM tests for SARS-CoV-19. After looking at the literature on enzyme‐linked immunosorbent assays, chemiluminescence immunoassays, and lateral flow assays tests they found that:
- Tests were positive
- Only 30% of the time during the first week of illness
- 72% of the time day 8 of illness to day 14 of illness
- 92% of the time day 15 to 21
- Data beyond 21 days was not considered reliable.
This emphasizes the limited use of these tests in diagnosing acute infection. Nasal swab PCR remains the test of choice.
Antibody tests for identification of current and past infection with SARS‐CoV‐2 Cochrane Systematic Review -Version published: 25 June 2020 https://doi.org/10.1002/14651858.CD013652
SARS-CoV-2 remains infectious in aerosols for at least 16 hours.
This is an early release article by the CDC. These investigators nebulized SARS-CoV-2 and measured the infectivity as far out as 16 hours. They found that SARS-CoV-2 remains infectious in suspended aerosols for at least 16 hours (at which point they stopped testing). This has implications for contact tracing. One may have been exposed to SARS-Co-V-2 long after the index case left the area. How this will change practice remains to be seen.
Fears SC, Klimstra WB, et al. Persistence of severe acute respiratory syndrome coronavirus 2 in aerosol suspensions. Emerg Infect Dis. (publication date online: 25 June 2020)
It is possible to pool patient samples and run a single test in low resource areas.
These authors model a unique solution to the lack of adequate PCR tests. They suggest pooling the tests of several patients and running them as a single sample. If the test is negative, you are done. If the test is positive, each individual needs to be tested separately. They present several scenarios. For example, if the PCR is 70% sensitive and there is a 1% positive rate, 13 patients could be tested as one sample. In this case, only 16% of the number of tests would be needed compared to if each patient was initially tested separately. They present several scenarios in their analysis. This is not ready for prime time but is an example of a unique solution when there may be limited reagents, etc. Of course, you still do need one swab per person.
Finally, how do you make a typical surgical mask into an N95 mask? Just add rubber-bands.
These authors point out that surgical masks are N95 masks in terms of particle permeability. The main issue is that surgical masks leak leading to inhaling non-filtered air. They propose two solutions: one using rubber-bands and the other using a rubber sheet (think inner tube from a truck tire). In limited testing, these modified surgical masks were found to be as good as N95 masks at filtering the inhaled air. These are not yet approved as an official solution, but they have applied for CDC/NIOSH certification.
Instructions for making the masks is here: https://www.fixthemask.com/make-it
Week of June 14th through June 20th
This week we have results from the “long awaited” (in COVID-19 time) randomized trials of hydroxychloroquine and dexamethasone for treatment of COVID-19 as well as new guidelines from the CDC for testing. We also have new information on the safety of convalescent plasma in treating COVID-19. Note that the hydroxychloroquine and dexamethasone trials have not yet been peer reviewed but the protocol, data, etc. are available online here.
1) Hydroxychloroquine does not work for hospitalized patients. We already know that hydroxychloroquine does not work to prevent infection. We now have information that it doesn’t work to treat COVID-19. This is a randomized, controlled trial of 11,000 plus hospitalized COVID-19 patients in the United Kingdom. (the “RECOVERY” trial). Within this study, 1542 patients were randomized to hydroxychloroquine and 3132 got usual care without hydroxychloroquine. The endpoint was mortality at 28 days. There was no difference in mortality (25.7% with hydroxychloroquine and 23.5% with standard care (hazard ratio 1.11 [95% confidence interval 0.98-1.26]). There was also no difference in hospital stay or other endpoints. Read more here.
In addition to this negative study, there are concerns that hydroxychloroquine may reduce the antiviral activity of remdesivir (more here). Given the preponderance of data, the FDA in the US has revoked the authorization to use hydroxychloroquine for COVID-19 (more here). There is now good evidence that hydroxychloroquine should not be used for treating COVID-19 in any clinical setting.
- A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19 NEJM. June 3, 2020 DOI: 10.1056/NEJMoa2016638
2) Dexamethasone is the first drug to reduce mortality in patients with COVID-19 who require respiratory support. This is an analysis of another arm of the “RECOVERY” trial. In this arm, 2104 patients were randomized to dexamethasone 6mg once a day for 10 days and were compared to 4321 patients randomized to usual care alone. The 8-day mortality was highest in those who required ventilation (41%), lower in those patients who required oxygen only (25%), and lowest among those who did not require any respiratory support (13%). The NNT to prevent one death in patients on a ventilator is 8. The NNT for patients treated with oxygen alone (non-invasively) is 25. Patients who did not require oxygen did not benefit.
To put this in perspective, the numbers have been reported as “a miracle” with a reduction of death of 1/3 in ventilated patients and 1/5 of those on non-invasive oxygen. But those are relative reductions and not absolute reductions in mortality. The NNT is a better measure of the absolute reduction in mortality. Still a positive outcome, but certainly not a “a miracle” cure.
The results of this study are in contrast to the recommendations not to use steroids in COVID-19. It reminds us that “expert opinion” can be wrong and a well conducted study can change practice. The same shift has occurred with hydroxychloroquine: “Expert opinion” suggested using it, well controlled studies have shown there is no benefit.
3) Convalescent plasma is safe when used to treat COVID-19 although we still do not have solid data on efficacy.The first study is a retrospective analysis of 5000 hospitalized patients who got convalescent plasma therapy. Sixty-six percent of the patients were in the ICU. Overall 7-day mortality was 14.9% with a mortality of 0.3% within 4 hours of plasma infusion. This is consistent with the expected mortality based on historical data (10-20%). Adverse events were rare and there was no signal suggesting convalescent plasma is harmful. They report 4 deaths, transfusion associated fluid overload (TACO) in 7 patients, transfusion related lung injury in 11 patients and severe allergic reaction in 4.
A second study of 25 patients treated at Huston Methodist hospitals came to a similar conclusion regarding the safety of convalescent plasma.
- J Clin Invest. June 11, 2020. https://doi.org/10.1172/JCI140200. (https://www.jci.org/articles/view/140200/pdf)
- Am J Pathol 2020,-:1e11;https://doi.org/10.1016/j.ajpath.2020.05.014
4) There is a new, comprehensive summary statement about testing released by the CDC. The full document is here. A brief summary:
- Antibody testing is not to be used for diagnosing an acute infection.
- An authorized PCR or antigen detection assay should be used to test patients with symptoms.
- Asymptomatic patients with known or suspected exposure to COVID-19 should be tested, hopefully as part of a contact tracing program.
- For those asymptomatic individuals without known exposure in special settings such as group homes or nursing homes there are several recommended options. These include(verbatim):
Approaches for early identification of asymptomatic individuals include:
- Initial testing of everyone residing and/or working in the setting,
- Regular (e.g., weekly) testing of everyone residing and/or working in the setting, and
- Testing of new entrants into the setting and/or those re-entering after a prolonged absence (e.g., one or more days)
Settings for which these approaches could be considered include:
- Long-term care facilities
- Correctional and detention facilities
- Homeless shelters
- Other congregate work or living settings including mass care, temporary shelters, assisted living facilities, and group homes for individuals with intellectual disabilities and developmental disabilities
- High-density critical infrastructure workplaces where continuity of operations is a high priority
The bottom line is that this is a comprehensive, complex document that can be found here.
Week of June 7th through June 13th
It has been a relatively quiet week in COVID-19. Mostly, our knowledge is more uncertain with the withdrawal of several large studies (see below)
1) The CDC has published illuminating information about the outbreak of COVID-19 on the aircraft carrier USS Theodore Roosevelt. While a convenience sample and not a randomized study, it is still instructive. Among the most important points:
- Those who practiced prevention had a lower rate of COVID-19 infection (e.g., wearing a face covering, 55.8% versus 80.8%; avoiding common areas, 53.8% versus 67.5%; and observing social distancing, 54.7% versus 70.0%, respectively).
- 60% of individuals had neutralizing antibodies after infection (which is stated as being a positive although it also means that 40% do not have neutralizing antibodies.)
- 20% of infected patients were asymptomatic.
- Loss of taste (ageusia) and anosmia were particularly strongly associated with COVID-19 infection (OR 10.3).
Payne DC, et al. SARS-CoV-2 Infections and Serologic Responses from a Sample of U.S. Navy Service Members — USS Theodore Roosevelt, April 2020. MMWR Morb Mortal Wkly Rep. ePub: 9 June 2020. DOI: http://dx.doi.org/10.15585/mmwr.mm6923e4external icon.
2) Studies withdrawn
Two large studies were withdrawn because of an inability to independently confirm the veracity of their databases. A third study was withdrawn because of methodologic problems. These studies are:
- Mehra MR et al., “Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19,” published in the New England Journal of Medicine: This paper looked at the safety of ARBS and ACE-I and suggested no detriment in those infected with COVID-19. We still don’t know the answer.
Mehra MR et al., Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Published in The Lancet. This paper suggested that hydroxychloroquine and chloroquine were harmful in those ill with COVID-19. We still don’t have an answer.
You can read more here: BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m2279 (Published 09 June 2020) BMJ 2020;369:m2279
- “Effectiveness of Surgical and Cotton Masks in Blocking SARS-CoV-2. A Controlled Comparison in 4 Patients”. This paper suggesting that surgical and cotton masks do not work was withdrawn because of methodological problems. We do have other good studies suggesting masks do work (see above, for example). https://www.acpjournals.org/doi/10.7326/L20-0745
Week of May 31st through June 6th
Six new advances in COVID-19 the week of May 31st through June 6th.
1) Finding a positive PCR after infection does not necessarily reflect infectivity. Numerous studies have found patients with a positive PCR for SARS-CoV-2 after recovery from clinical illness. The question has been, “Does this reflect infectivity?” There is now data suggesting that the answer is not necessarily. This is a retrospective study of 92 PCR positive samples which were submitted for culture. Overall, 29% of cultures were positive for SARS-CoV-2. However, no cultures were positive in those with a symptom onset > 8 days before the PCR or a RT-PCR cycle threshold (Ct) of >24 (the number of cycles of amplification before detection, with a Ct of > 24 being is a strong reaction suggesting a large amount of SARS-CoV-2 nucleic acids). The study concluded that the infectivity of patients with Ct >24 (e.g. even some of those with a large amount of viral RNA) and/or a duration of symptoms >8 days may be low.
It is reassuring that not all patients with a positive PCR after COVID-19 are infectious and that at 8 days after symptom onset none were culture positive. More information is needed on this topic to make definitive claims.
Accepted prepublication manuscript: Clinical Infectious Diseases, ciaa638, https://doi.org/10.1093/cid/ciaa638 Published: 22 May 2020e
2) Post-exposure prophylaxis does not seem to reduce the occurrence of symptomatic COVID-19.
This is a randomized, double blind, placebo-controlled trial of hydroxychloroquine in the prevention of COVID-19. The study included 821 individuals who were exposed to a known COVID-19 case. Exposure was defined as an occupational or household exposure within 6 feet for at least 10 minutes without the use of protective equipment (high risk, 719 participants) or with a mask but no eye protection (moderate risk, 108 participants). Participants were randomized to hydroxychloroquine 800mg followed by 600mg in 6-8 hours, then 600mg for 4 days) within 4 days of exposure. The outcome was laboratory confirmed COVID-19 or symptoms consistent with COVID-19.
There was no difference in the infection rate between the two groups (11.8% vs. 14.3% (difference of 2.5% CI 95 -7.0-2.2)). Discontinuation was significantly higher in the hydroxychloroquine group (75% compliance in hydroxychloroquine group vs. 83% in the placebo group). Side effects were reported by 40% of the active treatment group vs. 17% of the placebo group.
This study shows no benefit to hydroxychloroquine in reducing infection after a COVID-19 exposure. The weakness of this study is that it relied partly on participant symptom report and not all infections were verified by PCR. Additionally, it does not tell us about the rate of asymptomatic infection. There are ongoing studies of pre-exposure prophylaxis including a large study in health care workers.
NEJM June 3, 2020 DOI: 10.1056/NEJMoa2016638
3) We still don’t have an answer on convalescent plasma.
Anecdotal reports suggest that convalescent plasma therapy in patients with severe COVID-19 may be beneficial. The results of an open label, randomized trial of 103 select patients with life threatening COVID-19 who all got standard care with 52 getting convalescent plasma added to their regimen was released. There were multiple exclusion criteria.
Looking only at mortality, there was a non-statistically significant benefit to convalescent plasma (mortality 15.7% versus 24.0% 95% CI 0.29-1.46).
Why is an 8% difference not significant? The study was underpowered to find a difference. The study was designed to include 200 patients and only enrolled 103. This is called a “Type II error”. You can remember this by the mnemonic that in a type II error there are “too few” participants to find a difference that actually exists. This study suggests a difference, but more data is needed to make a definitive conclusion.
JAMA. Published online June 3, 2020. doi:10.1001/jama.2020.10044
4) A plea to treat air hunger in those with COVID-19 related ARDS who need intubation.
This pre-publication commentary reminds us to treat air hunger in those who are intubated and receiving low tidal volume ventilation. Low tidal volume ventilation leads to “permissive hypercapnia” with an increase in pCO2. This leads to a sensation of air hunger, which in other studies, is associated with psychological trauma leading to PTSD in some survivors of ARDS. The authors of this study point out that this is the same mechanism that is operative in torture (e.g. waterboarding). They make several points, including:
- Include narcotics in the initial sedation protocol and continued sedation management of intubated patients. Morphine 5mg IV has been shown to be very effective at reducing air hunger.
- Benzodiazepines do not reduce air hunger although they may reduce the resultant psychological trauma.
- Paralysis alone does not reduce air hunger, contrary to popular belief. It should also be noted that patients should not be paralyzed until they are fully sedated. While paralyzed, sedatives should not be weaned. Institutional protocols for paralysis should be followed.
5) Masks, Social Distancing or Both?
Adoption of social distancing and masks has not been universal at least partly because of the belief that these measures do not help reduce COVID-19 transmission. This study questions that rationale.
This is a systematic review and meta-analysis of 172 studies looking at transmission of coronaviruses (specifically COVID-19 but also SARS and MERS). All studies were ranked using Cochrane and GRADE methods. Forty-four studies met quality criteria and were included in the meta-analysis (a total of 25,697 patients). None were randomized controlled trials.
Social distancing of at least one meter was associated with a 10.2% reduction in transmission (CI 11.5 to 7.5) (n=10,736). The risk of transmission decreased by a relative risk of 2 per additional meter-distance (moderate certainty). Masks (n=2647), had a large effect on transmission with a risk difference of 14.3%. As one would expect, N95 masks performed better than disposable surgical masks or those with 12-16 layers of cotton (low certainty). Eye protection (n=3713) also reduced transmission (10.6%-low certainty). Subgroup and sensitivity analyses lead to the same conclusion.
It isn’t likely that a randomized trial of masks will be done given the ethical implications of knowingly exposing patients to a potentially fatal virus. The best data to date reinforces the directives to maintain social distancing and to wear masks to prevent disease transmission.
The Lancet June 1, 2020 https://doi.org/10.1016/S0140-6736(20)31142-9
6) And, as one might expect, even more stringent precautions work better.
This is an MMWR report on the results of stringent measures to reduce COVID-19 transmission in a high-density military population of 10,579 trainees. Steps taken include:
- Quarantine for 2 weeks upon arrival
- Social distancing of at least 6 feet
- Testing if the individual had symptoms
- The use of cloth masks
- Travel restrictions on those wanting to enter the base
Using these techniques, they were able to limit transmission to a total of 5 cases of whom 3 were contacts of the first case. The spread was extrapolated to be 47/100,000 people.
How this applies to the general public is not known. Military bases are a very structured and closed environment and behavior can be mandated unlike in the general population.
Marcus JE, Frankel DN, Pawlak MT, et al. COVID-19 Monitoring and Response Among U.S. Air Force Basic Military Trainees — Texas, March–April 2020. MMWR Morb Mortal Wkly Rep. ePub: 2 June 2020. DOI: http://dx.doi.org/10.15585/mmwr.mm6922e2external icon.
Week of May 24th through May 30th
Four clinically relevant updates for the past week
1) Even mildly symptomatic infections with SARS-CoV-2 leads to an antibody response.
One of the many unanswered questions about COVID-19 is the robustness of the immune response in patients who experienced only mild symptoms. This was a study of 160 hospital staff in Strasbourg, France who were symptomatic with PCR proven COVID-19 but who did not require hospitalization. Blood was drawn a median of 24 days after the onset of COVID-19 symptoms. Overall, 99.4% of patients had anti-SARS-CoV-2 antibodies. The percent of samples with neutralizing antibodies was 79%, 92% and 98% at 13-20, 21-27 and 28-41 days after symptom onset.
These findings indicate that serological testing for COVID-19 is a useful tool to determine who has had a previous symptomatic infection. Unfortunately, in the absence of serial blood draws, it is difficult to extrapolate the overall rate of neutralizing antibodies in the whole cohort at 41 days after symptom onset and how many who were negative at 13-20 days subsequently became positive for neutralizing antibodies. It is also presently unclear how protective these antibodies are.
MedRxiv (prepublication) doi: https://doi.org/10.1101/2020.05.19.20101832
2) The CDC has issued guidelines for antibody testing. Among the recommendations are:
- Using an FDA reviewed test.
- Using a test with a specificity of 99.5% or greater, as screening will likely result in a high level of false positives.
- Focusing on high risk individuals is more likely to be useful than mass screening.
- Being aware that testing for neutralizing antibodies has not yet been approved in the US.
- Being similarly aware that IgA testing is not recommended at this time (IgG and IgM testing are both available).
- Avoiding use of serologic test results to make decisions about who can return to work.
- Avoiding use of serologic tests “to make decisions about grouping persons residing in or being admitted to congregate settings, such as schools, dormitories, or correctional facilities.”
3) The results of the long-awaited remdesivir trial have been released; remdesivir seems to reduce the duration of illness in those hospitalized patients with mild illness. There was no mortality benefit observed in this study.
1063 patients with COVID-19 were randomized to either placebo or up to 10 days of remdesivir. The principle outcome was time to recovery, defined by either by discharge from the hospital or clinical recovery with continued hospitalization for isolation purposes only. The recovery time was 11 days in those getting remdesivir versus 15 days those getting placebo (p<0.001).
Unfortunately, there was no difference in mortality (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Additionally, the benefit was only seen in patients who were receiving low flow oxygen. Intubated patients, those requiring high flow oxygen and/or non-invasive ventilation and those not requiring oxygen did not benefit. Early treatment seems to be key in the use of remdesivir.
4) Another bad week for chloroquine/hydroxychloroquine and azithromycin
Individual studies have been negative for any benefit to chloroquine/hydroxychloroquine/azithromycin in hospitalized patients. Retrospective analysis is now available for 96,032 patients who were treated with chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide. Attempts were made to control for factors such as cardiovascular disease, diabetes mellitus, age, lung disease and baseline severity. Of the patients, 1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide. The other 81,144 patients were in the control group.
The bottom line is that there was no benefit to drug treatment and an increase in mortality with treatment (control group 9·3% vs 16.4% in the chloroquine group and up to 24% mortality with hydroxychloroquine plus a macrolide).
WHO has stopped ongoing studies of these drugs based on this data. Until there is a controlled trial, these drugs should not be used for inpatient treatment as there is likely significant harm. It should be noted, however, that this was not a controlled trial and adjustment for comorbidities is always imprecise.
The Lancet. May 22, 2020DOI:https://doi.org/10.1016/S0140-6736(20)31180-6
Week of May 17th through May 23rd
More cases of a COVID-19 associated systemic inflammatory syndrome have been reported in children
The CDC has advised being on the lookout for the increasingly reported Multisystem Inflammatory Syndrome in Children (MIS-C). Any such cases should be reported to the CDC. The case definition (verbatim from the CDC) is as follows:
- An individual aged <21 years presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND
- No alternative plausible diagnoses; AND
- Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or COVID-19 exposure within the 4 weeks prior to the onset of symptoms
- Fever >38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours
- Including, but not limited to, one or more of the following: an elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and low albumin
- Additional Considerations (per CDC)
Some individuals may fulfill full or partial criteria for Kawasaki Disease, but should be reported if they meet the case definition for MIS-C.
Consider MIS-C in any pediatric death with evidence of SARS-CoV-2 infection
Additional information can be found here: Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19)
BCG vaccine does not seem to protect against COVID-19
There was some speculation early in the COVID-19 pandemic that patients were protected against COVID-19 if they had had bacille Calmette-Guerin (BCG) immunization against tuberculosis. Unfortunately, a new study seems to refute this.
This was a retrospective study of 3064 Israelis born between 1979-1981 who got BCG and 2869 born between the years of 1983 and 1985 who did not (after universal vaccine was halted). No difference in COVID-19 infection was found between the two groups (vaccinated: 11.7%, unvaccinated: 10.4%). The study was unable to measure the severity of disease vs. immunization status because there were few patients with severe illness in this cohort.
SARS-COV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults. JAMA. Published online May 13, 2020
Guillain-Barre Syndrome joins encephalopathy as an additional possible result of COVID-19
It is known that COVID-19 can cause an encephalopathy which can then take months to resolve. A new paper reports five cases of a Guillain-Barre-like syndrome occurring in relation to COVID-19.
This is a report from Italy of five patients with COVID-19 who had an associated Guillain-Barre syndrome. Of these five, four had onset presenting as lower limb weakness and facial diplegia. The syndrome progressed to include flaccid paralysis, but not dysautonomia. Cerebrospinal fluid (CSF) polymerase chain reaction (PCR) in all patients was negative for COVID-19. Electromyogram (EMG) showed axonal Guillain-Barre in three patients and demyelination in two. Treatment was with plasma exchange and intravenous immunoglobulin (IVIG). As with many other COVID-19 patients, three members of the study were placed on ventilation.
Toscano G et al. Guillain–Barré syndrome associated with SARS-CoV-2. N Engl J Med 2020 Apr 17; [e-pub]. (https://doi.org/10.1056/NEJMc2009191)
New Online Risk Calculator Available
A group out of China has developed a risk calculator for predicting the severity of illness in those with COVID-19. They initially observed 1,590 patients and found that 10 risk factors seem to change the outcome of those with COVID-19 (derivation set).
These risk factors include:
- X-ray Appearance
- Number of comorbidities (defined on the calculator link)
- History of cancer
- Neutrophil to lymphocyte ratio
- Lactate dehydrogenase (LDH)
- Direct bilirubin
The group then applied their rule to another 710 patients (validation set). Using this tool, the group was able to categorize patients as low, medium or high risk for progressive disease. The probability for adverse events (invasive ventilation/ICU admission/death) in the various groups is as follows: low-risk group 0.7% (e.g. 0.7% with a low risk score went on to have an adverse event); medium-risk score group 7.3% had an adverse event; high-risk group score 59.3% had an adverse event. The calculator can be found here.
JAMA Intern Med. Published online May 12, 2020. doi:10.1001/jamainternmed.2020.2033
Week of May 10th through May 16th
1) CDC Updates Guidelines for Discontinuing Isolation in Persons with COVID-19
For individuals recovered from COVID-19 illness, the CDC has increased the recommended period of isolation from 7 days to 10 days after illness onset and at least 3 days after recovery. The CDC defines illness onset as the date symptoms begin. Recovery is defined as resolution of fever without the use of fever-reducing medications with progressive improvement or resolution of other symptoms. Ideally, isolation should be maintained for this full period to the extent that it is practicable under rapidly changing circumstances.
2) COVID-Associated Coagulopathy
It is now clear from multiple studies that 10-43% of patients with COVID-19, especially those who are critically ill, are hypercoagulable. The exact number is not well elucidated. Studies differed with variations in severity of illness presentation among patients.
This hypercoagulability results in both arterial and venous thromboses. It has been known almost from the start of the epidemic that an elevated d-dimer in COVID-19 patients is a marker for poor outcomes since the d-dimer is a marker for ongoing thrombosis. The thrombotic complications seen in COVID-19 include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, acute coronary syndrome (ACS)/myocardial infarction (MI), limb ischemia and gastrointestinal (GI) ischemia. There are also reports of cardiac valve clots.
Patients with COVID-19 associated coagulopathy generally have normal clotting studies (aPTT, PT/INR) but may have an elevated aPTT reflecting an anticardiolipin antibody/lupus-like anticoagulant (90% in one series of those with an elevated aPTT). Unlike in disseminated intravascular coagulation (DIC), hypercoagulable COVID-19 patients often have normal or slightly high platelet counts and high fibrinogen. These patients are hypercoagulable despite the elevated aPTT and should be anticoagulated as per standard of care.
There is consensus that “all” patients admitted to the hospital should be treated with prophylactic-dose heparin (e.g. enoxaparin or others) and should have a low threshold for evaluation of blood clot (e.g. chest CT, extremity doppler, etc.). If a patient is deteriorating and CT for PE will be delayed, it is reasonable to start full anticoagulation while awaiting study results, balancing treatment with consideration of bleeding risk.
Some institutions are starting full-dose anticoagulation on critically ill patients without known clot, which remains controversial.
NEJM May 5, 2020 DOI: 10.1056/NEJMc2013656
Abdominal Visceral Infarction in 3 Patients with COVID-19 https://wwwnc.cdc.gov/eid/article/26/8/20-1161_article?deliveryName=USCDC_333-DM28184
Journal of Thrombosis and Heamostasis, https://onlinelibrary.wiley.com/doi/10.1111/jth.14888
3) In Vivo Human Monoclonal Antibodies
A study reported the discovery of human monoclonal antibodies that neutralize SARS-CoV-2 (and SARS-CoV) in cell culture. While there is currently no vaccine that can prevent the disease, this monoclonal antibody could potentially offer future prevention and treatment. This is not clinically available at present, but the finding indicates that effective neutralizing antibodies can be identified as they target a communal epitope on the virus, thus increasing the probability of an effective vaccine being identified.
Wrapp et al., Structural Basis for Potent Neutralization of Betacoronaviruses by Single-Domain Camelid Antibodies, Cell (2020), https://doi.org/10.1016/j.cell.2020.04.031
Wang, C., Li, W., Drabek, D. et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat Commun 11, 2251 (2020). https://doi.org/10.1038/s41467-020-16256-y
4) Another bad week for hydroxychloroquine
Another week, another negative study of hydroxychloroquine in COVID-19. This is a study of 1446 consecutive patients admitted for COVID-19 excluding those who were intubated, died, or were discharged within 24 hours. Outcomes were intubation or death in a time-to-event analysis. Propensity scoring was used to adjust the data for disease severity, smoking, etc. They also did a multiple sensitivity analyses to test the robustness of their results. There was no difference between intubation plus death between the placebo and treatment groups (hazard ratio, 1.04, 95% confidence interval, 0.82 to 1.32).
NEJM May 7, 2020 DOI: 10.1056/NEJMoa2012410
Weeks of April 26th through May 9th
1) COVID-19 Disease and Kawasaki disease
Over the past week there have been several cases Kawasaki disease/an overlap syndrome of toxic shock and Kawasaki syndrome in children with COVID-19. Reports note fever, conjunctivitis, a polymorphous, blanching rash, tongue involvement and swelling of hands and feet.
The Pediatric Intensive Care Society from Britain has alerted providers to be vigilant in identifying these patients and note that they often have GI symptoms, abdominal pain, myocarditis and coronary artery findings consistent with Kawasaki Disease. Lab abnormalities include an elevated troponin, and elevated CRP and sedimentation rate. Of note, some of these patients have been COVID-19 negative.
Comment: The classic constellation of symptoms for Kawasaki disease include: Fever for at least 5 days, Mucositis, Conjunctivitis, Polymorphous rash, Distal extremity edema, and Lymphadenopathy (which is commonly absent). An incomplete syndrome is common. There may be accompanying carditis. The take home message for clinicians is to realize this association with COVID-19 likely exists and to have a low threshold for referral for a higher level of care.
Jones VG, Mills M, Suarez D, et al. COVID-19 and Kawasaki disease: novel virus and novel case. Hosp Pediatr. 2020; doi: 10.1542/hpeds.2020-0123
2) Self-Proning in the ED Improves Patients’ Oxygenation
A small, observational study of 50 patients with a median initial oxygen saturation of 80% found that adding oxygen by nasal canula or non-rebreather mask increased oxygen saturations to a median of 84%. Oxygen with self-proning increased oxygen saturations to a median of 94%. Ultimately, 24% went on to get intubated within the first 24 hours and 36% overall required intubation.
Comment: Awake proning is being used in the acute care wards and now in the ED to improve oxygenation. This observation study shows improvements in oxygenation, though long-term outcomes are unclear. Whether this technique reduces intubations is unknown; it is also unknown how much it reduces intubations in the ED.
These practices further support the more tranditional practices of paralysis and proning of patients with moderate/severe ARDS in the ICU with COVID.
Caputo ND, et al. Early Self‐Proning in Awake, Non‐intubated Patients in the Emergency Department: A Single ED’s Experience during the COVID‐19 Pandemic Academic Emergency Medicine 22 April 2020 https://doi.org/10.1111/acem.13994
3) Yet more good news about ACEI and ARBs in COVID-19 (but not so good about smoking, CAD, COPD)
An observational database study done at 169 hospitals in Europe, Asia and North American of 8910 patients with COVID-19 found that ACEI Sand ARBS did not worsen mortality and that ACEI seem to be protective (death in those on ACE inhibitors versus placebo (2.1% vs. 6.1%; odds ratio, 0.33; 95% CI, 0.20 to 0.54)). ARBs seemed to be neutral in terms of death. ARBs (6.8% vs. 5.7%; odds ratio, 1.23; 95% CI, 0.87 to 1.74).
CAD, age of 65 years of age, heart failure, a history of cardiac arrhythmias, COPD and current smoking all were associated with an increase in mortality.
Comment: This is the largest study to date and confirms prior data: ACEI and ARBs are at worst neutral and, in the case of ACEI may be protective in those with COVID-19. Underlying illness including COPD and current smoking are risk factors for death from COVID-19. This is not a randomized, controlled trial but is the largest data set we have to date.
Mehra MR et al. Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19 May 1, 2020 DOI: 10.1056/NEJMoa2007621
4) New Guidelines on Breast Feeding
The CDC has issued new guidelines which can be found here: https://www.cdc.gov/coronavirus/2019-ncov/hcp/care-for-breastfeeding-women.html
- Breast feeding is generally the best nutrition for an infant and COVID-19 does not SEEM to be a source of transmission of COVID-19 (though it can’t be entirely excluded yet).
- Whether to breast feed or not should be a shared decision between the mother/parents and provider.
- Hand washing and wearing a cloth facemask are critical. Note that the guideline makes no mention of N95 or surgical masks.
- Assume that the infant of a COVID-19 positive mother who is breast feeding is itself COVID-19 positive for purposes of isolation.
- Newborn and young child wellness visits (through 24 months) and vaccination should be prioritized.
- Telemedicine can provide lactation support for mothers breast feeding.
Comment: These are simplified but essentially the same as the prior breast-feeding guidelines for COVID-19 positive mothers.
5) Some good news: Remdesivir is given emergency approval by the FDA for use in COVID-19
An unpublishedstudy showed a benefit of Remdesivir in COVID-19 positive patients requiring oxygen or intubation an showed that the average time to recovery (discharge or no need for supplemental oxygen) was 11 days with Remdesivir than with placebo (15 days). There was a trend towards a mortality benefit but it did not meet statistical significance. Five day of drug seemed to be as effective as 10 days of drug.
Comment: This study continues since the requisite number of patients have not yet been recruited to assess all endpoints. We are still awaiting peer review.
6) New COVID-19 symptoms recognized by the CDC.
These can be found here https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html and include: Repeated shaking chills, muscle pain, headaches sore throat and loss of taste. The “classic” symptoms include fever, dyspnea, and cough.
There are reports of “frostbite-like” erythema and peeling of toes, especially in young patients though it is as of yet not categorized in terms of frequency. There are several possible mechanisms include microthrombi from hypercoagulability and vasospasm. There are no reviewed/published articles in the scientific literature as of yet.
A dermatology registry about COVID-19 skin manifestations is being compiled and can be found here: https://www.jaad.org/article/S0190-9622(20)30658-7/pdf
Finally, stroke and encephalopathy are being noted with increased frequency. Stroke seems more likely in the young while encephalopathy are being noted in those who are older.
Rev Neurol. 2020 May 1;70(9):311-322. doi: 10.33588/rn.7009.2020179.
Week of April 19th through April 25th
Further data on COVID-19 and pregnancy does not show excess maternal mortality or adverse fetal outcomes.
- A study from China of 118 pregnant patients who were either COVID-19 PCR positive (71%) or who had CT findings + symptoms of COVID-19 (29%) found that 92% had mild disease (the overall population rate of mild disease is approximately 81%). The other 8% had severe disease (defined in this study as hypoxia). Of the nine patients with severe disease, development was post-partum among six patients and only one patient needed non-invasive ventilation; there were no deaths. The baseline data of neonatal outcomes is not yet available, but the study authors do not raise any concerns about adverse neonatal outcomes (three spontaneous abortions, two ectopic pregnancies). 21% of deliveries (half of which were induced) were premature, but there was no neonatal asphyxia.
- Editor Comment: This is reassuring, and consistent with previous data showing that COVID-19 does not present more virulently in pregnancy. More data will likely be forthcoming.
Chen L. et al. Clinical Characteristics of Pregnant Women with COVID-19 in Wuhan, China. NEJM: April 17, 2020 DOI: 10.1056/NEJMc2009226 available here.
ACEI/ARBs do not seem to increase mortality, and may have some protective effects in patients with COVID-19
- The first study is an observational case series of 1178 hypertensive patients from China with COVID-19, 32% of which were taking an ACE or an ARB. The mortality rate in the patients with hypertension was 21% (for reference, these are select patients with hypertension and co-morbid illness) There was no mortality difference between hypertensive patients taking ARBs/ACEs and those not.
- A second and statistically superior study confirms the findings of this first study. This is a retrospective, multi-center study of 1128 adult patients with hypertension. Of these, 188 were taking an ACE/ARB. Overall mortality was lower in those on an ACEI/ARB (3.7% in those on an ACEI/ARB and 9.8% in those not on an ACEI/ARB). An analysis based on propensity score (designed to remove variables such as age, gender and comorbidities) confirmed that morality results still favored the ACEI/ARB group (adjusted HR, 0.37; 95% CI, 0.15-0.89; P = 0.03).
- Editor Comment: These results are reassuring, with one study suggesting that ACEI/ARB are at worst neutral in terms of mortality, and the other suggesting a statistically significant mortality benefit with both ACEI/ARB. More data will likely be forthcoming.
Li, J et al. Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China JAMA Cardiol. Published online April 23, 2020. doi:10.1001/jamacardio.2020.1624
Zhang, P. et al. Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19 Originally published17 Apr 2020 https://doi.org/10.1161/CIRCRE... Circulation Research
Some COVID-19 patients are hypercoagulable, and may present with stroke even in the absence of other severe manifestations of COVID-19. The risk is not well quantitated.
- A case series from Italy of patients admitted to an ICU with COVID-19 found increased levels of fibrinogen and an enhanced clot formation using thromboelastometry, including a shorter clot formation time. In keeping with normal enhanced clot formation, the d-dimer was also elevated. There have also been increasing reports of stroke in relatively young people, despite the absence of other severe manifestations of COVID-19, though there is not yet well-quantified data for this
- For admitted patients, The American Society of Hematology recommends prophylaxis with enoxaparin 40mg QD as standard with intermittent pneumatic compression stockings as an alternative. See the guidelines here.
Spiezia, L. et al. COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure. Thrombosis and Hemostasis 21 April 2020 DOI https://doi.org/10.1055/s-0040...
Week of April 12th through April 18th
1) Some pregnant women are COVID-19 positive and asymptomatic.
A letter in the New England Journal reports that of 211 asymptomatic pregnant women being delivered in New York, 1 in 8 (13.7%) were COVID-19 positive and of these 90% were asymptomatic.
This is not unexpected given the degree of disease in New York and the fact that we know a significant portion of patients with COVID-19 are asymptomatic.
The testing of women who go into labor should be individualized to each community and should follow the local testing practice pattern.
This is consistent with expert opinion that recommend COVID-19 testing for women scheduled for induction or Cesarean section 24-28 hours before admission and again on presentation. If screening is positive, the induction or operative delivery should be delayed if medically possible. All patients (obstetrical or not, in labor or not) should be screened for symptoms. A summary of these recommendations can be found here.
Desmond S, Fuchs K, D’Alton. M. Universal Screening for SARS-CoV-2 in Women Admitted for Delivery (letter). April 13, 2020 DOI: 10.1056/NEJMc2009316
2) Data regarding surgical masks is mixed but mostly positive.
A study of 246 patients with various viruses and not just COVID-19, showed a significant reduction of virus in the aerosol and droplets of those wearing masks. For the patients tested who had non-COVID19 coronavirus there was a significant decrease in virus particles in those wearing surgical masks (in respiratory droplets, from 30% to 0%; aerosols, 40% to 0%). The same is true for influenza infection (respiratory droplets, 26% to 4%; aerosols, 35% to 22%). Masks did not seem to reduce the number of virus particles for rhinovirus.
In a 2nd study of only 4 patients with collection medium only 20cm from an individual’s face the number of virus particles cultured was similar between those using and not using masks. However, this is only 4 patients and it does not tell us about virus spread outside of 20cm (e.g. is the velocity and distance of virus dispersement different than without a mask?).
Leung NHL et al. Respiratory virus shedding in exhaled breath and efficacy of face masks. Nat Med 2020 Apr 2; [e-pub]. (https://doi.org/10.1038/s41591-020-0843-2)
Bae S et al. Effectiveness of surgical and cotton masks in blocking SARS–CoV-2: A controlled comparison in 4 patients. Ann Intern Med 2020 Apr 6; [e-pub]. (https://doi.org/10.7326/M20-1342)
3) A randomized, double-blinded trial of chloroquine for COVID-19 was stopped early in Brazil because of the development of a prolonged QT and a trend toward a higher mortality with chloroquine 600mg BID.
Eighty-one of a planned 400 hospitalized patients were enrolled using either 600mg BID of chloroquine for 10 days or 450mg BID for 5 days. All patients also got azithromycin and ceftriaxone. The high-dose arm was stopped early because of significant prolongation of the QT in 25% with a trend towards increased mortality (17% in the high dose group vs. 13% with the lower dose). It is recommended to continue to follow the IDSA guidelines for treatment which can be found here.
Silva Borba MG, de Almeida F, Sousa Sampaio V. 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) doi: https://doi.org/10.1101/2020.0...
4) 30% ethanol is enough to inactivate the COVID-19 virus after 30 seconds of contact (Note: that this is not standard of care but might be applicable in low resource areas).
Questions about disinfected surfaces in the time of COVID-19 are legion. A study published by the CDC in the “Emerging Infectious Diseases” on 14 April 2020 suggests that 30% ethanol is just as effective as 80% ethanol. They did quantitative inactivation studies of COVID-19 viruses and looked at various dilutions of ethanol and 2-propranol. The caveat is the contact has to be for at least 30 seconds. All of the WHO-recommended solutions work, as well.
Discussion: This is not recommended this as a routine practice. If resources are very limited, this offers another option.
Kratzel A, Todt D, V’kovski P, Steiner S, Gultrom M, Thao TTN, et al. Inactivation of severe acute respiratory syndrome coronavirus 2 by WHO-recommended hand rub formulations and alcohols. Emerg Infect Dis. 2020 Jul [date cited]. https://doi.org/10.3201/eid2607.200915