COVID-19 Research Round-Up

Infections and Transmission in a Skilled Nursing Facility. Aronsetal. NEJM, April24,2020. DOI: 10.1056/NEJMoa2008457. Accessed April 27,2020.

Commentary Aaron Kofman, MD Emory UniversityRelevance: Presymptomatic and asymptomatic transmission have been increasingly well-described features of SARS-CoV-2 epidemiology.Findings: Residents in two skilled nursing facilities in King County, WA were enrolled in two serial point-prevalenceSurveys conducted 1 week apart.At time point 1, 27/48 (56%) of residents participating in the surveys that tested positive were asymptomatic, of whom 24 subsequently developed symptoms (would therefore be “presymptomatic”)Presymptomatic individuals had a median rRT-PCR Ct value of 23.1 (at time of presymptomatic-ness), with viable virus recovered from 17/24 individualsOf note, 26symptomaticstaff members who continued to work tested positive (19% of total)Whatthisstudyadds: Transmission of SARS-CoV-2 is extremely efficient within nursing facilities, with presymptomatic spread accounting for a large portion of cases and likely contributing to transmission. Low Ct values at time of presymptomatic-ness and viable virus recovery from a majority of these patients adds further evidence to the picture.Limitations/Conclusions: The relative degree of transmission from facility residents (presymptomatic, asymptomatic or symptomatic) as compared to staff is difficult to know from this study. With 19% of study workers symptomatic and testing positive for SARS-CoV-2, this may have played a substantial role in transmission as well, and there are likely additional presymptomatic cases among this group that could also account for transmission. Regardless, the study adds important characterization to the extreme vulnerability of nursing facility residents to COVID-19.

Transmission/InfectionControl

Commentary: Nithin Gopalsamy, MD Emory University “Aerodynamic Analysis of SARS-CoV-2 in Two Wuhan Hospitals.” Nature,April27,2020,1–6.https://doi.org/10.1038/s41586-020-2271-3.

Aerosol transmission of COVID-19 has been suggested though not well-characterized. Transmission is primarily thought to be via droplet and contact though retrospective study of SARS in 2003 suggested airborne spread may have also been present.Transmission is primarily thought to be via droplet and contact though retrospective study of SARS in 2003 suggested airborne spread may have also been present.Airborne SARS-CoV-2 and its aerosol deposits were quantified using droplet digital PCR of the viral RNA

Samples obtained from 30 sites in units and public areas in 2 hospitals in Wuhan –one representing a tertiary hospital and the other representing the make-shift hospitals constructedAmong patient areas, very low or non-detectable concentrations of airborne SARS-CoV-2 inside the rooms, suggesting effective negative pressure isolationAmong patient areas,highest concentration noted on toilets; very low or non-detectable concentrations of airborne SARS-CoV-2 inside the rooms, suggesting effective negative pressure isolationAmong medical staff areas, highest concentration noted in PPE removal roomsAmong public areas, concentration generally low; most notable site near entrance of department storeWith addition of disinfectant to high-risk areas, concentration reduced to undetectable levelsLimitations:PCR-positivity does not infer infectivity (unknown if these quantified particles harbor live virus actually leading to new cases). Small number of samples.Conclusions:Decontamination should remain a high priority with particular attention now to patient room toilets, PPE before its removal (if feasible), and high volume public areas such as store entrances. COVID appears to aerosolize though remains unclear if these aerosol particles contain live virus leading to transmission.Clinical SyndromeCovid-19: concerns grow over inflammatory syndrome emerging in childrenBMJ2020;369:m1710Doctors in the UK have been warned over a rising number of children presenting with a multisystem inflammatory state and needing intensive care.cases have in common “overlapping features of toxic shock syndrome and atypical Kawasaki disease with blood parameters consistent with severe covid-19 in children.” Abdominal pain and gastrointestinal symptoms were also reported as common features, as well as cardiac inflammation.Between 15 March and 22 April the hospitals saw 105 children who were sick with covid-19, 28 of whom required hospitalization.

Castagnoli, Riccardo et al. “Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Children and Adolescents: A Systematic Review.” JAMA Pediatrics, April 22, 2020. https://doi.org/10.1001/jamapediatrics.2020.1467. Satoshi Kamidani, MD

While data are available for adult patients with coronavirus disease 2019 (COVID-19), limited reports have analyzed pediatric patients infected with SARS-CoV-2.Designed to retrieve all articles published from December 1, 2019, to March 3, 2020. Retrospective cross-sectional and case-control studies, case series and case reports, bulletins, and national reports about the pediatric SARS-CoV-2 infection were included.A total of 815 articles were identified. 18 studies with 1065 participants (444 patients were younger than 10 years, and 553 were aged 10 to 19 years) with confirmed SARS-CoV-2 infection were included.All articles reflected research performed in China, except for 1 clinical case in Singapore.

Children at any age were mostly reported to have mild respiratory symptoms, fever, dry cough, and fatigue, or were asymptomatic.Bronchial thickening and ground-glass opacities were the main radiologic features, and these findings were also reported in asymptomatic patients.Most pediatric patients were hospitalized, and symptomatic children received mainly supportive care. 1 infantpresented with pneumonia, complicated by shock and kidney failure, and was successfully treated with intensive care.No deaths were reported in children aged 0 to 9 years whereas, 1 death was reported in the age range of 10 to 19 years.Limitations: A brief 3-month period reviewed. European and US studies in children withCOVID-19 were not available. The included studies were only observational designs, and many were simple case series or case reports.Conclusions: Most children with COVID-19 presented withmild symptoms, if any, generally required supportive care only, and typically had a good prognosis.

Immunocompromised Hosts

Amy Sherman, MD Pereira, Marcus R. et al. “COVID-19 in Solid Organ Transplant Recipients: Initial Report from the USE picenter.” American Journal of Transplantation n/a,no.n/a.AccessedApril28,2020.https://doi.org/10.1111/ajt.15941.

The role of chronic immunosuppression on outcomes for patients affected by Covid-19 is not known.The authors describe the characteristics of 90 solid organ transplant (SOT) recipients with Covid-19 at two large academic centers in NYC during the initial 3 weeks of the epidemic.Transplant recipients: 46/90 renal, 17/90 lung, 13/90 liver, 9/90 heart, 3/90 heart-kidney, 1/90 liver-kidney, 1/90 kidney-pancreas.Median time from transplant to Covid-19 diagnosis = 6.64 years24% with mild disease, 46% with moderate disease, and 30% with severe disease.Patients with severe disease tended to have hypertension, active cancer, and/or advanced age.For hospitalized patients (68/90), treatment strategies included reducing immunosuppression. Patients received a mix of hydroxychloroquine, azithromycin, and tocilizumab.Mortality: 16/90 died from Covid related complications. 37/90 discharged home.No cases of rejection or thromboembolic complications.Conclusions: Immunosuppressed patients presented with similar symptoms to those reported in the general population. Indications and optimal timing for treatment (esp immunomodulatory therapies) remains unknown for immunocompromised hosts. Severity of disease and mortality rates were high in this population.Limitations: The high mortality rate reported may reflect sampling bias (mostly hospitalized patients included), and does not take into account confounding factors (e.g. comorbidities and advanced age may have driven this conclusion, not immunosuppression itself).

Akalin, Enver et al. “Covid 19 and Kidney Transplantation.” New England Journal of Medicine, no.0(April24,2020):null.https://doi.org/10.1056/NEJMc2011117.

To investigate the clinical syndrome and risk factors of renal transplant recipients infected with SARS-CoV-2, a single center in NYC evaluated 36 consecutive patients between March 16 and April 1, 2020.72% were male, median age = 60 years old.39% were black, 42% were Hispanic.94% had hypertension, 69% had DM2, 36% had a history of smoking, and 17% had heart disease.Immunosuppression regimens included tacrolimus, prednisone, and/or mycophenolate mofetil.Most common symptom initially was fever, but only in 58% of patients.39% required mechanical ventilation.Lab findings: lymphopenia, thrombocytopenia, low CD3, CD4, and CD8 counts. Elevated inflammatory markers.Mortality: 10/36 patients (28%).Conclusions: As compared to the general population, kidney transplant-recipients with Covid-19 has less fever as a presenting symptom, lower CD3, CD4, CD8 counts, and more rapid clinical progression.The low CD3/CD4/CD8 counts support the need to decrease immunosuppressive therapies. Overall higher mortality reported in this population.Limitations: Single center study in NYC, may not be generalizable to other cities/transplant centers. Patients had significant comorbidities (e.g. HTN and DM2) that are known tobe risk factors for severe Covid disease.

Sankar J, Dhochak N, Kabra SK, Lodha R. COVID-19 in Children: Clinical Approach and Management [published online ahead of print, 2020 Apr 27]. Indian J Pediatr. 2020;1‐10. doi:10.1007/s12098-020-03292-1Good review of pediatric COVID-19but treatment protocols are based on Indian policy (admitting asymptomatic positives etc) https://dontforgetthebubbles.com/wp-content/uploads/2020/04/COVID-data-top-10.pdf: European summary of pediatric COVID-19Diagnostics: IDSA guidelines:IDSA COVID-19 Antibody Testing Primer Updated: April 29, 2020 Potential drawbacks if serological assays are not well-validated: ▪ False negative risks if performed early in disease course, especially in mild disease; ▪ False positive risks, particularly with tests for Immunoglobulin M (IgM) and potential crossreactivity with common cold coronaviruses (e.g. HKU1, NL63, OC43, 229E).There are a multitude of different antibody tests for COVID-19 with variable performance. Tests vary in the viral antigen(s) they target, e.g., nucleoprotein (N protein) or spike protein (S protein). It is not yet clear which antibody responses, if any, are protective or sustained. A “positive” test is exceptionally difficult to interpret because the performance of these tests is not well known. For some assays both sensitivity and specificity may be poor, or at the very least undefined. -Clinical laboratories will need to perform validation studies of commercial reagents. -Some FDA-authorized COVID-19 antibody tests are estimated to have 96-98% specificity, which would mean that a positive test result is more likely a false-positive result than a true positive result if the prevalence or pretest probability is 5% or less.

Therapeutics Initial results from the Adaptive COVID-19 Treatment Trial (ACTT)Remdesivir seems to shorten duration of illness by 3-4 days. Really. That’s it. But, if those few days are ventilator free days, recovery is definitely faster. Also, makes the case for early use of remdesivir before respiratory symptoms worsen.This study is an adaptive, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. The study is a multicenter trial that will be conducted in up to approximately 100 sites globally. The study will compare different investigational therapeutic agents to a control arm.

Magagnoli, Joseph et al. “Outcomes of Hydroxychloroquine Usage in United States Veterans Hospitalized with Covid-19.” MedRxiv,April23,2020,2020.04.16.20065920.https://doi.org/10.1101/2020.04.16.20065920.

The hydroxychloroquine saga has dominated much of the COVID-19 treatment landscape. Prior to this study from the VA healthcare system, a controversial open label non randomized study from France (Raoult et.al) touted the merits of combining hydroxychloroquine withAzithromycin to treat COVID-19.Following that initial study, the drug has gained popularity as the preferred off-label antiviral agent for COVID-19. Other studies have since emerged casting doubt on the safety and efficacy for hydroxychloroquine against SARS-CoV-2 most notably a recent study from Brazil which showed higher rates of deaths and adverse events in patients who received high dose hydroxychloroquine for treatment of COVID-19 and a lack of clinical improvement in treated patients.This was retrospective analysis of patients hospitalized for SARSCoV-2 infection in the Veterans Health System up until April 11, 2020. Patients were categorized based on treatment with hydroxychloroquine alone (HC), hydroxychloroquine plus azithromycin (Hc+AZ) or supportive care (no HC). A total of 368 patients were evaluated (HC, n=97; HC+AZ, n=113; no HC, n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%,6.9%, 14.1%, respectively. Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61, P=0.03) but not in the HC+AZ group (1.14; 95% CI, P=0.72)This study, though an observational retrospective cohort study by design, included a control group comparing the intervention (treatment with hydroxychloroquine) to supportive care. The lack of a control group has been a much-criticized feature of the previous cohort studies published on use of hydroxychloroquine to treat COVID-19.Importantly this study highlighted the apparent lack of benefit for those treated and the higher rates of death associated with receiving hydroxychloroquine.

Interpretation/limitations/conclusions: The main limitation of the study is the absence of randomization. The authors however make a decent attempt to adjust for COVID-19 related confounders. However, this does not fully rule out the possibility of selection bias or residual confounding.Also, the study included only men with median age of 65 and as such may not be generalizable to a more heterogenouspopulation. While we await randomized controlled studies assessing the usefulness of hydroxychloroquinein COVID-19, the data which are currently available suggest caution for its use given unclear benefit and possible harm.

Vaccines Amanat, Fatima, and Florian Krammer. “SARS-CoV-2 Vaccines: Status Report.” Immunity52,no.4(April2020):583–89.https://doi.org/10.1016/j.immuni.2020.03.007.Within the last decade, vaccine technologies have rapidly evolved.A vaccine target for SARS-CoV-2 (the S protein) was identified early in the pandemic, and is now being integrated into different vaccine platforms.The authors review the current landscape for SARS-CoV-2 vaccines.Challenges in the development of an effective coronavirus vaccine:Human coronavirus infections do not always induce long lived antibody responses.A durable response is needed for an efficacious vaccine. The most severe disease from Covid-19 has been seen in older adults. Due to immune senescence, it is difficult to produce a robust immune response in this population to confer protection.No clear animal model for early phase trials has been developed.For a mostly naïve population, protection via vaccination will likely require a prime-boost vaccination regimen (e.g. at least 2 vaccines in a series).Novel vaccine must be able to be mass-produced.Current pipeline of SARS-CoV-2 vaccine development:Target the S protein: RNA, DNA, recombinant protein, viral vector-based (VSV) vaccine platforms.Target the whole virion: Live attenuated and inactivated vaccinesConclusions: Developing safe and effective vaccines for humans usually takes years.With the rapid identification of the SARS-CoV-2 sequence, the process has been accelerated.However, since there are no current approved coronavirus vaccines, we must start from the beginning to build a viable vaccine, and also build the capacity for mass production.Even with new technologies and an accelerated process, SARS-CoV-2 vaccines will likely not be ready for at least 12-18 months.Wellness of patients and providershttps://www.cstsonline.org/resources/resource-master-list/coronavirus-and-emerging-infectious-disease-outbreaks-responseGreat resources-definitely worth a look.

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