The COVID-19 LST Report

In today's episode we discuss:

—Climate: A systematic review by an international team of researchers highlights the significant underrepresentation of geriatric patients in published COVID-19 randomized control trials (RCTs). In the 12 RCTs included in the review, patients had mean age of 56.3 years, and were on average 20 years younger than patients from large observational trials. One explanation for this discrepancy is the strict exclusion criteria used for RCTs, which commonly exclude patients with cognitive impairment and multiple comorbidities frequently seen in the elderly population. The authors strongly advocate for future RCTs to include this vulnerable population that has been disproportionately affected by the COVID-19 pandemic.

—Epidemiology: Pediatric ischemic stroke is an infrequent complication of SARS-CoV-2. Physician members of the International Pediatric Stroke Study Group surveyed 61 international sites to assess the prevalence of SARS-CoV-2 infection in pediatric stroke patients. They found 3.6% (6/166) of pediatric arterial ischemic stroke, 0.9% (1/108) of neonatal arterial ischemic stroke, 1.9% (1/54) of pediatric cerebral sinovenous thrombosis, and zero (0/33) neonatal cerebral sinovenous thrombosis patients were positive for SARS-CoV-2. Authors suggest these results indicate that SARS-CoV-2 does not appear to increase the risk of stroke in neonatal and pediatric populations but acknowledge that more robust testing is needed to determine any role the virus has in pediatric stroke.

—Transmission & Prevention: Dry heat incubation and ambient temperature fail to consistently inactivate SARS-CoV-2 on N95 respirators. Internists and microbiologists from University of New Mexico assessed whether dry heat incubation could decontaminate N95 respirators and found SARS-CoV-2 was not inactivated when N95 coupons inoculated with the virus were heated to 60-75 degrees Celsius for either 30 or 60 minutes when placed on parchment paper but was inactivated when placed on tissue culture plates. When intact 3M 1860 N95 respirators were incubated at 70-75 degrees Celsius for 60 minutes, SARS-CoV-2 was not inactivated. Authors suggests that dry heat incubation is not a consistently effective method for deactivating SARS-CoV-2 on N95 respirators.

—R&D: Diagnosis & Treatments: Efficacy of lopinavir/ritonavir in the treatment of COVID-19 was not found to be considerable according to a systematic review. An international research team from Nested Knowledge, Inc conducted a systematic review of 16 studies assessing the effectiveness and safety of lopinavir/ritonavir (LPV/r) in the treatment of COVID-19 and found the majority of included studies showed no significant improvement in clinical outcomes (RT-PCR negativity, chest-CT findings, mortality, adverse events) following LPV/r treatment, though they could not perform meta-analysis due to the high heterogeneity of the comparison groups. Though their review suggests little survival or clinical benefit of LPV/r in COVID-19, authors recommend larger clinical trials are needed to more definitively explore its potential benefits due to the limitations of currently available data.

—Mental Health & Resilience Needs: Experiences of New Zealand registered nurses of Chinese ethnicity during the COVID-19 pandemic are brought to light in one study. 

In today's episode we discuss:

—Climate: The US Centers for Disease Control COVID-19 Response Team used data from three online CARAVAN omnibus surveys (n=858) conducted to assess parental attitudes and concerns about schools reopening during the COVID-19 pandemic and found more white families were in favor of in-person school (62.3%) compared to Hispanic families (50.2%, p=0.014) and Black families (46.0%, p=0.007), while non-white parents were more concerned about schools opening safely (98.8% very or somewhat concerned) than were white families (86.0%, p=0.012). Authors suggest socioeconomic differences and structural inequities may drive these differing attitudes and recommend school districts consider each community's unique needs when devising school reopening plans.

—Epidemiology: In a retrospective cohort study evaluating albumin levels in correlation with disease severity and inflammatory markers (CRP, d-dimer, and IL-6), investigators in Milan, Italy analyzed data from 207 COVID-19 patients admitted to Fatebenefratelli-Sacco Hospital and found 50.7% patients had hypoalbuminemia (serum albumin <30 g/L), and that albumin levels were significantly inversely correlated with increased severity of disease and worse outcomes at day 30, as well as inversely correlated with inflammatory markers. The results suggest hypoalbuminemia and urinary protein wasting may be useful biomarkers on admission to determine disease severity.

—Understanding the Pathology: Microbiologists and infectious disease specialists from Anhui Medical University and the Anhui and Fuyang Centers for Disease Control in China analyzed SARS-CoV-2 IgM and IgG antibody responses using indirect ELISA in serum from 165 patients and found spike protein IgM and IgG was detectable in 12.5% of hospitalized patients on day 1 of infection, IgM peaked at 22-28 days and was undetectable in 30% and 79% of patients at three and seven months, respectively, and IgG peaked at four months and declined rapidly at seven months. Authors suggest their analysis can help guide SARS-CoV-2 diagnosis and vaccine development via an improved understanding of the human humoral response in COVID-19.

—Transmission & Prevention: A review of current data on COVID-19 transmission and vaccine efficacy by otolaryngologists from Harvard Medical School and Johns Hopkins School of Medicine illustrates how COVID-19 mRNA vaccines generate immunogenicity by creating IgG antibodies against the SARS-CoV-2 virus, however IgG antibodies, while preventing patients from clinically getting sick with COVID-19, do not stop the virus from replicating in the upper airway -- as this requires secretory IgA antibodies -- suggesting that transmission precautions should still be widely practiced even after vaccination.

—Management: A multicenter retrospective study conducted by French physicians at the Cochin Hospital utilized demographic data, clinical symptomatology, and results of lab tests from 605 patients with clinical suspicion of COVID-19 to create a pre-test probability score of SARS-CoV-2 infection (the PARIS score) and found that fever, myalgias, lymphopenia, and elevated CRP had the highest positive predictive value, though no clinical variable was individually significant. The high-probability PARIS score had a positive predictive value of 93%, while the low-probability score had a negative predictive value of 98%. 

In today's episode we discuss:

—Understanding the Pathology: SARS-CoV-2 Infection likely triggers an autoimmune response. A case control study from Northern Italy found elevated inflammatory markers and autoantibodies (ANA, ASCA, IgG and anti-Cardiolipin) in 40 hospitalized COVID-19 patients compared to healthy controls. These results add to the growing body of evidence suggesting the association of COVID-19 with autoimmune disease and inflammatory dysfunction. The authors suggest utilizing these antibodies as prognostic indicators, especially when considering treatment with plasma therapy.

—Management: Is there an effect of artificial liver blood purification treatment on the survival of critically ill COVID-19 patients? A prospective study by multiple infectious disease centers in China to investigated the efficacy of liver blood purification treatment on the survival of severe/critical COVID-19 patients with serum inflammatory factors greater than or equal to five times the upper limit. A total of 101 critical COVID-19 patients were enrolled in the study and divided into either the treatment group or the control group. The authors demonstrated that artificial liver therapy clears inflammatory mediators through blocking the cytokine storm thus preventing theses cases from worsening any further and improving the survival rate.  

—Mental Health & Resilience Needs: Mental health continues to take a toll approximately 35 days after hospitalization for COVID-19 infection. Investigators from Hackensack Meridian School of Medicine and Hospital in New Jersey conducted a single center prospective cohort study of 183 COVID-19 patients admitted to Hackensack Meridian Hospital in order to identify persistent physical symptoms, psychological health, social relationships, and activities of daily living all pertaining to their self-reported quality of life 35 ± 5 days after hospital discharge. The results revealed 16.9% of participants reported their mental health as poor or fair, impairing their daily living, physical and mental health, and quality of life, suggesting the importance of early intervention for both physical and mental symptoms, along with social support, as an essential part of full recovery from COVID-19.

In today's episode we discuss:

—Climate: Board members of the International Society of Vaccine (ISV) summarize their organization's recent efforts to provide information and resources about COVID-19 vaccines to members worldwide: they provide links to their recent virtual lecture series on COVID-19 vaccines and suggest their organization is a global leader on vaccine development that can provide balanced information to a variety of stakeholders. The authors encourage new researchers and developers to join the ISV at www.isv-online.org.

In today's episode we discuss:

—Epidemiology: What was the SARS-CoV-2-specific neutralizing antibody response in Norwegian healthcare workers after the first wave of COVID-19 pandemic? A multicenter prospective survey study of 607 healthcare workers (HCW) by a researcher at the Influenza Centre at the University of Bergen in Norway found 5% of participants (32/607) were seropositive for SARS-CoV-2 (spike-specific IgG, IgM, and IgA antibodies), including 21 who were positive at baseline and 11 who seroconverted during follow-up. 77% of the infected HCWs, in high-risk departments were young nurses aged 23-31. Results also showed that HCW were 11.6 times more likely to contact COVID-19 patients when compared to low-risk HCW or community members, while HCW with partial PPE were at a 2.5 fold higher risk. Authors highlight the importance of protecting high-risk frontline HCW and suggest prioritization of this group during vaccine distribution.

—Understanding the Pathology: Could there be an association of salivary content alteration and early ageusia symptoms in COVID-19 infections? Dental specialists in Saudi Arabia reviewed 36 studies on chemical and inflammatory changes that occur in SARS-CoV-2 infected salivary glands and propose a chemosensory mechanism to explain alterations in taste and smell found commonly seen in COVID-19. In patients reporting aguesia, they found changes in salivary hormones, inorganic compounds, pH, enzymes, and salivary flow rate, which are all involved in normal taste perception. Authors suggest with better understanding and characterization of these changes, we may be able to prevent or treat changes in smell or taste seen among COVID-19 patients.

—Transmission & Prevention: Specific occupations and risk of severe COVID-19 are positively correlated. In this large-scale prospective cohort study, authors from various public health institutes in Glasgow, UK, Limerick, Ireland, and Syracuse, NY, analyzed data from the UK Biobank, involving 120,075 participants aged 40-69 registered with the National Health Service (NHS) in England, Wales or Scotland, and grouped them into occupational groups with concomitant serious COVID-19 infection (having to be hospitalized), in order to asses risk of infection across essential occupations.

—Management: There may be a high prevalence of pulmonary sequelae at 3 months after hospital discharge in mechanically ventilated COVID-19 survivors. In this letter to the editor, Dutch researchers share their clinical data from 48 critically-ill COVID-19 patients who underwent follow-up screening three months after discharge that included pulmonary function testing (PFT), high resolution chest CT (HRCT), and 6-minute walk test (6-MWT).

—R&D: Diagnosis & Treatments: There is some data suggesting usage of smartwatch tracking data to detect COVID-19 cases early. An article reviews a study conducted by researchers at Scripps Research Translational Institute who compared the smartwatch data between 333 participants, 54 of which ended up reporting positive for COVID-19, and found that symptom tracking plus smartwatch biometric data collecting yielded more predictive results of COVID-19 positive test probability than symptom tracking alone.This study was conducted earlier this year and used a smartphone/smartwatch app called DETECT.

In today's episode we discuss:

—Climate: Operations officers from several international biomedical manufacturing companies discuss the ability of manufacturers to reduce distribution of counterfeit vaccines in light of counterfeit SARS-CoV-2 vaccines being found in Russia and Ecuador in 2020. Authors recommend using various tracking methods such as a GS1 2D DataMatrix barcode, QR code and matrix code, or Automatic Identification and Data Capture (AIDC) flow to scan and identify vaccines, trace them from the factory to delivery, and upload that data into an easily accessible system. They suggest such a tracing system is necessary to ensure the delivery of safe and authentic vaccines from factories to the public.

—Epidemiology: A team from Johns Hopkins University and Brown University conducted a systematic review and meta-analysis of 77 studies (38906 hospitalized patients) and found the overall prevalence of death from COVID-19 among hospitalized patients was 23% (19–27%) in the US and Europe versus 11% (7–16%) in China. Risk factors for death included age 60 or older (sRR = 3.6; 95% CI: 3.0–4.4; I^2 77%), male gender (sRR=1.3; 1.2–1.4; I^2 18%), smoking history (sRR=1.3; 1.1–1.6; I^2 68%), COPD (sRR=1.7; 1.4–2.0; I^2 66%), diabetes (sRR=1.5; 1.4–1.7; I^2 58%), heart disease (sRR=2.1; 1.8– 2.4; I^2 69%), CKD (sRR =2.5; 2.1–3.0; I^2 72%). They observed similar risk factors for severe disease (respiratory rate>30, oxygen saturation<93%, and PaO2/FiO2<300 and/or lung infiltrates>50% within 24–48 hours).

—Transmission & Prevention: Researchers from England studying COVID-19 transmission in the education system found that the overall risk of SARS-CoV2 infection among children and school staff was low: there was minimal evidence of transmission from student to student or student to faculty member, and infected children most commonly acquired SARS-CoV-2 from family members at home. Data suggests that the rate of transmission in schools was directly correlated with regional COVID-19 prevalence, suggesting that re-opening schools may not significantly increase infection rates among children or school staff unless this is during a surge or in high prevalence areas.

· Members of the US Centers for Disease Control COVID-19 Response Team summarize their recommended public health strategies for mitigation of community SARS-CoV-2 transmission: they recommend the use of face masks, maintaining physical distancing, prompt case investigation, avoiding crowded situations, increasing protection for persons at highest risk for severe COVID-19, adequately protecting healthcare workers, improved hygiene practices, avoiding unnecessary travel, and widespread use of safe vaccines. Authors suggest following such evidence-based measures will substantially contribute to combating transmission of COVID-19.

In today's episode we discuss:

—Understanding the Pathology: Researchers from the Department of Health & Exercise Science at Appalachian State University analyze the vascular impact of SARS-CoV-2 on 20 healthy young adults 3-4 weeks post-infection by doppler ultrasound of arterial blood flow in the upper and lower extremities (markers of vascular function) and pulse wave velocity (indicator of arterial stiffness). Results demonstrated that brachial artery flow-mediated dilation (FMD) was 6% lower after COVID-19 infection, which is clinically significant because each 1% decrease in FMD is associated with a 13% higher risk of cardiovascular events, suggesting that systemic vascular dysfunction and arterial stiffness may be a potential mechanism of COVID-19 vasculopathy.

—Management: A single-center observational cohort study from Turin, Italy analyzed coagulopathy in 36 hospitalized pediatric patients (ages birth to 21 years) with COVID-19 (n=30) and Multisystem Inflammatory Syndrome in Children (MIS-C) (n=6) and found that D-dimer values were not useful in predicting disease severity. Significant differences between D-dimer and CRP values were observed between COVID-19 and MIS-C patients, however there was no difference in coagulopathy incidence in these groups (as measured by fibrinogen levels). They recommend against universal pharmacologic prophylaxis in pediatric COVID-19 patients except in cases of multiple concurrent pro-thrombotic risk factors such as obesity, active malignancy, and sickle cell disease.

In today's episode we discuss:

—Climate: What are the COVID-19 vaccine trial ethics once we have efficacious vaccines? An expert opinion penned by bioethicists from the National Institutes of Health and Fogarty International Center in Bethesda, MD explore the ethics of continuing blinded, placebo-controlled trials for COVID-19 vaccines in the wake of a safe and efficacious vaccine being approved for widespread use. Authors argue it is ethical to continue trials if participants consent and the risk-benefit profile of the trial remains acceptable, because continuing trials could lead to the discovery of longer lasting vaccines, better immunity, or greater efficacy in subpopulations. However, the authors emphasize trial participants in blinded, placebo-controlled trials should be informed of the availability of the vaccine and allowed to leave the trial if they desire.

—Understanding the Pathology: The L37F mutation may be critical to asymptomatic COVID-19 infection and transmission. Computer scientists from the University of Illinois analyzed 75,775 SARS-CoV-2 complete genome isolates to explore virological characteristics in asymptomatic COVID-19. They found patients with asymptomatic COVID-19 were significantly more likely to have the SARS-CoV-2 single nucleotide mutation 11083G>T-(L37F) on Non-Structural Protein 6 (NSP 6)(r=0.61, p=5.42×10^-56) and countries with the highest L37F mutation ratio had lower death ratio. Artificial intelligence (AI), topological data analysis (TDA), and network analysis revealed L37F destabilized NSP6's structure in a way that impeded viral assembly and replication. Authors suggest L37F mutation as a possible explanation for asymptomatic COVID-19 and encourage further research on therapies targeting NSP6.

—Transmission & Prevention: Transmissibility of COVID-19 depends on the viral load around onset in adult and symptomatic patients. Infectious disease specialists and microbiologists from the Toyama University Graduate School of Medicine and Pharmaceutical Sciences in Japan conducted a case-control study comparing patients with 14 COVID-19 who did ("index patients") and 14 who did not transmit SARS-CoV-2 to another patient. They found index patients showed higher viral loads at onset compared to non-index patients (6.6 [5.2 to 8.2] log copies/μL vs. 3.1 [1.5 to 4.8]) and that, in general, symptomatic patients had a higher initial viral load (2.8 log copies/μL) than asymptomatic patients (0.9 log copies/μL, p<0.01). Authors suggest elevated nasopharyngeal viral load contributes to secondary transmission of SARS-CoV-2, and that understanding the viral threshold for infectivity can better quarantine and isolation policies.

· Peripheral oxygen saturation does not decrease in older persons wearing nonmedical face masks in community settings. Internists from McMaster University in Canada conducted a crossover study of 25 retirement home residents older than 65 to monitor self-measured peripheral oxygen saturation (SpO2) with use of a three-layer disposable nonmedical face mask. They found pooled mean SpO2 was 96.1%, 96.5%, 96.3% in the hour prior to use, during one hour of use, and one hour after wearing the masks, respectively.Authors suggest despite some public concerns about mask safety, the use of nonmedical face masks is not associated with a decrease in SpO2 in older populations.

In today's episode we discuss:

—Climate: The editorial team at JAMA explains their decision to publish the Lenze et al study "Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial." While it is a preliminary study with limitations, authors argue it warranted publication due to its design as a placebo-controlled, double-blind randomized clinical trial and the authors' methodological adjustments to conduct study activities without physical contact, such as arranging oxygen and medications deliveries for self-quarantining patients and obtaining consent virtually. The team suggests that the Lenze et al pilot study provides an excellent example of pandemic-appropriate research methods and lays the groundwork for research into preventing outpatients with COVID-19 from deteriorating into a more severe disease status.

—Epidemiology: A retrospective cohort study that analyzed pediatric electronic health record data from PEDSnet (n=135,794 patients <25 years) from found 4% of patients were infected with SARS-CoV-2 (n=5,374), while Kawasaki Disease prevalence decreased in 2020 compared to 2018 or 2019*. Risk factors for SARS-CoV-2 infection included preexisting chronic disease and increased age. Additionally, subjects of Hispanic, Black, or Asian race/ethnicity had a higher likelihood of positive test result compared to White race/ethnicity, though they received fewer tests per population. These results provide large-scale data on pediatric risk factors, which authors hope will add to the growing knowledge on SARS-CoV-2 and host biology in pediatric populations.

· Leaders in the United Kingdom's Department of Health conducted a systematic review and narrative synthesis of literature on SARS-CoV-2 infection in children published through March 9, 2020 (24 articles) and found that children under age 10 had similar infection rates to adults, but the observed rate of infection in children was perceived as lower since children often had undetected milder infections, and transmission usually occurred within familial clusters when children were exposed to an infected adult. Authors suggest further data collection is necessary to understand child to child transmission of SARS-CoV-2 and to detail the clinical course of COVID-19 in children.

—Understanding the Pathology: A cohort-control study by pediatric infectious disease specialist in Ankara, Turkey evaluated cytokine and chemokine levels from serum samples of 60 COVID-19 positive patients (30 pediatric, 30 adult) and found that COVID-19 patients had higher levels of IP10 and MIP-3B compared to 30 healthy controls (15 pediatric, 15 adult; p<0.001), while IP-10 was a predictor for disease severity in children and IL-6 a predictor for disease severity in adults. They suggest these findings provide insight into potential treatment targets for COVID-19 and further elucidate potential uses for inflammatory markers as prognostic indicators for pediatric and adult COVID-19 severity.

In today's episode we discuss:

—Epidemiology: A systematic review of 39 articles (30 retrospective and 9 prospective) on venous thromboembolic events (VTE) in COVID-19 by a team of cardiologists and molecular biologists from the Central South University in Hunan, China found that D-dimer, fibrinogen, and APTT may be useful in predicting thromboembolic events in patients with severe COVID-19.

—Understanding the Pathology: Physicians at the Icahn School of Medicine used enzyme-linked immunosorbent assay (ELISA) to screen patients (n=72,401) at Mount Sinai Health System for the SARS-CoV-2 spike protein antibody and found that 30,082 patients tested positive (titer 1:80 or higher) with quantitative microneutralization assay demonstrating that spike protein titer level positively correlated to neutralization titer (Spearman r: 0.87, p<0.000). A subgroup (n=121) had titers drawn at multiple timepoints (30, 82, and 148 days after symptom onset), and their ELISA titers still positively correlated with the neutralization titers after 148 days (r: 0.79; p=0.0001), suggesting that patients infected with SARS-CoV-2 form long lasting neutralizing antibodies and that understanding the kinetics of these antibodies could aid in the vaccine development.

—Management: Infectious disease physicians at the Imperial College London reviewed publications about bacterial and fungal coinfection with human coronaviruses and found that in the nine studies, 62/806 patients (8%) experienced coinfections during hospital admission. Because most patients across all studies received broad spectrum antibiotics (1450/2010; 72%), authors suggest the seemingly low occurrence of coinfection may be attributable to empiric antibiotic use and recommend conducting prospective studies to inform antibiotic stewardship during the COVID-19 pandemic.

· Members of the World Association of Perinatal Medicine propose consensus statements regarding SARS-CoV-2 infection in pregnant patients based on their review of the literature. They comment on diagnosis, screening in laboring patients, maternal and fetal complications, vertical transmission, delivery mode, breastfeeding, appropriate setting of care, and use of antiviral medications.