Literature Updates

COVID-19 patients with cardiovascular comorbidities or risk factors are more likely to develop cardiovascular complications while hospitalized, and more likely to die from COVID-19 infection, according to a study published in PLOS ONE. Researchers analyzed data from 21 published observational studies on a total of 77,317 hospitalized COVID-19 patients in Asia, Europe and the United States. At admission, 12.89% had cardiovascular comorbidities, 36.08% had hypertension and 19.45% had diabetes. Cardiovascular complications were documented during the hospital stay for 14.09% of the COVID-19 patients, the most common of these being arrhythmias or palpitations; significant numbers of patients also had myocardial injury. Pre-existing cardiovascular comorbidities or risk factors were found to be significant predictors of cardiovascular complications, but age and gender were not. Both age and pre-existing cardiovascular comorbidities or risk factors were significant predictors of death. DOI: 10.1371/journal.pone.0237131

In a study published in JAMA, a team of investigators from Brigham and Women's Hospital found no association between the number of in-person healthcare visits made by pregnant patients in the spring of 2020 and risk of infection with SARS-CoV-2. Findings are based on close to 3,000 patients delivering between April 19 and June 27, 2020 at four Mass General Brigham hospitals, all of whom were tested at admission for COVID-19. On average, the 111 patients who tested positive attended 3.1 visits in person versus 3.3 among those who tested negative. DOI: 10.1001/jama.2020.15242

Consistent with earlier reports, a study by researchers at the University of Minnesota has identified considerable disparities in the prevalence of COVID-19 across racial/ethnic subgroups of the U.S. population in 12 states. In addition, they observed high hospitalization rates for Hispanic individuals in most of the states analyzed and high hospitalization rates for American Indian and Alaskan Native populations in select states. The findings highlighted the need for increased data reporting and consistency within and across all states; only the 12 states have consistently reported hospitalizations by race/ethnicity during the April 30 through June 24, 2020 study period. DOI: 10.1001/jamainternmed.2020.3857 

COVID-19 mortality for those able to access hospital care did not differ between black and white patients after adjusting for sociodemographic factors and comorbidities, report researchers from Ascension Health in St. Louis in JAMA Network Open. The findings confirm earlier findings from studies in Louisiana and Georgia. In the analysis of 11,210 COVID-19 patients at 92 hospitals across 12 states, overall all-cause, in-hospital mortality was 20.3%; higher risk was associated with older age, male sex, Medicare insurance, coexisting chronic kidney disease, and coronary artery disease. DOI: 10.1001/jamanetworkopen.2020.18039

Two different types of detectable antibody responses in SARS-CoV-2 tell very different stories and may indicate ways to enhance public health efforts against the disease, according to researchers at The University of Texas MD Anderson Cancer Center. Antibodies to the SARS-CoV-2 spike protein receptor binding domain (S-RBD) are speculated to neutralize virus infection, while the SARS-CoV-2 nucleocapsid protein (N-protein) antibody may often only indicate exposure to the virus, not protections against reinfection. The results, published in JCI Insight, highlight findings from a quantitative serological enzyme-linked immunosorbent assay using SARS-CoV-2 S-RBD and N-protein for the detection of circulating antibodies in 138 serial serum samples from confirmed COVID-19 hospitalized patients and 464 healthy and non-COVID-19 serum samples that were collected between June 2017 and June 2020. Results showed that 3% of healthy and non-COVID-19 samples collected during the pandemic in Houston were positive for the N-protein antibody, but only 1.6% of those had the S-RBD antibody. Of samples with the S-RBD antibody, 86% had neutralizing capacity vs. only 74% of the samples with N-protein. When positive for both, 96.5% exhibited neutralizing capacity. Some commercially available serological tests confirm only the presence of antibodies to the N-protein. Results could aid in rapid assessment of the efficacy of vaccine candidates as they are translated into the broader population DOI: 10.1172/jci.insight.142386 

Researchers at Johns Hopkins University School of Medicine studying tissue removed from patients’ nose during endoscopic surgery believe they may have discovered the reason why so many people with COVID-19 lose their sense of smell, even when they have no other symptoms—extremely high levels of angiotensin converting enzyme II (ACE-2) only in the area of the nose responsible for smelling. Their findings, published in the European Respiratory Journal, offer clues as to why COVID-19 is so infectious and suggest that targeting this part of the body could potentially offer more effective treatments. In addition to surgically removed tissue samples from the olfactory epithelium of 23 patients, the research team also studied biopsies from the trachea of seven patients; none of the patients had been diagnosed COVID-19. The levels of ACE2 in olfactory epithelium cells was between 200 and 700 times higher than other tissue in the nose and trachea, and similarly high levels were found in all the samples regardless of whether the patient had been treated for chronic rhinosinusitis or another condition. ACE2 was not detected on olfactory neurons, the nerve cells that pass information about smells to the brain. DOI: 10.1183/13993003.01948-2020

In the most comprehensive study of COVID-19 pediatric patients to date, Massachusetts General Hospital and Mass General Hospital for Children (MGHfC) researchers provide critical data showing that children play a larger role in the community spread of COVID-19 than previously thought. In a study of 192 children ages 0-22, 49 tested positive for SARS-CoV-2, and another 18 had late-onset, COVID-19-related illness. The infected children had a significantly higher level of virus in their airways than hospitalized adults in ICUs for COVID-19 treatment. Lower numbers of the virus receptor in younger children did not correlate with a decreased viral load. The researchers also studied immune response in Multisystem Inflammatory Syndrome in Children that can develop several weeks after SARS-CoV-2 infection to discover that the heart seems to be the favorite organ targeted for serious systemic complications, as in adults. Findings from nose and throat swabs and blood samples from the MGHfC Pediatric COVID-19 Biorepository carry implications for the reopening of schools, daycare centers and other locations with a high density of children and close interaction with teachers and staff members, researchers note. The study published in the Journal of Pediatrics. DOI: 10.1016/j.jpeds.2020.08.037

Mild cases of COVID-19 can trigger robust memory T cell responses, even in the absence of detectable virus-specific antibody responses, researchers report in Cell. To date, there is limited evidence of reinfection in humans with previously documented COVID-19 and most studies of immune protection against SARS-CoV-2 in humans have focused on the induction of neutralizing antibodies that tend to wane and are not detectable in all patients. Here, researchers assessed SARS-CoV-2-specific T cell and antibody responses in more than 200 individuals from Sweden across the full spectrum of exposure, infection, and disease. During the acute phase of infection, the T cell responses were associated with various clinical markers of disease severity. After recovery, the strongest T cell responses were present in individuals who had a severe course of the disease. Progressively lower T cell responses were observed in individuals who recovered from very mild COVID-19, and family members exposed to the virus, but were detectable months after infection and sometimes in the absence of SARS-CoV-2-specific antibodies. Findings suggest that reliance on antibody responses may underestimate the extent of population-level immunity against SARS-CoV-2. DOI: 10.1016/j.cell.2020.08.017 

Researchers at Case Western Reserve University have added to the growing body of understanding about how hydroxychloroquine (HCQ) is not a possible defense against COVID-19. Specifically, they found that HCQ is not effective in preventing COVID-19 in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA)—two patient groups who frequently take the drug. Recent studies have shown that HCQ is not effective in treating moderate-to-severe hospitalized cases; its value early in the disease or for mild cases is still under review. The Case Western Reserve team drew on a large national database, pulling de-identified patient data from 36 health systems, to compile a much larger study than previous work. While prior studies had fewer than 20 COVID-19 patients with SLE and/or RA, this study had 159. Findings published in the Annals of the Rheumatic Diseases. DOI: 10.1136/annrheumdis-2020-218683

A Viewpoint published in JAMA Internal Medicine, remdesivir is used as an illustration of how drug sponsors have taken advantage of policy loopholes to obtain orphan drug benefits for drugs that address public health crises, in this case for the COVID-19 pandemic, rather than rare diseases. The authors, from the University of Michigan and Boston University, argue that Congress and the FDA should ensure that the benefits of the Orphan Drug Act are only used in a manner consistent with its purpose. DOI: 10.1001/jamainternmed.2020.2759

The results of an online questionnaire of 609 breast cancer survivors in the U.S., 63% of whom were currently receiving cancer care, suggest that nearly half (44%) of patients experienced delays in care during the early weeks of the COVID-19 pandemic. Postponement of routine follow-up appointments was most often cited (79%), followed by breast reconstruction surgery (66%), diagnostic imaging (60%) and lab testing (50%). Approximately 30% of respondents reported delays in hospital- or clinic-based cancer therapies, including radiation, infusion therapies and surgical tumor removal. Younger women were more likely to experience delays, but black and white patients were equally impacted. The study, by researchers at the University of Illinois at Chicago, published in Breast Cancer Research and Treatment. DOI: 10.1007/s10549-020-05828-7 

Researchers from Evelina London Children's Hospital and King's College London have uncovered how the immune system is altered in a rare COVID-19 related illness in children referred to as multisystem inflammatory syndrome in children (MIS-C). The condition, first treated at Evelina London in mid-April 2020, causes severe inflammation in blood vessels and can lead to heart damage. Their small study, published in Nature Medicine, showed that children in the acute stage of MIS-C have raised levels of cytokines and reduced levels of lymphocytes and that the immune system changes gradually returned to normal by the time the children had recovered. The children responded to treatments that calm the immune system, such as corticosteroid and immunoglobulins. DOI: 10.1038/s41591-020-1054-6

A second study by the same research team at the University of Sydney (Australia), newly published in Transboundary and Emerging Diseases, confirms the association between lower humidity and an increase in community transmission of COVID-19. The study estimated that for a 1% decrease in relative humidity, patient cases might increase by 7%-8%. That’s equivalent to a twofold increase in COVID-19 notifications per a 10% drop in relative humidity, raising the prospect of seasonal disease outbreaks. Reduced humidity was found in several different regions of Sydney to be consistently linked to increased cases, and the same link was not found for other weather factors such as rainfall, temperature or wind. DOI: 10.1111/tbed.13766

Smell disorder experts in Europe have shown how smell loss associated with COVID-19 infection differs from what is typically experienced with a bad cold or flu. The main differences are that COVID-19 can breathe freely, do not tend to have a runny or blocked nose, and cannot detect bitter or sweet tastes. These findings, published in Rhinology, lend weight to the theory that COVID-19 infects the brain and central nervous system. For the small study, the research team carried out smell and taste tests on 10 COVID-19 patients, 10 people with bad colds and a control group of 10 healthy people, all matched for age and sex. DOI: 10.4193/Rhin20.251

A study from early in the global coronavirus pandemic that evidenced the benefits of using a corticosteroid such as dexamethasone to combat COVID-19 in severely ill patients could have saved lives, according to an article by an international team of researchers that published in Expert Review of Respiratory Medicine. The proportion of hospitalized COVID-19 patients with acute respiratory distress syndrome on respiratory support treated with corticosteroids died significantly less often (28%) than those who did not receive them (69%). Similar conclusions were reached in mid-June by Oxford University's RECOVERY trial, leading to the UK government's decision that dexamethasone could be made available to patients—a move subsequently taken around the world. DOI: 10.1080/17476348.2020.1804365

In an article published in npj Digital Medicine, a Harvard Medical School-led multi-institutional research team describe a COVID-19 centralized medical records repository that they’ve created for the purpose of rapid data collection and data analysis and visualization. The platform contains data from 96 hospitals in five countries (U.S., France, Italy, Germany and Singapore) and has yielded intriguing, albeit preliminary, clinical clues about how the disease presents, evolves and affects different organ systems across different categories of patients with COVID-19. For now, the platform represents more of a proof-of-concept than a fully evolved tool, the research team cautions, with initial observations enabled by the data raising more questions than they answer. Their report provides insights from early analysis of records from 27,584 patients and 187,802 lab tests collected in the early days of epidemic, from Jan. 1 to April 11. Among the long list of reported observations are variation by country of patient age, remarkably consistent lab test findings, and major abnormalities evident on day one of diagnosis for C-reactive protein and D-dimer protein with test results progressively worsening in patients who went on to develop more severe disease or died. The participating countries are part of the Consortium for Clinical Characterization of COVID-19 by EHR. DOI: 10.1038/s41746-020-00308-0 

After examining 64 samples of breast milk from 18 U.S. women infected with SARS-CoV-2, researchers at the University of California San Diego School of Medicine and University of California Los Angeles have concluded that breast milk is an unlikely source of infection for breastfeeding infants. Although one of the samples tested positive for viral RNA, subsequent tests found that the virus was unable to replicate. Study results, which published in JAMA, might give women the reassurance they need not to forego breastfeeding that has invaluable benefits for mom and baby. The samples were collected by the Mommy's Milk Human Milk Research Biorepository. The researchers also mimicked conditions of the Holder pasteurization process commonly used in human donor milk banks by adding SARS-CoV-2 to breast milk samples from two different donors who were not infected. The samples were heated to 62.5°C for 30 minutes and then cooled to 4°C. Following pasteurization, infectious virus was not detected in either sample. DOI: 10.1001/jama.2020.15580 

Researchers at Hackensack Meridian Health have utilized its statewide observational database of more than 5,000 hospitalized COVID-19 patients to show that a monoclonal antibody drug normally used in rheumatoid arthritis and cancer treatments, tocilizumab, improves hospital survival in critically ill patients admitted to the intensive care unit. The observational study, published in Lancet Rheumatology, included 630 patients who were admitted to one of 13 hospital ICUs from March 1 to April 22. Of these, 210 received tocilizumab off-label when their respiratory symptoms were declining. Those receiving the drug had a roughly 36% decrease in hospital-related mortality compared to those who did not. Importantly, it appeared that higher levels of a blood test marker of inflammation, C-reactive protein, could predict which ICU patients might benefit most from the tocilizumab therapy, potentially allowing doctors to tailor therapy to those most in need. DOI: 10.1016/S2665-9913(20)30277-0

Ten COVID-19 patients with hypoxia respond positively to icatibant treatment, report Radboud University Medical Center (Netherlands) researchers in JAMA Network Open. Icatibant is used in patients with a rare condition (hereditary angioedema) who sometimes develop acute subcutaneous fluid deposits due to local leakage of blood vessels. The drug quickly stops the leakage by blocking the bradykinin receptor B2R. For this study, COVID-19 patients were given three doses of icatibant by subcutaneous injection at six-hour intervals. One patient who had been in the ICU recovered sufficiently within 24 hours to be moved to the ward and discharged after seven days; eight of the remaining nine patients needed less oxygen supplementation within 24 hours and the ninth after 38 hours. In 18 comparable patients who served as controls, substantially higher levels of oxygen supplementation were needed over time. The finding has led to a phase 2 follow-up study at ten Dutch hospitals into the drug lanadelumab, which remains active for much longer than icatibant and may be even more effective. DOI: 10.1001/jamanetworkopen.2020.17708

Data from the first COVID-19 patients treated at three large Massachusetts hospitals reveal important trends, including disproportionate representation of vulnerable populations, high rates of disease-related complications, and the need for post-discharge, post-acute care and monitoring. For the study, published in EClinicalMedicine, researchers created a detailed registry based on physician review of 247 patient charts. Patients were included if they were admitted from March 7 through 30, 2020, with confirmed SARS-CoV-2 infection, to one of three Mass General Brigham system's hospitals—MGH, Brigham and Women's Hospital, and Newton-Wellesley Hospital. Most of the study patients were initially treated with hydroxychloroquine (72%) and statins (76%), a practice that has since changed. The ethnic and socio-economic mix of patients was notable: 30% were Hispanic, 21% were enrolled in Medicaid, and 12% were dual-enrolled Medicare/Medicaid. Study patients also showed a surprising range of symptoms and outcomes, with 42% requiring intensive care during their stay. At the end of the data collection period, 86.2% of patients were discharged alive, 0.8% were still in the hospital, and 13% had died. Among those discharged alive, 32.9% were discharged to a post-acute facility, 14.6% newly required supplemental oxygen, 8.9% newly required tube feeding, and 16% required new prescriptions for antipsychotics, benzodiazepines, methadone or opioids. About 10% of the study patients were readmitted when followed for an average of 80 days after discharge. DOI: 10.1016/j.eclinm.2020.100504

Industry Updates

Wits University is the lead institution in South Africa for a COVID-19 vaccine trial of NVX-CoV2373 (Novavax) that has just begun screening participants. The trial leverages technology used successfully to develop vaccines against influenza virus and experimental vaccines against Ebola and Respiratory Syncytial Virus. NVX-CoV2373 is engineered from the genetic sequence of SARS-CoV-2 and in preclinical studies demonstrated the elicitation of antibodies that block the binding of spike protein to receptors targeted by the virus. In nonhuman primates, the vaccine candidate has shown protection against SARS-Cov-2 infection in nasal passages as well as against lung disease. In its phase 1 clinical trial in Australia, NVX-CoV2373 was found to be generally well-tolerated and elicited robust antibody responses numerically superior to that seen in human convalescent sera. The phase 2 study in South Africa will enroll up to 2,904 volunteers (roughly 2,650 healthy, HIV-negative adults and 240 medically stable, HIV-positive adults) between the ages of 18 and 65 and evaluate the safety, immunogenicity, and efficacy of NVX-CoV2373. Press release.

Researchers at Washington State University are part of a new nationwide study to examine the benefits and risks of breastfeeding during COVID-19 infection. Limited research conducted on this topic has to date yielded mixed results, and detection of viral RNA in milk doesn’t necessarily mean the virus is viable or transmissible. Uncertainty around potential viral transmission has led to different policies on maternal-infant separation when moms have tested positive for COVID-19. The new study is supported by a $200,000 collaborative grant awarded through the National Science Foundation Rapid Response Research funding mechanism. Other participating institutions are the University of Idaho, the University of Washington and Tulane University. The study is now actively recruiting women aged 18 and over who have received a positive COVID-19 test result within the past week and have infants up to two years old. Fifty enrollees, half breastfeeding their baby and half not, will be followed for a period of two months. At specified intervals throughout the study, the women will collect biological samples from themselves and their babies. They’ll also be interviewed by phone about their family's health, COVID-19 exposures and symptoms, and infant care and feeding practices. Press release.

The Patient-Centered Outcomes Research Institute reports that is has approved $22.6 million in funding for seven studies assessing various healthcare approaches to improve outcomes among people infected by the novel coronavirus and lessen the effects of COVID-19 on patients, healthcare workers and communities. Approvals include a study comparing the impacts on patients from state and local pandemic mitigation policies, another comparing education strategies for infection control in nursing homes, and several evaluating whether telehealth approaches achieve comparable or better outcomes for patients. Other studies will pay particular attention to healthcare access and disparities in outcomes among racial and ethnic minorities and underserved populations. Recipient institutions include the University of California at San Francisco, the RAND Corporation, Joan and Sanford I. Weill Medical College of Cornell University, University of Pennsylvania Perelman School of Medicine, State University of New York, University of Southern California and Penn State University Hershey Medical Center. Press release. 

Adaptive Phage Therapeutics (APT) has announced a $9.8 million award from the Department of Defense for research development of multiple high-priority, bacteriophage-based display vaccine candidates against the novel coronavirus. The effort will advance and evaluate vaccine candidates in phase 1 clinical trials. APT is the only biotechnology company with a phage-based COVID-19 vaccine program projected to enter clinical trials in 2020. Phage-based vaccines offer significant potential benefits by establishing a platform approach with the ability to quickly adjust the vaccine in response to mutations in the coronavirus. They are additionally “self-adjuvanted,” meaning they automatically activate and boost immune response with the ability to display multiple antigens. APT is a clinical-stage company founded to provide an effective therapeutic response to the global rise of multi-drug resistant pathogenic bacteria. Press release.