July 10, 2020 | It could take up to two years to develop robust controlled human infection models for SARS-CoV-2 that meet essential criteria for limiting risk for study volunteers, according to a recent report in the New England Journal of Medicine. This, plus more, is included in this week’s announcements and updates from the clinical research industry.

Literature Updates

In an article published in the New England Journal of Medicine, members of the National Institutes of Health's Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) Vaccines Working Group assess practical considerations and prerequisites for using controlled human infection models (CHIMs) that can be used for human challenge studies in support of SARS-CoV-2 vaccine development. The authors say it could take two years to develop robust CHIMs that meet the essential criteria for limiting risk for study volunteers, and that randomized, controlled trials of SARS-CoV-2 are the fastest and most effective path forward for establishing vaccine safety and efficacy. Parallel development of CHIMs may provide complementary tools to address additional questions, such as the duration of immunity and correlates of protection, if such studies can be conducted ethically. They propose that development of a SARS-CoV-2 GMP stock, preferably with attenuating mutations, proceed along with preparation of facilities and procedures and engagement of a broad set of stakeholders. The researchers also recommend developing CHIMs for seasonal coronaviruses, which cause about 30% of cases of the common cold and can provide insights into more deadly coronaviruses. DOI: 10.1056/NEJMp2020076

Patients with COVID-19 appear to be at heightened risk of acute ischemic stroke compared with patients with influenza, according to researchers with Weill Cornell Medicine. Their retrospective cohort study, published in JAMA Neurology, was conducted at two academic hospitals in New York City. Between March 4 and May 2, 2020, 1,916 patients (1.6%) with emergency department visits or hospitalizations with COVID-19 had an elevated risk of ischemic stroke, compared with 1,486 patients with emergency department visits or hospitalizations having influenza A/B from Jan. 1, 2016 through May 31, 2018. DOI: 10.1001/jamaneurol.2020.2730

A study published in the British Journal of Dermatology provides evidence in support of the link between “COVID toes”—red sores or lesions on the feet and hands in children and young adults—and COVID-19. Investigators in Spain found that the SARS-CoV-2 virus was present in skin biopsies in children with symptoms of COVID toes, despite negative results from traditional tests. Analyses detected the virus in skin's blood vessel endothelial cells, as well as in the sweat glands. Electron microscopy in one biopsy also found evidence of viral particles within endothelial cells. DOI: 10.1111/bjd.19327

A prospective, survey-based study published in JAMA Otolaryngology - Head & Neck Surgery has found that smell and taste impairment completely resolved in 48.7% of 202 mildly symptomatic adult patients with COVID-19 at four weeks from the onset. Another 40.7% reported an improvement in the severity and 10.6% reported the symptom was unchanged or worse. Persistent loss of smell or taste was not associated with persistent SARS-CoV-2 infection. The study was conducted at Treviso Regional Hospital (Italy) between March 19 and March 22, 2020. DOI: 10.1001/jamaoto.2020.1379

A study involving 16 COVID-19 patients with oxygen levels as low as 50%, without shortness of breath or dyspnea, found that several pathophysiological mechanisms account for most (if not all) cases of “silent” or “happy” hypoxemia. This understanding of the condition could prevent unnecessary intubation and ventilation in patients. The researchers, from Hines Veterans Affairs Hospital and Loyola University of Chicago Stritch School of Medicine, note that assessing a patient's oxygen level with a pulse oximeter is remarkably accurate when oxygen readings are high but can markedly exaggerate the severity of low levels of oxygen. The brain also does not respond until oxygen falls to very low levels, which is typically when patients become short of breath. In addition, more than half of the patients had low levels of carbon dioxide, which may diminish the impact of an extremely low oxygen level. It’s possible that the coronavirus is exerting a peculiar action on how the body senses low levels of oxygen, which could be linked to the lack of smell experienced by two-thirds of COVID-19 patients. Results published online in the American Journal of Respiratory and Critical Care Medicine. DOI: 10.1164/rccm.202006-2157CP

Neurological complications of COVID-19 can include delirium, brain inflammation, stroke and nerve damage, according to a study led by University College London and University College London Hospitals (UCLH) researchers and published in Brain. One rare and sometimes fatal inflammatory condition, known as acute disseminated encephalomyelitis (ADEM), appears to be increasing in prevalence due to the pandemic. Some patients in the study did not experience severe respiratory symptoms, and the neurological disorder was the first and main presentation of the virus. The study provides a detailed account of neurological symptoms of 43 people (aged 16-85) treated at the National Hospital for Neurology and Neurosurgery at UCLH who had either confirmed or suspected COVID-19. Among these were 10 cases of transient encephalopathies (temporary brain dysfunction) with delirium, 12 cases of brain inflammation, eight cases of strokes, and eight others with nerve damage (mainly Guillain-Barré syndrome). Most of those with brain inflammation conditions were diagnosed with ADEM. DOI: 10.1093/brain/awaa240

Among 147 cases of confirmed COVID-19 in King County, Washington, receiving emergency medical services between Feb. 1 and March 18, 2020, 29.3% had no symptoms of fever, cough, or shortness of breath, according to a study from Seattle-based researchers that published in JAMA Open Network. Fever, tachypnea, or hypoxia were present, respectively, in 51.2%, 32.1% and 53.6% of patients. As of June 1, mortality among the study cohort was 52.4%. Most were older and had multiple chronic health conditions. Findings suggest that the conventional description of febrile respiratory illness may not adequately identify COVID-19 in the prehospital emergency setting. DOI: 10.1001/jamanetworkopen.2020.14549

A case study appearing in the Annals of Neurology describe a patient with severe COVID-19 who, despite prolonged unresponsiveness and structural brain abnormalities, demonstrated functionally intact brain connections and weeks later recovered the ability to follow commands. This suggests that unresponsive patients with COVID-19 may have a better chance of recovery than expected. The patient was a 47-year-old man who developed progressive respiratory failure and, despite intensive treatment, fluctuated between coma and a minimally conscious state for several weeks. In addition to standard brain imaging tests, he had images of his brain taken by resting-state functional magnetic resonance imaging (rs-fMRI) that evaluates the connectivity of brain networks. Unexpectedly, rs-fMRI revealed robust functional connectivity within the default mode network thought to be involved in human consciousness. The investigation was led by a team at Massachusetts General Hospital. DOI: 10.1002/ana.25838

Weill Cornell Medicine researchers have found that obesity was an independent risk factor for respiratory failure but not for in-hospital mortality in a study of 1,687 persons hospitalized with confirmed COVID-19 at two New York City hospitals. The findings, published in the Annals of Internal Medicine, explain in part the extensive use of invasive mechanical ventilation reported in the U.S. where the prevalence of obesity exceeds 40%. The study also points to a possible obesity paradox in COVID-19: the hazard of dying was highest for underweight persons, lowest for overweight persons, and progressively increased with higher degrees of obesity. DOI: 10.7326/M20-2730

Also reported in the Annals of Internal Medicine was a study conducted by researchers at Johns Hopkins University School of Medicine describing positive outcomes in two male patients (ages 69 and 47) with COVID-19 and acute respiratory distress syndrome (ARDS) who were treated with three infusion each of regulatory T cells (Tregs). They’re now planning a multicenter, randomized, double-blind, placebo-controlled trial of cord blood (CB) Tregs for ARDS associated with COVID-19. In one early-phase study, CB Tregs manufactured by Cellenkos have shown promise in treating inflammatory bone marrow failure. DOI: /10.7326/L20-0681

Asthma does not appear to increase the risk of contracting COVID-19 or influence its severity, according Rutgers University researchers in an article appearing in the Journal of Allergy & Clinical Immunology. People with asthma—even those with diminished lung function who are being treated to manage asthmatic inflammation—seem to be no worse affected by SARS-CoV-2 than a non-asthmatic person. The authors note that their hypervigilance about personal hygiene and social distancing may be contributing to their overall health, and that commonly used inhaled corticosteroids could also be reducing the virus' ability to establish an infection. But studies have also shown that steroids may worsen the inflammatory response and delay clearing of the SARS and MERS viruses from the respiratory tract. Of additional note is that asthma sufferers tend to be younger than those with reported high-risk conditions and may also have fewer other diseases making them more susceptible to the virus. DOI: 10.1016/j.jaip.2020.06.008

The doping agent erythropoietin (Epo, an anemia medication) could attenuate severe progression of COVID-19, based on an evidence review led by researchers at the Max Planck Institute of Experimental Medicine in Göttingen (Germany) and published in Molecular Medicine. Findings suggest the growth factor could mitigate severe disease progression and protect patients from long-term neurological effects when the SARS-CoV-2 virus attacks the brain. Among their findings: an Iranian patient with severe COVID-19 symptoms and poor blood values who was able to leave the hospital seven days after being treated with Epo, and the fact that severe illness is rarer in higher-lying regions of South America where people are better adapted to oxygen deficiency because they have more red blood cells. It has also been observed that dialysis patients, who regularly receive Epo, withstand COVID-19 remarkably well. A randomized clinical trial is now being planned. DOI: 10.1186/s10020-020-00186-y.

Obese people in black and minority ethnic communities (BME) are at around two times higher the risk of contracting COVID-19 than white Europeans, a study conducted by researchers at the University of Leicester has found. The researchers cross-referenced health records in the UK Biobank to a national COVID-19 laboratory test data bank between March 16 and June 14, 2020. Of that cohort, 5,623 unique test results were available. The greater risk of COVID-19 in BME people was only apparent at higher BMI values. Results, published in Diabetes, Obesity and Metabolism, suggest that the combination of obesity and BME status may place individuals at particularly high risk of contracting COVID-19, consistent with findings for associations of BMI and ethnicity with cardiometabolic dysfunction. DOI: 10.1111/dom.14125

In a research letter published in JAMA Cardiology, a group of physicians in Spain describe an 81-year-old patient with hypertension, coronary artery disease and recent COVID-19 infection who developed late drug-eluting stent thrombosis. It is the first such report and the cause of the complication appears to be multifaceted. Optical coherence tomography unraveled several potential underlying mechanical factors (stent under-expansion, uncovered struts, and malapposition) that may have predisposed the patient to stent thrombosis. Intense inflammatory and prothrombotic milieu, which is characteristic of COVID-19 infection, may constitute the triggering event but COVID-19 disease could not be established as the cause. DOI: 10.1001/jamacardio.2020.2459

A psychology professor at Carnegie Mellon University has produced a body of research that suggests that interpersonal stressors many are experiencing during quarantine are associated with an increased vulnerability to upper respiratory viruses and perhaps coronavirus. His findings published in Perspectives on Psychological Science. Stay-at-home measures issued by many communities have increased loneliness, loss of employment and familial conflict, which may be powerful predictors of how a person will respond if exposed to COVID-19. In a series of earlier studies, such stressors were associated with a greater chance of developing an upper respiratory illness in people exposed to cold viruses. DOI: 10.1177/1745691620942516

Cleveland Clinic researchers report in JAMA Network Open that they have found a significant increase in patients experiencing stress cardiomyopathy (aka broken heart syndrome) during the COVID-19 pandemic. Patients typically experience symptoms such as chest pain and shortness of breath, but usually do not have acutely blocked coronary arteries. The left ventricle of the heart, however, may show enlargement. Other symptoms include irregular heartbeat, fainting, low blood pressure and cardiogenic shock. For the study, cardiologists looked at 258 patients coming into Cleveland Clinic and Cleveland Clinic Akron General with acute coronary syndrome (ACS) between March 1 and April 30, 2020 and compared them with four control groups of ACS patients prior to the pandemic. Diagnosis of stress cardiomyopathy rose from a pre-pandemic level of 1.7% to 7.8% among the 258 patients, who also had a longer length of hospital stay than those hospitalized in the pre-pandemic period. All patients diagnosed with stress cardiomyopathy tested negative for COVID-19. DOI: 10.1001/jamanetworkopen.2020.14780

Researchers from the University of Houston and Medistar Corporation report in Materials Today Physics that they have designed a "catch and kill" nickel foam air filter that can trap the virus responsible for COVID-19, killing it instantly. In testing at the Galveston National Laboratory, run by the University of Texas Medical Branch, they found 99.8% of SARS-CoV-2 was killed in a single pass through the filter when heated to 392 degrees Fahrenheit. It is reportedly compatible with conventional heating, ventilation and air conditioning systems. High-priority venues—including hospitals and healthcare facilities—would be in the initial roll-out of the device. DOI: 10.1016/j.mtphys.2020.100249

A pair of studies appearing in the Clinical Journal of the American Society of Nephrology have found that most kidney transplant recipients with COVID-19 do not need to be hospitalized, and that patients on dialysis who develop COVID-19 may have symptoms that are different from other patients with the infectious disease. Researchers for the first study, who are clinicians at Columbia University Medical Center, describe their experience with 41 patients with confirmed or suspected cases COVID-19, 32% of whom required hospitalization. These patients were more likely to have shortness of breath and higher levels of a blood marker for impaired kidney function. Notably, there was also wide variation in the amount of time it took patients to improve. The other study, led by an investigator from Tongren Hospital of Wuhan University, looked at 49 hospitalized dialysis patients and 52 hospitalized patients without kidney failure with confirmed COVID-19. Among patients on dialysis, most common symptoms were fatigue and anorexia, with fever and cough being less common. Common complications including shock, acute respiratory distress syndrome, arrhythmia, and acute cardiac injury were also significantly higher in patients on dialysis; also, 14% of patients on hemodialysis died versus 4% of controls. DOI: 10.2215/CJN.05170420 (story one) and DOI: 10.2215/CJN.04160320 (story two).

A study published in the Journal of Gastrointestinal Surgery by researchers at Beth Israel Deaconess Medical Center has found delaying surgeries increases risk in some gastrointestinal malignancies. Their analysis examined the results of 43 peer-reviewed studies published between 2005 and 2020 that investigated how surgical delays affect patients with colorectal, pancreatic or gastric cancer. A surgical delay of 30 to 40 days was associated with shorter survival times in patients with colon cancer, as was a delay of seven to eight weeks after chemotherapy and/or radiation therapy in patients with rectal cancer. For pancreatic cancer, two studies found that cancer progression increased in patients who experienced surgical delays over 30 days. For gastric cancer, none of the studies found worse patient survival with increased time to surgery. DOI: 10.1007/s11605-020-04712-5

Amid news that the U.S. has bought up virtually the entire global supply of remdesivir, a new Boston University School of Public Health study outlines how the drug could save lives in countries with less hospital capacity, such as South Africa, where COVID-19 is beginning to overwhelm intensive care units (ICUs). Recent research has suggested that remdesivir can reduce deaths from COVID-19 by as much as 30% but has a more significant effect on how long patients need intensive care, from an average of 15 days down to an average of 11 days. The peer-reviewed study, published in Clinical Infectious Diseases, estimates that remdesivir's ability to shorten ICU stays could increase the number of patients treated in South Africa's ICUs by more than 50%. This increased capacity could save as many as 6,862 lives per month as the country's cases peak. DOI: 10.1093/cid/ciaa937

A review published in The Lancet Neurology and led by University of Liverpool researchers has shown that cases of brain complications linked to COVID-19 are occurring across the globe. Strokes, delirium and other neurological complications are reported from most countries where there have been large outbreaks of the disease. The review found almost 1,000 patients with COVID-19-associated brain, spinal cord and nerve disease. One particularly concerning complication linked to COVID-19 is encephalitis. DOI: 10.1016/S1474-4422(20)30221-0

In a paper published in Cancer and Metastasis Reviews, researchers from Beth Israel Deaconess Medical Center and Brigham and Women's Hospital (BWH) propose that controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral and other therapies. They suggest that pro-resolution lipid mediators—a family of molecules naturally produced by the body and currently in clinical trials for other inflammatory diseases—may be harnessed to resolve cytokine storm. Molecules called resolvins, discovered at BWH in 2002, actively turn off inflammation and have previously demonstrated they (and related pro-resolution molecules) could play a role in preventing cancer metastasis and progression. DOI: 10.1007/s10555-020-09889-4

Differences in lung physiology and immune function in children could be why they are more often spared from severe illness associated with COVID-19 than adults, according to pediatric and adult physicians at The University of Texas Health Science Center at Houston and Baylor College of Medicine. Their perspectives paper, published in the American Journal of Physiology-Lung Cellular and Molecular Physiology, reports that only about 1.7% of the first 149,082 cases in the U.S. were infants, children, and adolescents younger than 18 years old, although they make up 22% of the population. Only three pediatric deaths were identified by the Centers for Disease Control and Prevention as of April 2020. Angiotensin-converting enzyme 2s (ACE2) are the doors that allow SARS-CoV-2 to enter the body's cells, and children naturally have less ACE2 in the lungs than adults. The immune system in children also respond to viruses differently, in part because they retain T-cells, leaving less opportunity for severe illness to occur. Further, lung tissue in children has a higher concentration of regulator T-cells, which corresponds to higher levels of Interleukin 10, an anti-inflammatory cytokine. DOI: 10.1152/ajplung.00183.2020

In the Annals of Internal Medicine, researchers present alternative methods for evaluating treatments for COVID-19 than the often-used endpoint of “time to a positive outcome.” Survival analysis techniques, they say, may not be appropriate in the presence of death as a competing risk. Moreover, almost all trials have quantified treatment effects by using the hazard ratio, which is difficult to interpret for a positive event. They use two recent trials evaluating treatments (remdesivir and convalescent plasma) as examples of a valid, well-established yet underused procedure for estimating the cumulative recovery or improvement rate curve across the study period. An intuitive and clinically interpretable summary of treatment efficacy based on this curve is also proposed. DOI: 10.7326/M20-4044

Updates from Industry

NIST has released a new material that can aid in the evaluation and development of diagnostic assays for SARS-CoV-2. This material consists of two synthetic RNA fragments from the SARS-CoV-2 genome that include the targets of many molecular diagnostic tests. The RNA fragments are characterized for concentration using digital PCR and can be used to assess the limits of detection for assays and to calibrate other in-house or commercial SARS-CoV-2 controls. We are offering a unit of this material at no cost to research institutions, testing laboratories and commercial vendors of assays/controls and are requesting feedback on its utility and suitability. More information.

In a nationwide survey, 90% of adults report that they have experienced emotional distress related to the COVID-19 pandemic. The 16-question internet survey was a collaborative effort of researchers at Beth Israel Deaconess Medical Center, Massachusetts General Hospital and the University of North Carolina at Chapel Hill School of Medicine. It was completed by 1,500 people during the second half of May when more than 20,000 people in the U.S. were being diagnosed with COVID-19 daily and 1,000 or more people were dying from the disease. Observations included higher levels of emotional distress among racial and ethnic minorities, especially those identifying as Hispanic/Latinx, and greater impacts among both men and women with children under 18. Adults younger than 50 were also much more likely than older adults to be affected emotionally by the pandemic. The study’s website includes a list of coping resources along with a downloadable version of the findings. Press release.

The Transplant Research and Education Center, housed at the Terasaki Research Institute for Biomedical Innovation, launched the COVID-19 Kidney/Transplant Listening & Resource Center (KTLRC) for the dialysis and organ transplant community. The KTLRC is a toll-free call center intended to answer questions about COVID-19 and transplant and to provide educational materials and referrals to additional resources. It is part of an IRB-approved study at the University of California, Los Angeles, which will support the continued improvement of educational and telemedicine resources for kidney and transplant patients by making it responsive to the needs and concerns that they share. Incoming calls will determine what common questions, fears, and challenges that dialysis and transplant patients and their caregivers are having during the pandemic, as well as what types of assistance they find most helpful and how they’d prefer educational information to be delivered. Press release.

A potential COVID-19 vaccine developed at Flinders University has commenced phase 1 trials at the Royal Adelaide Hospital in South Australia. The vaccine candidate, called COVAX-19, was co-developed by Vaxine Pty Ltd and based on the company's recombinant spike protein approach. It is based on Vaxine's earlier SARS coronavirus vaccine and non-inflammatory Advax-CpG55.2 adjuvants. The vaccine model was developed with artificial intelligence and received support from the National Institute of Allergy and Infectious Diseases. The study will provide initial safety and immune response data on 40 healthy participants between 18 and 65 years of age who have already been pre-screened. Participants will receive two doses of the vaccine, or placebo injections, and then have blood tests to measure protective antibody and T-cell responses. Press release.

The National Institute of Allergy and Infectious Diseases (NIAID) has established a new clinical trials network that aims to enroll thousands of volunteers in large-scale clinical trials testing a variety of investigational vaccines and monoclonal antibodies intended to protect people from COVID-19. The COVID-19 Prevention Trials Network (COVPN) was established by merging four existing NIAID-funded clinical trials networks: the HIV Vaccine Trials Network (Seattle), the HIV Prevention Trials Network (Durham, N.C.), the Infectious Diseases Clinical Research Consortium (Atlanta), and the AIDS Clinical Trials Group (Los Angeles). The COVPN is a functional unit of President Trump’s Operation Warp Speed, a partnership led by the U.S. Department of Health and Human Services to invest in and coordinate the development, manufacturing and distribution of COVID-19 diagnostics, therapeutics and vaccines. The network will use a harmonized vaccine protocol developed by the Accelerating COVID-19 Therapeutic Interventions and Vaccines public-private partnership, enabling analyses of correlates of protection across multiple vaccine trials. It is expected to operate more than 100 clinical trial sites across the U.S. and internationally. Fred Hutchinson Cancer Research Center will serve as the COVPN’s operational center and, together with the University of Maryland School of Medicine, lead vaccine testing. Monoclonal antibody clinical testing efforts will be led by the University of North Carolina, Chapel Hill, and Emory University in Atlanta. Press release.

Canadian researchers have launched a clinical trial focused on boosting the immune system of cancer patients to protect them from developing severe COVID-19 and other dangerous lung infections. The trial involves IMM-101, a preparation of heat-killed bacteria manufactured by Immodulon Therapeutics that broadly stimulates the innate arm of the immune system. Researchers from The Ottawa Hospital came up with the idea for the trial and worked with the Canadian Cancer Trials Group at Queen's University to design and run it in centers across the country starting this summer. Press release.