Michael Ward is Chair, Veterinary Public Health and Food Safety in the Sydney School of Veterinary Science. He is a veterinary epidemiologist with experience in analytical epidemiological methods, spatial epidemiology and simulation modeling. He has more than 30 years experience in conducting research on infectious diseases.
Michael is a veterinary graduate of the University of Queensland and has held positions within the Queensland Department of Primary Industries and the veterinary schools at Purdue University (Indiana) and Texas A&M University. He returned to Australia from Texas in 2008 to take up his present position. Michael is currently the Editor-in-Chief, Transboundary and Emerging Diseases.
Alessandra Renieri graduated in Medicine at the University of Siena and obtained a PhD in Human Genetics at the University of Torino. Subsequently she received a specialist degree in Medical Genetics at the University of Florence and she then went back to Siena where she worked first as Medical Assistant and then as researcher. In 2000 she was appointed Associate Professor and from 2007 she is Full Professor of Medical Genetics at the School of Medicine of the University of Siena. From July 1st, 2019, she has been a member of the Committee for Advanced Therapies (CAT) at the European Medicines Agency.
David G. Grenache, PhD, DABCC, MT(ASCP), FAACC, has been elected to serve on the AACC Board of Directors as president-elect starting in January 2019.
Dr. Grenache is the chief scientific officer and medical director of the chemistry, immunology, and esoteric analytic chemistry labs at TriCore Reference Laboratories in Albuquerque, New Mexico. He is also a clinical professor of pathology at the University of New Mexico. An AACC member since 1994, Dr. Grenache has been actively engaged in association leadership for many years. He currently serves on the board of editors for AACC’s The Journal of Applied Laboratory Medicine, AACC Policy & External Affairs Committee, and as an ex officio member of the association’s Education Core Committee. He also previously held the position of AACC secretary from 2014-2016, chaired the 2018 organizing committee for the AACC Annual Scientific Meeting & Clinical Lab Expo, and helped create the framework for AACC’s Society for Young Clinical Laboratorians while also serving as its first chair.
As progress has been made on this front, concern has shifted to testing accuracy, predominantly with antibody tests, which are designed to identify prior infection.
But according to a new Dartmouth-led paper published in the New England Journal of Medicine, more emphasis should be placed on addressing the inaccuracy of diagnostic tests, which play a key role in containing the pandemic.
“Diagnostic tests, typically involving a nasopharyngeal swab, can be inaccurate in two ways,” explains lead author Steven Woloshin, MD, MS, a professor of medicine and community and family medicine at Dartmouth’s Geisel School of Medicine, and of The Dartmouth Institute for Health Policy and Clinical Practice. “A false-positive result mistakenly labels a person infected, with consequences including unnecessary quarantine and contact tracing. False-negative results are far more consequential because infected persons who might be asymptomatic may not be isolated and can infect others.”
In their paper, Woloshin and his colleagues discuss factors contributing to the current limitations of diagnostic tests–including variability in test sensitivity and the lack of a standard process for validating test accuracy–and also cite several large studies whose frequent false-negative results are cause for concern.
The researchers draw several conclusions from their work. “Diagnostic testing will help to safely open the country, but only if the tests are highly sensitive and validated against a clinically meaningful reference standard–otherwise we cannot confidently declare people uninfected,” says Woloshin.
The FDA should also ensure that test manufacturers provide details of their tests’ clinical sensitivity and specificity at the time of market authorization. Tests without such information will have less relevance to patient care.
“Measuring the sensitivity of tests in asymptomatic people is an urgent priority,” says Woloshin. “A negative result on even a highly sensitive test cannot rule out infection if the pretest probability–an estimate before testing of a person’s chance of being infected–is high, so clinicians shouldn’t trust unexpected negative results.”
This estimate might depend on how common COVID-19 is where a person lives, their exposure history, and symptoms, he says.
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The Dartmouth Institute for Health Policy and Clinical Practice is a world leader in studying and advancing models for disruptive change in healthcare delivery. The work of Dartmouth Institute faculty and researchers includes developing the concept of shared decision-making between patients and healthcare professionals, creating the model for Accountable Care Organizations (ACOs), and introducing the game-changing concept that more healthcare is not necessarily better care.
Early data from a clinical study suggest that blocking the Bruton tyrosine kinase (BTK) protein provided clinical benefit to a small group of patients with severe COVID-19. Researchers observed that the off-label use of the cancer drug acalabrutinib, a BTK inhibitor that is approved to treat several blood cancers, was associated with reduced respiratory distress and a reduction in the overactive immune response in most of the treated patients.
The findings were published June 5, 2020, in Science Immunology. The study was led by researchers in the Center for Cancer Research at the National Cancer Institute (NCI), in collaboration with researchers from the National Institute of Allergy and Infectious Diseases (NIAID), both part of the National Institutes of Health (NIH), as well as the U.S. Department of Defense’s Walter Reed National Military Medical Center, and four other hospitals nationally.
These findings should not be considered clinical advice but are being shared to assist the public health response to COVID-19. While BTK inhibitors are approved to treat certain cancers, they are not approved as a treatment for COVID-19. This strategy must be tested in a randomized, controlled clinical trial in order to understand the best and safest treatment options for patients with severe COVID-19.
The BTK protein plays an important role in the normal immune system, including in macrophages, a type of innate immune cell that can cause inflammation by producing proteins known as cytokines. Cytokines act as chemical messengers that help to stimulate and direct the immune response. In some patients with severe COVID-19, a large amount of cytokines are released in the body all at once, causing the immune system to damage the function of organs such as the lungs, in addition to attacking the infection. This dangerous hyperinflammatory state is known as a “cytokine storm.” At present, there are no proven treatment strategies for this phase of the illness. The study was developed to test whether blocking the BTK protein with acalabrutinib would reduce inflammation and improve the clinical outcome for hospitalized patients with severe COVID-19.
This prospective off-label clinical study included 19 patients with a confirmed COVID-19 diagnosis that required hospitalization, as well as with low blood-oxygen levels and evidence of inflammation. Of these patients, 11 had been receiving supplemental oxygen for a median of two days, and eight others had been on ventilators for a median of 1.5 (range 1-22) days.
Within one to three days after they began receiving acalabrutinib, the majority of patients in the supplemental oxygen group experienced a substantial drop in inflammation, and their breathing improved. Eight of these 11 patients were able to come off supplemental oxygen and were discharged from the hospital. Although the benefit of acalabrutinib was less dramatic in patients on ventilators, four of the eight patients were able to come off the ventilator, two of whom were eventually discharged. The authors note that the ventilator patient group was extremely clinically diverse and included patients who had been on a ventilator for prolonged periods of time and had major organ dysfunction. Two of the patients in this group died.
Blood samples from patients in the study showed that levels of interleukin-6 (IL-6), a major cytokine associated with hyperinflammation in severe COVID-19, decreased after treatment with acalabrutinib. Counts of lymphocytes, a type of white blood cell, also rapidly improved in most patients. A low lymphocyte count has been associated with worse outcome for patients with severe COVID-19. The researchers also tested blood cells from patients with severe COVID-19 who were not in the study. In comparison with samples from healthy volunteers, they found that these patients with severe COVID-19 had higher activity of the BTK protein and greater production of IL-6. These findings suggest that acalabrutinib may have been effective because its target, BTK, is hyperactive in severe COVID-19 immune cells.
MOSCOW, RUSSIA - APRIL 4, 2020: Medical workers in protective suits carry a man on a stretcher inside the Novomoskovsky multipurpose medical center for patients suspected of the COVID-19 coronavirus infection. Vyacheslav Prokofyev/TASS (Photo by Vyacheslav ProkofyevTASS via Getty Images)
Science’s COVID-19 reporting is supported by the Pulitzer Center.
In January, one of the first publications on those sickened by the novel coronavirus in Wuhan, China, reported that three out of every four hospitalized patients were male. Data from around the world have since confirmed that men face a greater risk of severe illness and death from COVID-19 than women and that children are largely spared. Now, scientists investigating how the virus does its deadly work have zeroed in on a possible reason: Androgens—male hormones such as testosterone—appear to boost the virus’ ability to get inside cells.
A constellation of emerging data supports this idea, including COVID-19 outcomes in men with prostate cancer and lab studies of how androgens regulate key genes. And preliminary observations from Spain suggest that a disproportionate number of men with male pattern baldness—which is linked to a powerful androgen—end up in hospitals with COVID-19. Researchers are rushing to test already approved drugs that block androgens’ effects, deploying them early in infection in hopes of slowing the virus and buying time for the immune system to beat it back.
“Everybody is chasing a link between androgens … and the outcome of COVID-19,” says Howard Soule, executive vice president at the Prostate Cancer Foundation, who on 13 May ran a Zoom call presenting the newest research that drew 600 scientists and physicians. A second call scheduled for today will discuss incipient clinical trials.
Epidemiological data from around the world have confirmed the early reports of male vulnerability. In Lombardy in Italy, for example, men comprised 82% of 1591 patients admitted to intensive care units (ICUs) from 20 February to 18 March, according to a JAMA paper. And male mortality exceeded that of women in every adult age group in another JAMA study of 5700 New York City patients hospitalized with COVID-19.
Now, researchers are on the trail of a mechanism for this male bias—an effort led by prostate cancer researchers, who have a deep acquaintance with androgens.
Christina Jamieson of the University of California (UC), San Diego, who has developed organoids to study prostate cancer, recalls that she was in a Zoom meeting honing ideas on how to link her research to COVID-19 when her sister, also a UC San Diego scientist, sent her a one-word text. It read: “TMPRSS2.”
It was 16 April, and within minutes Jamieson had found the publication that prompted the text: a Cell paper by Markus Hoffmann of the Leibniz Institute for Primate Research and colleagues. The paper sent a lightning bolt through the prostate research community, because it showed that infection with SARS-CoV-2, the virus that causes COVID-19, relies in part on TMPRSS2, a membrane-bound enzyme. The enzyme cleaves the “spike” protein on the coronavirus’ surface, allowing the virus to fuse with the host cell’s membrane and get inside the cell.
Jamieson and other prostate cancer researchers were familiar with the enzyme, because in about half of all prostate cancers, a TMPRSS2 mutation revs up an oncogene that kicks cell growth into overdrive. In the prostate, TMPRSS2 is produced when male hormones bind to the androgen receptor. “Doing research, it’s like you’re trying to throw an anchor into the vast ocean of possibilities,” Jamieson says. The discovery that TMPRSS2 helps the virus enter cells “felt like the anchor hit ground.”
Researchers haven’t established that androgens control TMPRSS2 in the lung—ground zero for SARS-CoV-2 infection—as they do in the prostate; studies in lung tissue and cells from mice and humans come to conflicting conclusions. But after the Cell paper was published, Andrea Alimonti, head of molecular oncology at Università della Svizzera italiana, strengthened the androgen link by looking at data on more than 42,000 men with prostate cancer in Veneto in Italy. He and colleagues found that patients on androgen-deprivation therapy (ADT)—drugs that slash levels of testosterone—were only one-quarter as likely to contract COVID-19 as men with prostate cancer not on ADT, they reported in the Annals of Oncology (see table, below). Men on ADT were also less likely to be hospitalized and to die, although numbers were small.
The drug acalabrutinib, FDA-approved for the treatment of several types of B cell cancers, improved the oxygenation levels and decreased molecular markers of inflammation in a majority of 19 patients hospitalized for the treatment of severe COVID-19, according to a new study by Mark Roschewski and colleagues.
The drug was administered to 11 patients on supplemental oxygen and 8 patients on mechanical ventilation over a 10-to-14-day course of treatment. At the end of treatment, 8 of 11 patients on supplemental oxygen were breathing room air, and 4 of 8 patients on ventilation were extubated, with 2 of the 8 breathing room air. Measurements of two proteins related to inflammation decreased in the majority of patients, with no signs of toxicity from the drug.
The study is not a clinical trial, but rather an off-label observational study to see if acalabrutinib could help dampen the massive immune response — sometimes called a “cytokine storm” — that is associated with the most severe cases of COVID-19.
Acalabrutinib inhibits the Bruton tyrosine kinase (BTK) protein, which aids immune cells called macrophages in activating a variety of other proteins in the body’s innate immune response. Patients with severe COVID-19 have a hyperinflammatory immune response that appears to be driven by macrophage activation, leading to acute respiratory distress syndrome (ARDS) and often death.
Roschewski et al. also studied BTK activation and immune markers in whole blood from 4 COVID-19 patients and 5 healthy individuals. BTK activation levels and the presence of the inflammatory protein IL-6 were higher in the COVID-19 patients, further suggesting that BTK may play a critical role in the disease’s progression.
An international prospective randomized controlled clinical trial is now underway to confirm the safety and efficacy of this BTK inhibitor as a therapeutic strategy against COVID-19, the authors note.
Reference: “Inhibition of Bruton tyrosine kinase in patients with severe COVID-19” by Mark Roschewski, Michail S. Lionakis, Jeff P. Sharman, Joseph Roswarski, Andre Goy, M. Andrew Monticelli, Michael Roshon, Stephen H. Wrzesinski, Jigar V. Desai, Marissa A. Zarakas, Jacob Collen, Keith Rose, Ahmed Hamdy, Raquel Izumi, George W. Wright, Kevin K. Chung, Jose Baselga, Louis M. Staudt and Wyndham H. Wilson, 5 June 2020, Science Immunology.
Next-generation sequencing of the COVID-19 virus is providing powerful metagenomic data, which, combined with clinical data, will inform the search for effective treatments, as reported in the peer-reviewed journal Pediatric Allergy, Immunology, and Pulmonology. Click here to read the article now.
“Continued genomic and epigenomic analysis of SARS-CoV-2 is critical,” say Drs. Dehority and Dinwiddie from The University of New Mexico School of Medicine, “as it can be used to determine the number of virus strains, how the virus is introduced into new regions, the number of introductions of the virus, if there is community spread of virus, if outbreaks are linked, and how the virus is evolving.”
Genetic analysis will also guide and inform efforts to develop vaccines and both novel and repurposed therapeutic agents, by testing for viral susceptibility or resistance to these interventions.
Pediatric Allergy, Immunology, and Pulmonology Editor-in-Chief Mary Cataletto, MD, Professor of Clinical Pediatrics, Stony Brook University School of Medicine, states that: “As of May 25, 2020, 1,637,456 cases of COVID-19 have been reported to the Centers for Disease Control with 97,669 deaths. The use of these new techniques not only for identification but ongoing surveillance of novel viral pathogens can contribute to early strategic public health responses.”.
First review of all available evidence including 172 observational studies looking at how physical distancing, face masks, and eye protection affect the spread of COVID-19, SARS, and MERS in both community and healthcare settings across 16 countries.
Physical distancing of at least 1 metre lowers risk of COVID-19 transmission, but distances of 2 metres could be more effective.
Face coverings and masks might protect both healthcare workers and the general public against infection with COVID-19, and protective eye covering may also provide additional benefit–although the certainty of the evidence is low for both forms of protection.
Importantly, even when properly used and combined, none of these interventions offers complete protection and other basic protective measures (such as hand hygiene) are essential to reduce transmission.
Keeping at least one metre from other people as well as wearing face coverings and eye protection, in and outside of health-care settings, could be the best way to reduce the chance of viral infection or transmission of COVID-19, according to a systematic review and meta-analysis synthesising all the available evidence from the scientific literature, published in The Lancet.
However, none of these interventions, even when properly used and combined, give complete protection from infection, and the authors note that some of the findings, particularly around face masks and eye protection, are supported by low-certainty evidence [1], with no completed randomised trials addressing COVID-19 for these interventions.
The study, conducted to inform WHO guidance documents, is the first time researchers have systematically examined the optimum use of these protective measures in both community and healthcare settings for COVID-19. The authors say it has immediate and important implications for curtailing the current COVID-19 pandemic and future waves by informing disease models, and standardising the definition of who has been ‘potentially exposed’ (ie, within 2 metres) for contact tracing.
Many countries and regions have issued conflicting advice about physical distancing to reduce transmission of COVID-19, based on limited information. In addition, the questions of whether masks and eye coverings might reduce transmission of COVID-19 in the general population, and what the optimum use of masks in healthcare settings is, have been debated during the pandemic.
“Our findings are the first to synthesise all direct information on COVID-19, SARS, and MERS, and provide the currently best available evidence on the optimum use of these common and simple interventions to help “flatten the curve” and inform pandemic response efforts in the community”, says Professor Holger Schünemann from McMaster University in Canada, who co-led the research. “Governments and the public health community can use our results to give clear advice for community settings and healthcare workers on these protective measures to reduce infection risk.”
The currently best available evidence suggests that COVID-19 is most commonly spread by respiratory droplets, especially when people cough and sneeze, entering through the eyes, nose, and mouth, either directly or by touching a contaminated surface. At the moment, although there is consensus that SARS-CoV-2 mainly spreads through large droplets and contact, debate continues about the role of aerosol spreading.
For the current analysis, an international team of researchers did a systematic review of 172 observational studies assessing distance measures, face masks, and eye protection to prevent transmission between patients with confirmed or probable COVID-19, SARS, or MERS infection and individuals close to them (eg, caregivers, family, healthcare workers), up to May 3, 2020.
Pooled estimates from 44 comparative studies involving 25,697 participants were included in the meta-analysis. Of these, 7 studies focused on COVID-19 (6,674 participants), 26 on SARS (15,928), and 11 on MERS (3,095).
The COVID-19 studies included in the analysis consistently reported a benefit for the three interventions and had similar findings to studies of SARS and MERS.
Analysis of data from nine studies (across SARS, MERS and COVID-19, including 7,782 participants) looking at physical distance and virus transmission found that keeping a distance of over one metre from other people was associated with a much lower risk of infection compared with less than one metre (risk of infection when individuals stand more than a metre away from the infected individual was 3% vs 13% if within a metre), however, the modelling suggests for every extra metre further away up to three metres, the risk of infection or transmission may halve (figure 3). The authors note that the certainty of their evidence on physical distancing is moderate [1] and that none of the studies quantitatively evaluated whether distances of more than 2 metres were more effective, although meta-analyses provided estimates of risk.
Thirteen studies (across all three viruses, including 3,713 participants) focusing on eye protection found that face shields, goggles, and glasses were associated with lower risk of infection, compared with no eye covering (risk of infection or transmission when wearing eye protection was 6% vs 16% when not wearing eye protection). The authors note that the certainty of the evidence for eye coverings is low [1].
Evidence from 10 studies (across all three viruses, including 2,647 participants) also found similar benefits for face masks in general (risk of infection or transmission when wearing a mask was 3% vs 17% when not wearing a mask). Evidence in the study was looking mainly at mask use within households and among contacts of cases, and was also based on evidence of low certainty [1].
For healthcare workers, N95 and other respirator-type masks might be associated with a greater protection from viral transmission than surgical masks or similar (eg, reusable 12-16 layer cotton or gauze masks). For the general public, face masks are also probably associated with protection, even in non-health-care settings, with either disposable surgical masks or reusable 12-16 layer cotton ones. However, the authors note that there are concerns that mass face mask use risks diverting supplies from health-care workers and other caregivers at highest risk for infection.
They also stress that policy makers will need to quickly address access issues for face masks to ensure that they are equally available for all. “With respirators such as N95s, surgical masks, and eye protection in short supply, and desperately needed by healthcare workers on the front lines of treating COVID-19 patients, increasing and repurposing of manufacturing capacity is urgently needed to overcome global shortages”, says co-author Dr Derek Chu, Assistant Professor at McMaster University. “We also believe that solutions should be found for making face masks available to the general public. However, people must be clear that wearing a mask is not an alternative to physical distancing, eye protection or basic measures such as hand hygiene, but might add an extra layer of protection.”
The authors also stress the importance of using information about how acceptable, feasible, resource intense, and equally accessible to all the use of these interventions are when devising recommendations. “Across 24 studies of all three viruses including 50,566 individuals, most participants found these personal protection strategies acceptable, feasible, and reassuring, but noted harms and challenges including frequent discomfort and facial skin breakdown, increased difficulty communicating clearly, and perceived reduced empathy from care providers by those they were caring for”, says Dr Sally Yaacoub from the American University of Beruit in Lebanon.
According to co-author Karla Solo from McMaster University in Canada: “While our results provide moderate and low certainty evidence, this is the first study to synthesise all direct information from COVID-19 and, therefore, provides the currently best available evidence to inform optimum use of these common and simple interventions.”
Despite these important findings, the review has some limitations including that few studies assessed the effect of interventions in non-healthcare settings, and most evidence came from studies of SARS and MERS. Finally, the effect of duration of exposure on risk for transmission was not specifically examined.
Writing in a linked Comment, lead author Professor Raina MacIntyre (who was not involved in the study) from the Kirby Institute, University of New South Wales in Australia, describes the study as “an important milestone”, and writes, “For health¬care workers on COVID¬19 wards, a respirator should be the minimum standard of care. This study by Chu and colleagues should prompt a review of all guidelines that recommend a medical mask for health workers caring for COVID¬19 patients. Although medical masks do protect, the occupational health and safety of health workers should be the highest priority and the precautionary principle applied.”
She continues, “[They] also report that respirators and multilayer masks are more protective than are single layer masks. This finding is vital to inform the proliferation of home¬made cloth mask designs, many of which are single¬layered. A well designed cloth mask should have water¬resistant fabric, multiple layers, and good facial fit…Universal face mask use might enable safe lifting of restrictions in communities seeking to resume normal activities and could protect people in crowded public settings and within households.”
NOTES TO EDITORS
The study was in part funded by the World Health Organization. It was conducted by researchers at McMaster University, Canada; the American University of Beirut, Lebanon; German Hospital of Buenos Aires, Argentina; Southlake Regional Health Centre, Canada; University of British Columbia, Canada; McMaster University, Canada; The Research Institute of St. Joe’s Hamilton, Canada; Pontificia Universidad Católica de Chile, Chile; Beijing University of Chinese Medicine, China; Dongzhimen Hospital, China; Guangzhou University of Chinese Medicine, The Fourth Clinical Medical College, China; China academy of Chinese Medical Science, China; American University of Beirut, Lebanon; Rafik Hariri University Hospital, Lebanon; The London School of Hygiene & Tropical Medicine, UK; University of Hull, UK.
[1] This study used GRADE categories of evidence. These include: high certainty (ie, we are very confident that the true effect lies close to that of the estimate of the effect); moderate certainty (we are moderately confident in the effect estimate; the true effect is probably close to the estimate, but it is possibly substantially different); low certainty (our confidence in the effect estimate is limited; the true effect could be substantially different from the estimate of the effect); very low certainty (we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect).
