Stem Cell Clinic

What Is The Economic Value of Receiving CAR T-Cell Therapy in an Outpatient Setting? – AJMC.com Managed Markets Network

Chimeric antigen receptor (CAR) T-cell therapy has been shown to improve health-related quality of life in patients with relapsed/refractory diffuse large B-cell lymphoma (LBCL). Currently, CAR T-cell therapies are primarily administered in inpatient settings. In a study published in JAMA Network Open, researchers found CAR T-cell therapy administered to patients with relapsed or refractory LBCL in outpatient settings was associated with lower estimated overall costs.

In a study published in JAMA Network Open, researchers found CAR T-cell therapy administered to patients with relapsed or refractory LBCL in outpatient settings was associated with lower estimated overall costs. CAR-T cell therapies also hold promise for patients with hematologic malignant neoplasms that are unresponsive or resistant to standard treatments, researchers said.

The treatment involves harvesting and reengineering an individuals own cells to attack specific malignant cells. CAR-T cells were initially developed using knowledge gleaned from allogeneic stem cell transplantsthat donor mature immune cells can attack healthy cells in the recipient patient.

In an economic evaluation, researchers used a decision-tree model to document patient clinical outcomes and costs, using only hypothetical patients and facilities. Excluding the CAR T-cell acquisition cost, researchers found hospitalization and office visits comprised 65.3% of the costs in inpatient settings and 48.4% of the costs in outpatient settings. Specifically, outpatient administration of CAR T-cell therapy in nonacademic specialty oncology networks was associated with a $32,987 (40.4%) reduction in total costs. Sensitivity analyses were carried out to address assumptions made to build the model.

Before the approval of CAR T-cell therapy, the available treatments for patients with relapsed or refractory LBCL included high-dose chemotherapy, salvage chemotherapy, and autologous hematopoietic stem cell transplantation (auto-HSCT); however, the prognosis after these treatments is often poor, authors said.

Researchers analyzed a predefined period from lymphodepletion to 30 days after the receipt of CAR T-cell infusion, in order to account for potential incidences of adverse events. Data were collected from several sources including theHealthcare Cost and Utilization Project National Inpatient Sample and the Medicare Hospital Outpatient Prospective Payment System. Investigators used secondary literature to inform model inputs.

Total cost of therapy included any costs associated with lymphodepletion, acquisition and infusion of CAR T-cells and management of acute adverse events.

The model also showed:

In this scenario, the model found patients who received CAR T-cell therapy in a nonacademic specialty oncology network setting would save $27,294 compared with the inpatient setting. In addition, in the scenario analysis the decrease in incremental cost reductions was associated with a lower overall incidence of AEs, which reduced the consequences of associated AE management costs, while the monitoring required at baseline was held constant.

The results indicate CAR T-cell therapy with a better safety profile may be more economical and could further leverage the outpatient site of care, researchers said. They concluded, The potential availability of CAR T-cell therapies with lower AE rates that are suitable for outpatient administration may reduce the total costs of care.

One limit to the study highlighted by the authors is the fact that outpatient administration may not be an option for all patients with LBCL.Eligibility can be contingent on the patients health status, support system, or the availability of housing near hospitals.

However, some specialists predict a gradual shift of all CAR T-cell therapies to the outpatient setting. Part of the reason for that [shift] is the way that it's reimbursed as an outpatient therapy is slightly more favorableso, financially it is better to do that, said John Sweetenham, MD, professor in the Department of Internal Medicine at UT Southwestern Medical Center and the Associate Director for Clinical Affairs at UTSWs Harold C. Simmons Comprehensive Cancer Center.

He continued, The problem is that these are very toxic treatments, and that many of the patients are not going to be manageable in the outpatient setting; but I do see that as one of the factors which is influencing a slow transition to outpatient CAR-Ts.

Expanded access to novel therapies in immune-oncology (IO) like CAR T-cell therapy also remains a priority among community level oncologists. Reimbursement, operational, and medical challenges associated with cellular therapy inhibit widespread uptake of the therapy, explained Lee Schwartzberg, MD, FACP, chief medical officer and board member at OneOncology. Only a small number of patients, frankly, have been treated with the first-generation CAR-T cells. So we need to develop new technologies and new operational models to do this, he said in an interview with The American Journal of Managed Care.

Reference

Lyman GH, Nguyen A, Snyder S, et al. Economic evaluation of chimeric antigen receptor T-cell therapy by site of care among patients with relapsed or refractory large B-cell lymphoma [published online April 6, 2020]. JAMA Netw Open. doi: 10.1001/jamanetworkopen.2020.2072.

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What Is The Economic Value of Receiving CAR T-Cell Therapy in an Outpatient Setting? - AJMC.com Managed Markets Network

Healing the heart by returning it to its infancy – FierceBiotech

Nearly a decade ago, researchers at UT Southwestern Medical Center discovered that when mouse hearts were damaged in the first seven days of life, they would regenerate. They reasoned that if they could find a way to recreate that regenerative ability later in life, it might provide a new way to treat heart damage.

Now, that same team has discovered that a protein called calcineurin plays a key role in blocking the ability of heart muscle to regenerate after the first week of life. The discovery could be used to develop treatments that reverse this process, in essence returning the heart to its developmental stage, they reported in the journal Nature.

The discovery builds on previous work at UT Southwestern that focused on the protein Meis1, a transcription factor that prevents heart cells from dividing. When the researchers deleted the gene in mice that makes that protein, their cardiomyocytes continued to divide after the first week of life. But the effect was transient.

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RELATED: Stem cells don't repair injured hearts, but inflammation might, study finds

Then the researchers discovered that another protein called Hoxb13 was also key, because it shuttles Meis1 into the cell nucleus. So they deleted the genes for both Meis1 and Hoxb13 in adult mice to see what would happen after a heart attack.

It worked. The ability of the animals hearts to pump blood quickly returned to near-normal levels, they said. Even though the mice were adults, their hearts looked much like they would in animals that were still developing.

After a series of further experiments, the UT Southwestern scientists discovered that calcineurin regulates both Hoxb13 and Meis1. Inhibiting calcineurin prolongs the window of cardiomyocyte proliferation, they wrote in the study.

The idea of treating heart damage by turning back the clock isnt new. In fact, several research teams have tried using stem cells to repair damaged heart tissue. But those efforts have been disappointing so far.

Last year, a team from the Cincinnati Children's Hospital Medical Center tracked stem cells injected into the hearts of mice and concluded that it was not the cells themselves, but rather their ability to activate macrophage cells from the immune system that promoted healing. That led the researchers to suggest that efforts to regenerate the heart focus less on stem cells and more on other processes in the body that might promote healing.

The discovery of calcineurins role in regulating the regeneration of the heart is notable due to the fact that there are already drugs on the market that target the protein. Thats because calcineurin plays a role in a variety of diseases, including rheumatoid arthritis and diabetes. Testing these drugs, either individually or in combination, and developing new medicines that target calcineurin directly could offer new strategies for repairing hearts damaged by heart attacks, high blood pressure, viruses and more, suggested co-author Hesham Sadek, M.D., Ph.D., a professor of internal medicine, molecular biology and biophysics at UT Southwestern.

"By building up the story of the fundamental mechanisms of heart cell division and what blocks it, Sadek said in a statement, we are now significantly closer to being able to harness these pathways to save lives.

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Healing the heart by returning it to its infancy - FierceBiotech

Academy adds new members from UW who ‘expand the boundaries of knowledge’ – University of Wisconsin-Madison

Six University of WisconsinMadison faculty have been elected to the American Academy of Arts and Sciences.

Bioethicist R. Alta Charo, psychologist Seth Pollak, philosopher Steven Nadler, historian Louise Young, geographer Lisa Naughton and chemist Martin Zanni are among the 276 new members announced April 23. Election to the academy recognizes distinguished contributions by these scholars to their fields.

Former UWMadison Provost Sarah Mangelsdorf was also elected to the academy this year. Mangelsdorf began her tenure as president of the University of Rochester in July 2019.

Charo

Charo is the Warren P. Knowles Professor of Law and Bioethics and an expert on law and policy related to research ethics, stem cell research and new medical technology. She has served as an adviser and expert to the federal government and multiple presidential administrations on ethical concerns in cutting-edge research. And she recently co-chaired a National Academy of Sciences panel to develop recommendations around human gene editing.

Pollak

Pollak is the College of Letters & Science Distinguished Professor of Psychology. At UWMadisons Waisman Center, he researches the link between childhood stress and well-being. Pollaks team has uncovered the lasting effects of negative experiences in childhood and seeks to use this knowledge to improve the social and emotional experiences of children and the adults they become.

Nadler

Nadler is the William H. Hay II Professor and Evjue-Bascom Professor in Humanities and a philosopher specializing in early modern and Jewish philosophy. He has authored 13 books, including Rembrandts Jews, a Pulitzer Prize finalist, and the graphic book, co-authored with his son Ben Nadler, Heretics!: The Wondrous (and Dangerous) Beginnings of Modern Philosophy. Nadler currently serves as director of UWMadisons Institute for Research in the Humanities.

Young

Young is a professor of Japanese history. Her research has covered Japan in and around the Second World War, and she has authored two books on Japans culture before and during the war. Her current book projects include a history of the countrys transition from feudal systems to a modern class hierarchy and a reexamination of Japans role in creating the modern world from the mid-19th century onward.

Naughton

Naughton is a professor of geography focused on the social and political consequences of biodiversity conservation. Her research has focused on protected areas, wildlife and land use conflicts in South America, and she has studied public attitudes toward wolf recovery in the Upper Midwest. She directed UWMadisons Land Tenure Center from 2009 to 2013 and chaired the Nelson Institutes graduate program in Conservation Biology and Sustainable Development from 2007 to 2010.

Zanni

Zanni is the V.W. Meloche-Bascom Professor of Chemistry. Using an innovative method known as two-dimensional spectroscopy, the Zanni lab studies topics in biophysics and the energy sciences. They have researched carbon nanotube energy transfer, solar cell charge transfer, and the ways in which protein aggregations lead to diseases such as Type 2 diabetes and cataracts. Zanni was elected a fellow of the American Physical Society in 2010.

The news that six colleagues are new members of the American Academy of Arts and Sciences is further evidence for a fact: Faculty at UWMadison are extraordinary, says UWMadison Provost Karl Scholz. We congratulate these six for this wonderful recognition and thank them, and all in the UWMadison community, for relentless efforts to expand the boundaries of knowledge and understanding of the human condition.

The academy was formed in 1780 to honor exceptional individuals and engage them in advancing the public good. Members have included Benjamin Franklin, Alexander Hamilton, Margaret Mead and Martin Luther King Jr. This years new members include former Attorney General Eric Holder, author Ann Patchett and filmmaker Richard Linklater.

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Academy adds new members from UW who 'expand the boundaries of knowledge' - University of Wisconsin-Madison

What Factors Influence Hematological Recovery in Patients Who Receive CAR-T Therapies? – Cancer Therapy Advisor

A few weeks afterreceiving chimeric antigen receptor (CAR) T-cell (CAR-T) therapy, many patientsexperience prolonged reductions in blood cell counts, possibly making them morevulnerable to infections.

Two recent studies characterized the extent and duration of postCAR-T cytopenia among patients receiving CAR-T therapy for hematological malignancies with 1 study offering insights on some of the possible factors that may influence hematological count recovery.

Whats important to know is that by day 90, mostpatients recover, noted UroosaIbrahim, MD, stemcell transplantation and cellular therapy fellow at the Tisch Cancer Instituteof the Icahn School of Medicine at Mount Sinai,New York, who coauthored 1 of the studies. Were supporting them for [approximately]3 months [with treatment], but then theyll recover, which is good to know.

One study by MemorialSloan Kettering Cancer Center (MSKCC) researchers followed 83 adult patientswho received CAR-T therapy: 40 patients received 1 of 2 Food and DrugAdministration (FDA)-approved therapies, axicabtageneciloleucel (axi-cel; Yescarta) ortisagenlecleucel (tisa-cel; Kymriah), to treat relapsed/refractory B-cell lymphoma.

The remainder comprised 37 patients with relapsed/refractory B-cell acute lymphoblastic leukemia who were currently enrolled in a clinical trial in which they received an experimental CAR-T therapy where cells express the 19-28z CAR construct (ClinicalTrials.gov Identifier: NCT01044069), and 6 multiple myeloma patients who received a different experimental CAR-T construct that targets the B-cell maturation antigen (BCMA) (ClinicalTrials.gov Identifier: NCT03070327). The findings were presented at the annual Transplantation and Cellular Therapy Meetings of ASCT and CIBMTR in February 2020.1

By 1 month, theresearchers observed that 24% of patients experienced a complete recovery ofhemoglobin, platelets, absolute neutrophil count, and white blood cell counts recovery being defined as reaching safe levels, and without requiringtransfusions or treatment with growth factors.

Recovery of hemoglobinwas noted in 61% of patients, platelets in 51% of patients, absolute neutrophilcount in 33% of patients, and white blood cell count in 28% of patients.Examining 41 patients at 3 months, those figures were 93%, 90%, 81%, and 59%,respectively, and overall, 56% saw a complete blood count recovery.

The results werebroadly consistent with recent research by Dr Ibrahim and Keren Osman, MD,associate professor and director of medicine at the Icahn School of Medicine atMount Sinai and director of cellular therapy service in the bone marrow andstem cell transplantation program at the schools Tisch Cancer Institute. Thatstudy comprised 50 patients 41 with multiple myeloma and 9 with diffuse largeB-cell lymphoma who received either axicabtagene ciloleucel, or 1 of 2 experimentalanti-BCMA CAR-T therapies, bb2121 or bb21217.

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What Factors Influence Hematological Recovery in Patients Who Receive CAR-T Therapies? - Cancer Therapy Advisor

FDA Approves New Therapy for Triple Negative Breast Cancer That Has Spread, Not Responded to Other Treatments – FDA.gov

For Immediate Release: April 22, 2020

Today, the U.S. Food and Drug Administration granted accelerated approval to Trodelvy (sacituzumab govitecan-hziy) for the treatment of adult patients with triple-negative breast cancer that has spread to other parts of the body. Patients must have received at least two prior therapies before taking Trodelvy.

Metastatic triple-negative breast cancer is an aggressive form of breast cancer with limited treatment options. Chemotherapy has been the mainstay of treatment for triple-negative breast cancer. The approval of Trodelvy today represents a new targeted therapy for patients living with this aggressive malignancy, said Richard Pazdur, M.D., director of the FDAs Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDAs Center for Drug Evaluation and Research. There is intense interest in finding new medications to help treat metastatic triple-negative breast cancer. Todays approval provides patients whove already tried two prior therapies with a new option.

Trodelvy is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate, meaning that the drug targets the Trop-2 receptor that helps the cancer grow, divide and spread, and is linked to topoisomerase inhibitor, which is a chemical compound that is toxic to cancer cells. Approximately two of every 10 breast cancer diagnoses worldwide are triple-negative. Triple-negative breast cancer is a type of breast cancer that tests negative for estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2) protein. Therefore, triple-negative breast cancer does not respond to hormonal therapy medicines or medicines that target HER2.

As part of FDAs ongoing and aggressive commitment to address the novel coronavirus pandemic, we continue to keep a strong focus on patients with cancer who constitute a vulnerable population at risk of contracting the disease, said Pazdur. At this critical time, we continue to expedite oncology product development. This application was approved more than a month ahead of the FDA goal date an example of that commitment. Our staff is continuing to meet with drug developers, academic investigators, and patient advocates to push forward the coordinated review of treatments for cancer.

The FDA approved Trodelvy based on the results of a clinical trial of 108 patients with metastatic triple-negative breast cancer who had received at least two prior treatments for metastatic disease. The efficacy of Trodelvy was based on the overall response rate (ORR) which reflects the percentage of patients that had a certain amount of tumor shrinkage. The ORR was 33.3%, with a median duration of response of 7.7 months. Of the patients with a response to Trodelvy, 55.6% maintained their response for 6 or more months and 16.7% maintained their response for 12 or more months.

The prescribing information for Trodelvy includes a Boxed Warning to advise health care professionals and patients about the risk of severe neutropenia (abnormally low levels of white blood cells) and severe diarrhea. Health care professionals should monitor patients blood cell counts periodically during treatment with Trodelvy and consider treatment with a type of therapy called granulocyte-colony stimulating factor (G-CSF), which stimulates the bone marrow to produce white blood cells called granulocytes and stem cells and releases them into the bloodstream, to help prevent infection, and should initiate anti-infective treatment in patients with febrile neutropenia (development of fever when white blood cell are abnormally low).

Additionally, health care professionals should monitor patients with diarrhea and give fluid, electrolytes, and supportive care medications, as needed. Trodelvy may need to be withheld, dose reduced or permanently discontinued for neutropenia or diarrhea. Trodelvy can cause hypersensitivy reactions including severe anaphylactic (allergic) reactions. Patients should be monitored for infusion-related reactions and health care professionals should discontinue Trodelvy if severe or life-threatening reactions occur. If patients experience nausea or vomiting while taking Trodelvy, health care professionals should use antiemetic preventive treatment, to prevent nausea and vomitting. Patients with reduced uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) activity are at increased risk for neutropenia following initiation of Trodelvy treatment.

The most common side effects for patients taking Trodelvy were nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia (hair loss), constipation, decreased appetite, rash and abdominal pain.

Women who are pregnant should not take Trodelvy because it may cause harm to a developing fetus or newborn baby. The FDA advises health care professionals to inform females of reproductive age to use effective contraception during treatment with Trodelvy and for 6 months after the last dose. Male patients with female partners of reproductive potential should also use effective contraception during treatment with Trodelvy and for three months after the last dose.

Trodelvy was granted accelerated approval, which enables the FDA to approve drugs for serious conditions to fill an unmet medical need based on a result that is reasonably likely to predict a clinical benefit to patients. Further clinical trials are required to verify and describe Trodelvys clinical benefit.

The FDA granted this application Priority Review and Breakthrough Therapy designation, which expedites the development and review of drugs that are intended to treat a serious condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies. Trodelvy was also granted Fast Track designation, which expedites the review of drugs to treat serious conditions and fill an unmet medical need.

The FDA granted approval of Trodelvy to Immunomedics, Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nations food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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FDA Approves New Therapy for Triple Negative Breast Cancer That Has Spread, Not Responded to Other Treatments - FDA.gov

A rampage through the body – Science Magazine

The lungs are ground zero, but COVID-19 also tears through organ systems from brain to blood vessels.

Science's COVID-19 coverage is supported by the Pulitzer Center.

The coronavirus wreaked extensive damage (yellow) on the lungs of a 59-year-old man who died at George Washington University Hospital, as seen in a 3D model based on computed tomography scans.

On rounds in a 20-bed intensive care unit one recent day, physician Joshua Denson assessed two patients with seizures, many with respiratory failure, and others whose kidneys were on a dangerous downhill slide. Days earlier, his rounds had been interrupted as his team tried, and failed, to resuscitate a young woman whose heart had stopped. All of the patients shared one thing, says Denson, a pulmonary and critical care physician at the Tulane University School of Medicine. They are all COVID positive.

As the number of confirmed cases of COVID-19 approaches 2.5 million globally and deaths surpass 166,000, clinicians and pathologists are struggling to understand the damage wrought by the coronavirus as it tears through the body. They are realizing that although the lungs are ground zero, the virus' reach can extend to many organs including the heart and blood vessels, kidneys, gut, and brain.

[The disease] can attack almost anything in the body with devastating consequences, says cardiologist Harlan Krumholz of Yale University and Yale-New Haven Hospital, who is leading multiple efforts to gather clinical data on COVID-19. Its ferocity is breathtaking and humbling.

Understanding the rampage could help doctors on the front lines treat the roughly 5% of infected people who become desperately and sometimes mysteriously ill. Does a dangerous, newly observed tendency to blood clotting transform some mild cases into life-threatening emergencies? Is an overzealous immune response behind the worst cases, suggesting treatment with immune-suppressing drugs could help? And what explains the startlingly low blood oxygen that some physicians are reporting in patients who nonetheless are not gasping for breath? Taking a systems approach may be beneficial as we start thinking about therapies, says Nilam Mangalmurti, a pulmonary intensivist at the Hospital of the University of Pennsylvania (HUP).

What follows is a snapshot of the fast-evolving understanding of how the virus attacks cells around the body. Despite the more than 1500 papers now spilling into journals and onto preprint servers every week, a clear picture is elusive, as the virus acts like no pathogen humanity has ever seen. Without larger, controlled studies that are only now being launched, scientists must pull information from small studies and case reports, often published at warp speed and not yet peer reviewed. We need to keep a very open mind as this phenomenon goes forward, says Nancy Reau, a liver transplant physician who has been treating COVID-19 patients at Rush University Medical Center. We are still learning.

WHEN AN INFECTED PERSON expels virus-laden droplets and someone else inhales them, the novel coronavirus, called SARS-CoV-2, enters the nose and throat. It finds a welcome home in the lining of the nose, according to a recent arXiv preprint, because cells there are rich in a cell-surface receptor called angiotensin-converting enzyme 2 (ACE2). Throughout the body, the presence of ACE2, which normally helps regulate blood pressure, marks tissues potentially vulnerable to infection, because the virus requires that receptor to enter a cell. Once inside, the virus hijacks the cell's machinery, making myriad copies of itself and invading new cells.

As the virus multiplies, an infected person may shed copious amounts of it, especially during the first week or so. Symptoms may be absent at this point. Or the virus' new victim may develop a fever, dry cough, sore throat, loss of smell and taste, or head and body aches.

If the immune system doesn't beat back SARS-CoV-2 during this initial phase, the virus then marches down the windpipe to attack the lungs, where it can turn deadly. The thinner, distant branches of the lung's respiratory tree end in tiny air sacs called alveoli, each lined by a single layer of cells that are also rich in ACE2 receptors.

Normally, oxygen crosses the alveoli into the capillaries, tiny blood vessels that lie beside the air sacs; the oxygen is then carried to the rest of the body. But as the immune system wars with the invader, the battle itself disrupts healthy oxygen transfer. Frontline white blood cells release inflammatory molecules called chemokines, which in turn summon more immune cells that target and kill virus-infected cells, leaving a stew of fluid and dead cellspusbehind (see graphic, below). This is the underlying pathology of pneumonia, with its corresponding symptoms: coughing; fever; and rapid, shallow respiration. Some COVID-19 patients recover, sometimes with no more support than oxygen breathed in through nasal prongs.

But others deteriorate, often suddenly, developing a condition called acute respiratory distress syndrome. Oxygen levels in their blood plummet, and they struggle ever harder to breathe. On x-rays and computed tomography scans, their lungs are riddled with white opacities where black spaceairshould be. Commonly, these patients end up on ventilators. Many die, and survivors may face long-term complications (see sidebar, p. 359). Autopsies show their alveoli became stuffed with fluid, white blood cells, mucus, and the detritus of destroyed lung cells.

Some clinicians suspect the driving force in many gravely ill patients' downhill trajectories is a disastrous overreaction of the immune system known as a cytokine storm, which other viral infections are known to trigger. Cytokines are chemical signaling molecules that guide a healthy immune response; but in a cytokine storm, levels of certain cytokines soar far beyond what's needed, and immune cells start to attack healthy tissues. Blood vessels leak, blood pressure drops, clots form, and catastrophic organ failure can ensue.

Some studies have shown elevated levels of these inflammation-inducing cytokines in the blood of hospitalized COVID-19 patients. The real morbidity and mortality of this disease is probably driven by this out of proportion inflammatory response to the virus, says Jamie Garfield, a pulmonologist who cares for COVID-19 patients at Temple University Hospital.

But others aren't convinced. There seems to have been a quick move to associate COVID-19 with these hyperinflammatory states. I haven't really seen convincing data that that is the case, says Joseph Levitt, a pulmonary critical care physician at the Stanford University School of Medicine.

He's also worried that efforts to dampen a cytokine response could backfire. Several drugs targeting specific cytokines are in clinical trials in COVID-19 patients. But Levitt fears those drugs may suppress the immune response that the body needs to fight off the virus. There's a real risk that we allow more viral replication, Levitt says.

Meanwhile, other scientists are zeroing in on an entirely different organ system that they say is driving some patients' rapid deterioration: the heart and blood vessels.

IN BRESCIA, ITALY, a 53-year-old woman walked into the emergency room of her local hospital with all the classic symptoms of a heart attack, including telltale signs in her electrocardiogram and high levels of a blood marker suggesting damaged cardiac muscles. Further tests showed cardiac swelling and scarring, and a left ventriclenormally the powerhouse chamber of the heartso weak that it could only pump one-third its normal amount of blood. But when doctors injected dye in her coronary arteries, looking for the blockage that signifies a heart attack, they found none. Another test revealed the real cause: COVID-19.

How the virus attacks the heart and blood vessels is a mystery, but dozens of preprints and papers attest that such damage is common. A 25 March paper in JAMA Cardiology found heart damage in nearly 20% of patients out of 416 hospitalized for COVID-19 in Wuhan, China. In another Wuhan study, 44% of 36 patients admitted to the intensive care unit (ICU) had arrhythmias.

The disruption seems to extend to the blood itself. Among 184 COVID-19 patients in a Dutch ICU, 38% had blood that clotted abnormally, and almost one-third already had clots, according to a 10 April paper in Thrombosis Research. Blood clots can break apart and land in the lungs, blocking vital arteriesa condition known as pulmonary embolism, which has reportedly killed COVID-19 patients. Clots from arteries can also lodge in the brain, causing stroke. Many patients have dramatically high levels of D-dimer, a byproduct of blood clots, says Behnood Bikdeli, a cardiovascular medicine fellow at Columbia University Medical Center.

The more we look, the more likely it becomes that blood clots are a major player in the disease severity and mortality from COVID-19, Bikdeli says.

Infection may also lead to blood vessel constriction. Reports are emerging of ischemia in the fingers and toesa reduction in blood flow that can lead to swollen, painful digits and tissue death.

In the lungs, blood vessel constriction might help explain anecdotal reports of a perplexing phenomenon seen in pneumonia caused by COVID-19: Some patients have extremely low blood-oxygen levels and yet are not gasping for breath. In this scenario, oxygen uptake is impeded by constricted blood vessels rather than by clogged alveoli. One theory is that the virus affects the vascular biology and that's why we see these really low oxygen levels, Levitt says.

If COVID-19 targets blood vessels, that could also help explain why patients with pre-existing damage to those vessels, for example from diabetes and high blood pressure, face higher risk of serious disease. Recent Centers for Disease Control and Prevention (CDC) data on hospitalized patients in 14 U.S. states found that about one-third had chronic lung diseasebut nearly as many had diabetes, and fully half had pre-existing high blood pressure.

Mangalmurti says she has been shocked by the fact that we don't have a huge number of asthmatics or patients with other respiratory diseases in her hospital's ICU. It's very striking to us that risk factors seem to be vascular: diabetes, obesity, age, hypertension.

Scientists are struggling to understand exactly what causes the cardiovascular damage. The virus may directly attack the lining of the heart and blood vessels, which, like the nose and alveoli, are rich in ACE2 receptors. By altering the delicate balance of hormones that help regulate blood pressure, the virus might constrict blood vessels going to the lungs. Another possibility is that lack of oxygen, due to the chaos in the lungs, damages blood vessels. Or a cytokine storm could ravage the heart as it does other organs.

We're still at the beginning, Krumholz says. We really don't understand who is vulnerable, why some people are affected so severely, why it comes on so rapidly and why it is so hard [for some] to recover.

THE WORLDWIDE FEARS of ventilator shortages for failing lungs have received plenty of attention. Not so a scramble for another type of equipment: kidney dialysis machines. If these folks are not dying of lung failure, they're dying of renal failure, says neurologist Jennifer Frontera of New York University's Langone Medical Center, which has treated thousands of COVID-19 patients. Her hospital is developing a dialysis protocol with a different kind of machine to support more patients. What she and her colleagues are seeing suggests the virus may target the kidneys, which are abundantly endowed with ACE2 receptors.

According to one preprint, 27% of 85 hospitalized patients in Wuhan had kidney failure. Another preprint reported that 59% of nearly 200 hospitalized COVID-19 patients in China's Hubei and Sichuan provinces had protein in their urine, and 44% had blood; both suggest kidney damage. Those with acute kidney injury were more than five times as likely to die as COVID-19 patients without it, that preprint reported.

The lung is the primary battle zone. But a fraction of the virus possibly attacks the kidney. And as on the real battlefield, if two places are being attacked at the same time, each place gets worse, says co-author Hongbo Jia, a neuroscientist at the Chinese Academy of Sciences's Suzhou Institute of Biomedical Engineering and Technology.

One study identified viral particles in electron micrographs of kidneys from autopsies, suggesting a direct viral attack. But kidney injury may also be collateral damage. Ventilators boost the risk of kidney damage, as do antiviral compounds including remdesivir, which is being deployed experimentally in COVID-19 patients. Cytokine storms can also dramatically reduce blood flow to the kidney, causing often-fatal damage. And pre-existing diseases like diabetes can increase the chances of kidney injury. There is a whole bucket of people who already have some chronic kidney disease who are at higher risk for acute kidney injury, says Suzanne Watnick, chief medical officer at Northwest Kidney Centers.

ANOTHER STRIKING SET of symptoms in COVID-19 patients centers on the brain and nervous system. Frontera says 5% to 10% of coronavirus patients at her hospital have neurological symptoms. But she says that is probably a gross underestimate of the number whose brains are struggling, especially because many are sedated and on ventilators.

Frontera has seen patients with the brain inflammation encephalitis, seizures, and a sympathetic storm, a hyperreaction of the sympathetic nervous system that causes seizurelike symptoms and is most common after a traumatic brain injury. Some people with COVID-19 briefly lose consciousness. Others have strokes. Many report losing their sense of smell and taste. And Frontera and others wonder whether, in some cases, infection depresses the brain stem reflex that senses oxygen starvationanother explanation for anecdotal observations that some patients aren't gasping for air, despite dangerously low blood oxygen levels.

ACE2 receptors are present in the neural cortex and brain stem, says Robert Stevens, an intensive care physician at Johns Hopkins Medicine. And the coronavirus behind the 2003 severe acute respiratory syndrome (SARS) epidemica close cousin of today's culpritwas able to infiltrate neurons and sometimes caused encephalitis. On 3 April, a case study in the International Journal of Infectious Diseases, from a team in Japan, reported traces of new coronavirus in the cerebrospinal fluid of a COVID-19 patient who developed meningitis and encephalitis, suggesting it, too, can penetrate the central nervous system.

But other factors could be damaging the brain. For example, a cytokine storm could cause brain swelling. The blood's exaggerated tendency to clot could trigger strokes. The challenge now is to shift from conjecture to confidence, at a time when staff are focused on saving lives, and even neurologic assessments like inducing the gag reflex or transporting patients for brain scans risk spreading the virus.

Last month, Sherry Chou, a neurologist at the University of Pittsburgh Medical Center, began to organize a worldwide consortium that now includes 50 centers to draw neurological data from care patients already receive. Early goals are simple: Identify the prevalence of neurologic complications in hospitalized patients and document how they fare. Longer term, Chou and her colleagues hope to gather scans and data from lab tests to better understand the virus' impact on the nervous system, including the brain.

No one knows when or how the virus might penetrate the brain. But Chou speculates about a possible invasion route: through the nose, then upward and through the olfactory bulbexplaining reports of a loss of smellwhich connects to the brain. It's a nice sounding theory, she says. We really have to go and prove that.

A 58-year-old woman with COVID-19 developed encephalitis, with tissue damage in the brain (arrows).

Most neurological symptoms are reported from colleague to colleague by word of mouth, Chou adds. I don't think anybody, and certainly not me, can say we're experts.

IN EARLY MARCH, a 71-year-old Michigan woman returned from a Nile River cruise with bloody diarrhea, vomiting, and abdominal pain. Initially doctors suspected she had a common stomach bug, such as Salmonella. But after she developed a cough, doctors took a nasal swab and found her positive for the novel coronavirus. A stool sample positive for viral RNA, as well as signs of colon injury seen in an endoscopy, pointed to a gastrointestinal (GI) infection with the coronavirus, according to a paper posted online in The American Journal of Gastroenterology (AJG).

Her case adds to a growing body of evidence suggesting the new coronavirus, like its cousin SARS, can infect the lining of the lower digestive tract, where ACE2 receptors are abundant. Viral RNA has been found in as many as 53% of sampled patients' stool samples. And in a paper in press at Gastroenterology, a Chinese team reported finding the virus' protein shell in gastric, duodenal, and rectal cells in biopsies from a COVID-19 patient. I think it probably does replicate in the gastrointestinal tract, says Mary Estes, a virologist at Baylor College of Medicine.

Recent reports suggest up to half of patients, averaging about 20% across studies, experience diarrhea, says Brennan Spiegel of Cedars-Sinai Medical Center in Los Angeles, coeditor-in-chief of AJG. GI symptoms aren't on CDC's list of COVID-19 symptoms, which could cause some COVID-19 cases to go undetected, Spiegel and others say. If you mainly have fever and diarrhea, you won't be tested for COVID, says Douglas Corley of Kaiser Permanente, Northern California, co-editor of Gastroenterology.

The presence of virus in the GI tract raises the unsettling possibility that it could be passed on through feces. But it's not yet clear whether stool contains intact, infectious virus, or only RNA and proteins. To date, We have no evidence that fecal transmission is important, says coronavirus expert Stanley Perlman of the University of Iowa. CDC says that, based on experiences with SARS and with the coronavirus that causes Middle East respiratory syndrome, the risk from fecal transmission is probably low.

The intestines are not the end of the disease's march through the body. For example, up to one-third of hospitalized patients develop conjunctivitispink, watery eyesalthough it's not clear that the virus directly invades the eye.

Other reports suggest liver damage: More than half of COVID-19 patients hospitalized in two Chinese centers had elevated levels of enzymes indicating injury to the liver or bile ducts. But several experts told Science that direct viral invasion isn't likely the culprit. They say other events in a failing body, like drugs or an immune system in overdrive, are more likely causes of the liver damage.

This map of the devastation that COVID-19 can inflict on the body is still just a sketch. It will take years of painstaking research to sharpen the picture of its reach, and the cascade of effects in the body's complex and interconnected systems that it might set in motion. As science races ahead, from probing tissues under microscopes to testing drugs on patients, the hope is for treatments more wily than the virus that has stopped the world in its tracks.

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A rampage through the body - Science Magazine