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Saturday, July 25, 2020

Intravenous n-acetylcysteine blocks inflammation in severe COVID-19

Abstract

Glucose 6-phosphate dehydrogenase (G6PD) deficiency facilitates human coronavirus infection due to glutathione depletion. G6PD deficiency may especially predispose to hemolysis upon coronavirus disease-2019 (COVID-19) infection when employing pro-oxidant therapy. However, glutathione depletion is reversible by N-acetylcysteine (NAC) administration. We describe a severe case of COVID-19 infection in a G6PD-deficient patient treated with hydroxychloroquine who benefited from intravenous (IV) NAC beyond reversal of hemolysis. NAC blocked hemolysis and elevation of liver enzymes, C-reactive protein (CRP), and ferritin and allowed removal from respirator and veno-venous extracorporeal membrane oxygenator and full recovery of the G6PD-deficient patient. NAC was also administered to 9 additional respirator-dependent COVID-19-infected patients without G6PD deficiency. NAC elicited clinical improvement and markedly reduced CRP in all patients and ferritin in 9/10 patients. NAC mechanism of action may involve the blockade of viral infection and the ensuing cytokine storm that warrant follow-up confirmatory studies in the setting controlled clinical trials.

Efficacy of Hydroxychloroquine as Prophylaxis for Covid-19

Limitations in the design of the experiment of Boulware et al[1] are considered in Cohen[2]. They are not subject to correction but they are reported for readers’ consideration. However, they made an analysis for the incidence based on Fisher’s hypothesis test for means while they published detailed time dependent data which were not analyzed, disregarding an important information. Here we make the analyses with this time dependent data adopting a simple regression analysis.
We conclude their randomized, double-blind, placebo-controlled trial presents statistical evidence, at 99% confidence level, that the treatment of Covid-19 patients with hydroxychloroquine is effective in reducing the appearance of symptoms if used before or right after exposure to the virus. For 0 to 2 days after exposure to virus, the estimated relative reduction in symptomatic outcomes is 72% after 0 days, 48.9% after 1 day and 29.3% after 2 days. For 3 days after exposure, the estimated relative reduction is 15.7% but results are not statistically conclusive and for 4 or more days after exposure there is no statistical evidence that hydroxychloroquine is effective in reducing the appearance of symptoms.
Our results show that the time elapsed between infection and the beginning of treatment is crucial for the efficacy of hydroxychloroquine as a treatment to Covid-19.
Important: e-prints posted on arXiv are not peer-reviewed by arXiv; they should not be relied upon without context to guide clinical practice or health-related behavior and should not be reported in news media as established information without consulting multiple experts in the field.

Herd immunity thresholds for SARS-CoV-2 estimated from unfolding epidemics

Ricardo Aguas, Rodrigo M. Corder, Jessica G. King, Guilherme Goncalves, Marcelo U. Ferreira, M. Gabriela M. Gomes

Amplyx Pharmaceuticals’ Fosmanogepix Hits the Mark in Phase II Candida Study

The deadly fungal infection candida auris reared its head this week in a Los Angeles healthcare facility and could be related to COVID-19 cases through the conservation of personal protective equipment strategies.
A combination of COVID-19 and candida auris is something of a perfect storm of infections. Both are difficult to treat, COVID-19 due to the novelty as a disease and the myriad of symptoms it has, and candida auris, which is highly resistant to antimicrobials and is considered one of the highest threats by the U.S. Centers for Disease Control and Prevention. The fungal infection quickly spreads from the contaminated patient and can infect surface areas and more. Last year, in a New York hospital, a patient’s room had to be completely renovated following the death of that patient.
The deadly nature of candida auris, which is part of a family of Candida fungi, and other fungal infections that are resistant to antimicrobials, is why researchers at San Diego-based Amplyx Pharmaceuticals are diligently working to develop a first-line treatment for patients with invasive fungal infections caused by Candida. The company posted Phase II data that showed its experimental asset fosmanogepix demonstrated a treatment success rate of 80%.
Amplyx Chief Executive Officer Ciara Kennedy told BioSpace in an interview that treatment options for Candida are ineffective and there is a dire need for a new antimicrobial. COVID-19 has shown the world that new vaccines, antibiotics and antimicrobials are highly needed, despite many companies having fled the space. Fosmanogepix, which is being developed both as an intravenous and oral treatment, is a new kind of medication that is showing promise as a treatment for Candida and other types of resistant pathogens highlighted by the CDC in a recent report.
“The question is, will it really do the job?” she posed. So far, the answer seems to be a resounding yes.
With antimicrobial research, Kennedy said animal models have been historically relatable to human outcomes in this setting. The Phase II data provided what Kennedy called a “stellar result,” particularly as some of the drugs used in this space have about a 70% success rate and can come with some safety issues. In the Phase II study, fosmanogepix was well-tolerated with no treatment-related serious adverse events or discontinuations. Full results from the mid-stage study will be presented at an upcoming medical conference.
Not only did it have a strong overall outcome, but Kennedy said patients were able to transition from an intravenous treatment to an oral treatment, which is an important factor. Typically, fungal infections such as the Candida family are contracted in a hospital or long-term care setting. Being able to treat patients intravenously, then discharge them from a hospital with an oral treatment in hand, will be a crucial factor in treating the issue.
“You want to really make sure this infection doesn’t come back,” Kennedy said.
Invasive fungal infections represent a serious threat to millions of patients worldwide, resulting in more than 1.5 million deaths annually and mortality rates ranging from 15% to 65%. These infections continue to be a global health issue, especially for critically ill patients in hospitals and patients with compromised immune systems, including cancer and transplant patients.
While the deadly candida auris only hits about 1,000 patient in the United States annually, there are more cases across the globe. Additionally, the broader candida bucket is about 100,000 patients per year with a 30% to 40% mortality rate, Kennedy said.
“We think we have the ideal drug for treating candida auris because of its activity and its safety profile. Our drug is the most active agent against candida auris, irrespective of its resistant profile,” Kennedy said.
In addition to candida, Amplyx is also investigating fosmanogepix are ongoing in patients with serious and life threatening aspergillus and rare mold infections, some of which have high rates of mortality. The emergence of drug-resistant aspergillus added to the watch list for global health threats, underscoring the need for innovation in the development of antifungals, especially those with a novel mechanism of action.

FDA OKs 1st Test to Screen People With No Known, Suspected COVID-19 Infection

Today, the U.S. Food and Drug Administration reissued the LabCorp COVID-19 RT-PCR Test emergency use authorization (EUA) to include two new indications for use: testing for people who do not have COVID-19 symptoms or who have no reason to suspect COVID-19 infection, and to allow pooled sample testing. The FDA reissued the LabCorp COVID-19 RT-PCR Test EUA to expand use of the test to anyone, after the company provided scientific data showing the test’s ability to detect SARS-CoV-2 in a general, asymptomatic population. Additionally, the reissuance includes authorization for LabCorp to test pooled samples containing up to five individual swab specimens collected under observation. Sample pooling allows for fewer tests to be run overall, conserving resources and potentially allowing more samples to be evaluated quicker.
“FDA’s authorization of the first diagnostic test to be used for anyone, regardless of whether they are showing symptoms of COVID-19 or have other exposure risk factors, is a step toward the type of broad screening that may help enable the reopening of schools and workplaces,” said FDA Commissioner Stephen M. Hahn, M.D. “By authorizing another test for use with pooled samples, we also further help increase the possibility that patients may be able to receive results sooner, while also conserving vital testing supplies, which are under increased demand during the pandemic. Continuing to facilitate increased access to accurate and reliable tests for all Americans is critically important and the FDA continues to work around the clock with test developers to support this goal.”
The FDA recognizes that organizations may want to conduct screening of asymptomatic people as part of a broader strategy to help ensure the safety of their employees, patients, students and others. Last month, the FDA posted updated templates with recommendations for test developers to demonstrate validation for a test to be authorized for screening of asymptomatic people, as well as for sample pooling. Last week, the FDA authorized the first COVID-19 test that could be used with pooled samples.
The LabCorp test remains prescription-only and is authorized for human specimen collection either at home using the Pixel by LabCorp or other home sample collection kits authorized for use with LabCorp’s test, or by a health care provider. However, only health care provider-collected samples may be pooled at this time. Additionally, the data reviewed by the FDA demonstrated that the test is as accurate in the broader asymptomatic population as it is among people suspected to have COVID-19.

‘Why COVID-19 is killing U.S. diabetes patients at alarming rates’

Devon Brumfield could hear her father gasping for breath on the phone.
Darrell Cager Sr., 64, had diabetes. So his youngest daughter urged him to seek care. The next day, he collapsed and died in his New Orleans home.
The daughter soon learned the cause: acute respiratory distress from COVID-19. His death certificate noted diabetes as an underlying condition. Brumfield, who lives in Texas and also has type 2 diabetes, is “terrified” she could be next.
“I’m thinking, Lord, this could happen to me,” she said of her father’s death in late March.
She has good reason to fear. As U.S. outbreaks surge, a new government study shows that nearly 40% of people who have died with COVID-19 had diabetes.
Among deaths of those under 65, half had the chronic condition. The U.S. Centers for Disease Control and Prevention analyzed more than 10,000 deaths in 15 states and New York City from February to May.
Jonathan Wortham, a CDC epidemiologist who led the study, called the findings “extremely striking,” with serious implications for those with diabetes and their loved ones.
A separate Reuters survey of states found a similarly high rate of diabetes among people dying from COVID-19 in 12 states and the District of Columbia.
Ten states, including California, Arizona and Michigan, said they weren’t yet reporting diabetes and other underlying conditions, and the rest did not respond – rendering an incomplete picture for policymakers and clinicians struggling to protect those most at-risk.
America’s mortality rates from diabetes have been climbing since 2009 and exceed most other industrialized nations. Blacks and Latinos suffer from diabetes at higher rates than whites and have disproportionately suffered from COVID-19.
“Diabetes was already a slow-moving pandemic. Now COVID-19 has crashed through like a fast-moving wave,” said Elbert Huang, a professor of medicine and director of the University of Chicago’s Center for Chronic Disease Research and Policy.
Keeping diabetes under control – among the best defenses against COVID-19 – has become difficult as the pandemic disrupts medical care, exercise and healthy eating routines.
The high price of insulin has also forced some people to keep working – risking virus exposure – to afford the essential medicine. And as the country grapples with an economic crisis, millions of Americans have lost their jobs and their employer-sponsored health insurance.
Much of this could have been anticipated and addressed with a more comprehensive, national response, said A. Enrique Caballero, a Harvard Medical School endocrinologist and diabetes researcher.
Top health officials should have done more to emphasize the threat to people with diabetes and assuage their fears of hospital visits, he said, while also focusing more on helping patients manage their condition at home.
Policymakers had ample warning that COVID-19 posed a high risk for diabetes patients. In 2003, during the coronavirus outbreak known as SARS, or Severe Acute Respiratory Syndrome, more than 20% of people who died had diabetes.
In 2009, during the H1N1 flu pandemic, patients with diabetes faced triple the risk of hospitalization.
Most recently in 2012, when the coronavirus Middle East Respiratory Syndrome, or MERS, emerged, one study found 60% of patients who entered intensive care or died had diabetes.
The COVID-19 pandemic, however, has unearthed previously unknown complications because it has lasted longer and infected many more people than earlier coronavirus epidemics, said Charles S. Dela Cruz, a Yale University physician-scientist and Director of the Center of Pulmonary Infection Research and Treatment.
Doctors warn that the coronavirus pandemic may indirectly lead to a spike in diabetes-related complications – more emergency-room visits, amputations, vision loss, kidney disease and dialysis.
“My fear is we will see a tsunami of problems once this is over,” said Andrew Boulton, president of the International Diabetes Federation and a medical professor at the University of Manchester in England.

‘ONE BIG PUZZLE’

Researchers have scrambled for months to unravel the connections between diabetes and the coronavirus, uncovering an array of vulnerabilities.
The virus targets the heart, lung and kidneys, organs already weakened in many diabetes patients. COVID-19 also kills more people who are elderly, obese or have high blood pressure, many of whom also have diabetes, studies show.
On the microscopic level, high glucose and lipid counts in diabetes patients can trigger a “cytokine storm,” when the immune system overreacts, attacking the body. Damaged endothelial cells, which provide a protective lining in blood vessels, can lead to inflammation as white blood cells rush to attack the virus and may cause lethal clots to form, emerging research suggests.
“It’s all one big puzzle,” said Yale’s Dela Cruz. “It’s all interrelated.”
Many of their vulnerabilities can be traced to high blood sugar, which can weaken the immune system or damage vital organs. COVID-19 appears not only to thrive in a high-sugar environment but to exacerbate it. Recent evidence suggests the virus may trigger new cases of diabetes.
David Thrasher, a pulmonologist in Montgomery, Alabama, said up to half of COVID-19 patients in his local hospital ICU have diabetes. “They are often my most challenging patients,” he said, and the immune system response may be a big reason why.

‘DIABETES BELT’

The pandemic has ripped through several southern states with some of the nation’s highest diabetes rates. A Reuters examination of state data found that nearly 40% of COVID-19 deaths were people with diabetes in Alabama, Louisiana, Mississippi, North Carolina, South Carolina and West Virginia. Much of this area lies within what the CDC calls the “diabetes belt.”
Alabama has the highest percentage of adults with diabetes at 13.2%, or more than 550,000 people, CDC data show. Diabetes patients accounted for 38% of the state’s COVID-related deaths through June, officials said. Karen Landers, Alabama’s assistant state health officer, said she is particularly heartbroken at the deaths of diabetes patients in their 30s and 40s.
Medical professionals in these states say they struggle to keep patients’ diabetes under control when regular in-person appointments are canceled or limited because of the pandemic.
Sarah Hunter Frazer, a nurse practitioner at the Medical Outreach Ministries clinic for low-income residents in Montgomery, Alabama, said diabetes is common among her COVID-19 patients. With clinic visits on hold, she stays in touch by phone or video chat. If a problem persists, she insists on an outdoors, face-to-face meeting. “We meet them under a shade tree behind the clinic,” Frazer said.
In similar fashion, doctors at the University of North Carolina stepped up their use of telemedicine to reach at-risk rural patients. Despite those efforts, John Buse, a physician and director of the university’s diabetes center, said he’s certain some foot ulcers and dangerously high blood sugars are being missed because people avoid health facilities for fear of the virus.

‘UNDER CONTROL’

Many diabetes patients with severe or deadly cases of COVID-19 were in good health before contracting the virus.
Clark Osojnicki, 56, of Stillwater, Minnesota, had heard early warnings about the risks of the coronavirus for people with diabetes, said his wife, Kris Osojnicki. But the couple didn’t think the admonitions applied to him because his glucose levels were in a healthy range.
“He was incredibly active,” she said.
On a Sunday in mid-March, Osojnicki jogged alongside his border collie, Sonic, on an agility course for dogs inside a suburban Minneapolis gym. Three days later, Osojnicki developed a fever, then body aches, a cough and shortness of breath. He was soon in the hospital, on a ventilator. Clark, a financial systems analyst, died April 6 from a blood clot in the lungs.
Osojnicki is among 255 recorded deaths in Minnesota of people with COVID-19 and diabetes mentioned on their death certificate as of mid-July, according to state data. The records describe people who died as young as 34.

WORKING FOR INSULIN

For years, the skyrocketing cost of insulin has fueled much of the national outrage over drug prices. Early in the pandemic, the American Diabetes Association asked states to eliminate out-of-pocket costs for insulin and other glucose-lowering medications through state-regulated insurance plans.
But no state has fully followed that advice, the ADA said. Vermont suspended deductibles for preventive medications, like insulin, starting in July. Other states ordered insurers to make prescription refills more available but didn’t address cost.
Robert Washington, 68, knew his diabetes put him at risk from COVID-19. When his employer, Gila River’s Lone Butte Casino in Chandler, Arizona, reopened in May, he decided to keep working as a security guard so he could afford insulin.
Washington’s supervisors had assured him he could patrol alone in a golf cart, said his daughter, Lina. But once back at work, he was stationed at the entrance, where long lines of gamblers waited, most without masks, Robert told his daughter.
“He was terrified at what he saw,” Lina said.
He tested positive for the virus in late May and was admitted to the hospital days later. He died from complications of COVID-19 on June 11, his daughter said.
A week after Washington’s death, the casino again closed as COVID-19 cases exploded in the state. The casino did not respond to a request for comment.
“It’s hard to accept he is gone. I have to stop myself from wanting to call him,” said Lina, a sports anchor and reporter at a Sacramento, California, TV station. “A lot of these deaths were in some way preventable.”