Wednesday, May 06, 2020

Under This Doctor’s Care, Most COVID-19 Patients Are Recovering. Here’s His Unusual Approach

One of the biggest hurdles in dealing with a pandemic caused by a completely new virus is grappling with the sheer amount of unknown information.

In the case of the novel coronavirus, SARS-CoV2, this was particularly difficult because the presentation of each patient seemed so vastly different from the previous case.

Furthermore, many patients seemed to improve clinically before deteriorating, requiring an admission to the intensive care unit for weeks at a time. The pernicious behavior of the virus made pandemic response that much more difficult, and the unpredictable nature of the disease consumed and strained health care resources.

Physicians who were treating COVID-19 patients took note and communicated to others by phone call, conference, or social media, but there was no central repository for their experiences, which ensured that the virus spread much faster than information.

Now, approximately four months since the first reported case in America, we are beginning to understand why.

Dr. Thomas Yadegar, a critical care physician for 20 years and now director of the intensive care unit at Providence Cedars-Sinai Tarzana Medical Center in Tarzana, California, has been on the front lines of the pandemic response.

The first time one of his patients deteriorated, he was completely stumped for the first time in his two decades in the ICU.

Many of his patients were in acute respiratory distress. But many other patients were experiencing abnormal coagulation, inflammatory heart disease, and some were even experiencing neurological deficits and weakened muscles.

“I have 20 years of critical care experience, and I can’t explain what just happened to my patient,” Yadegar said.

One evening after an exhausting shift, he sat down and pored over patient charts for all those cases, searching for a common thread. Finally, after one of the worst headaches of his life, he found it.

It was inflammation.

Early in the pandemic, Yadegar’s unit used treatment guidelines that came from doctors around the world, which recommended avoiding anti-inflammatory treatment and recommended early and aggressive use of ventilators to prevent patients from declining further.

But those guidelines were aimed at treating a severe viral respiratory disease by using a ventilator to assist with oxygenating the blood while the body uses its inflammatory pathways to mount a response to the virus.

Those guidelines did not address the treatment for when other organ systems began to fail.

In fact, using a ventilator is a highly invasive procedure, and the repeated and forced inspiration of air irritates the lungs, which feeds back into the inflammatory cycle. Many patients, once on a ventilator, never recover.

The only way to explain the highly complex disease course that seems to change from one patient to the next is that the virus is causing an autoimmune response, in which the body’s natural defense mechanisms go haywire and begin destroying the body they’re trying to protect.

The disease course is so unpredictable because every person’s immune system is unique to that person.

This phenomenon is not unheard of, and a common virus, Epstein-Barr virus, is known for potentially initiating the body’s inflammatory pathways to attack the nervous system and causing Guillain-Barre syndrome.

The main difference with SARS-CoV2 is that it’s much more efficient at doing this—and often in a catastrophic manner.

Yadegar and the ICU he manages have adjusted their protocols. Now, patients who test positive in his hospital for SARS-CoV2 are not sent home immediately, but tested for inflammatory markers.

Those with elevated inflammatory markers are kept in the hospital with a close eye on their oxygen saturation levels. If the patient begins to desaturate, the medical team evaluates the patient before starting a course of steroids and an IL-6 inhibitor.

IL-6 (interleukin-6) is a powerful mediator for the inflammatory pathway, so an IL-6 inhibitor would prevent a significant amount of inflammation from happening. Steroids have strong anti-inflammatory effects and also suppress the immune system more broadly.

The two of those do not treat the virus, but the potentially deadly autoimmune response it can cause.

But Yadegar cautioned that “you have to treat each patient within their own protocol.” Doctors must always treat the patients in front of them and cannot simply rely on these types of drugs for all critically ill COVID-19 patients.

That’s because using an IL-6 inhibitor with steroids would effectively strip the body of its immune response. If there’s a concomitant infection, which is extremely common in the hospital setting and even more so if a patient is on a ventilator, then using this combination of drugs will, almost certainly, kill the patient.

Still, Yadegar and his team have had remarkable success. They have not put a patient on a ventilator in at least two weeks, and the mortality rate in their ICU has been in the single digits, whereas nationally the mortality rate of critically ill patients has been between 40% and 70%.

There’s one thing we have known from the start about the COVID-19 virus, which is that it’s a tricky and pernicious one.

One of the important things that Yadegar has learned is that patients admitted to the ICU are often not coming in due to the direct effect of the virus, but rather from the out-of-control autoimmune process.

Information like that can only be had from front-line clinicians, and we should do our best to ensure they are heard.

The Centers for Disease Control and Prevention periodically hosts a Clinical Outreach and Communication Activity, in which clinicians are able to discuss their findings and experiences.

The CDC should be using those frequently to update information about COVID-19 and its multiple disease manifestations and to make the information easily and publicly accessible.

Furthermore, the CDC should be actively seeking this information from the front lines of COVID-19 hot spots, where the most relevant data will be found.

With steps like these, clinicians can be assured of clear lines of communication that may help drive down mortality rates in the future and ease the process of reopening the country.



Critically-ill coronavirus patient with 'very grim' outlook is saved after NHS doctors gave him promising arthritis drug that is being trialed worldwide

A critically-ill coronavirus patient was saved after getting a promising arthritis drug that is being trialled by doctors worldwide.

Leonard Whitehurst was admitted to the Royal Cornwall Hospital on March 16 with a confirmed case of COVID-19.

Over the course of his stay, his condition deteriorated until his prognosis was 'very grim', according to medics who treated him.

One of the 72-year-old's doctors decided to give him tocilizumab on compassionate grounds, after it showed promise in treating COVID-19 patients in Italy.

Tocilizumab, marketed as RoActemra or Actemra, is used to suppress the immune system of rheumatoid arthritis patients.

For COVID-19, it has the potential to stop the 'cytokine storm' that happens when the immune system goes into overdrive and starts attacking the body.

As soon as Mr Whitehurst was given the drug as a last-ditch attempt, his condition began improving. He is now recovering at home.

Dr Giorgio Gentile believes he is the first to have tried the arthritis drug in the UK back in March following the advice of worldwide doctors.

Now, tocilizumab is part of three major trials involving British patients - with the first results expected by June or July.

Dr Gentile, a consultant nephrologist from Italy, has worked at the Royal Cornwall Hospitals Trust since 2015, having moved here with his family.

He revealed that Mr Whitehurst needed 19 litres of oxygen but had not been put on a ventilator.

Dr Gentile said: 'Leonard was deteriorating quickly and escalation to intensive care for ventilation was not an option.

'As the patient wasn't prepared to be artificially ventilated, the outlook was very grim.

'I was desperate to try to save the patient. To me, tocilizumab seemed like the only viable option left to try and save his life.'

Dr Gentile had been regularly reviewing the medical literature of COVID-19 that was coming out from countries which battled the peak of their outbreaks before the UK.

He also maintained regular contacts with his network of colleagues involved on the frontline against COVID-19 in Italy - the only European country to record more deaths than the UK.

Doubts have been raised about the safety of tocilizumab, which has a long list of side effects including a cough or sore throat, blocked or runny nose, headaches or dizziness, mouth ulcers, high blood pressure, weight gain and stomach problems.

Tocilizumab has been shown to increase the risk of infections in patients with rheumatoid arthritis, including pneumonia and upper respiratory tract infections, according to Versus Arthritis.

Trials on patients with RA before approval were not designed to assess long-term efficacy and safety.

The Food and Drug Administration has received reports on 1,128 people who died after taking Actemra, according to a report by Stat News in 2017. It said the FDA declined to comment about Actemra.

Dr Gentile had become aware of multiple anecdotal reports of people in very severe conditions who had dramatically improved after treatment with tocilizumab.

'The AIFA, which is the Italian equivalent of the Medicines and Healthcare products Regulatory Agency, had just approved a large trial with tocilizumab and was actively recruiting people,' added Dr Gentile.

'The Italian experience seemed to mirror a preliminary yet promising experience from Chinese scientists, who used tocilizumab in 21 patients with very encouraging results.'

Another promising study of 20 patients in China, published in mid-March, claimed tocilizumab cured 95 per cent of critically ill patients.

Dr Gentile said: 'Our patient had all the laboratory signs of the so-called "cytokine storm", which I was aware of thanks to a paper published in the peer-reviewed journal, The Lancet.

'The same paper speculated that tocilizumab could be used to treat patients with severe COVID-19 pneumonia and hyper-inflammation, who are at high risk of progression towards acute respiratory distress syndrome and death.

'Luckily, we have brave, compassionate and open-minded leadership here at the RCHT. They gave me the green light to use tocilizumab on compassionate grounds. 'The patient agreed to receive the treatment, which was then quickly administered.'

The other drugs being looked at as a treatment for COVID-19 include a combination of Lopinavir and Ritonavir (known by the brand name Kaletra), which is used to treat HIV; low-dose Dexamethasone,a steroid used to reduce inflammation; azithromycin, a commonly used antibiotic which may have antiviral properties; and the steroid Tocilizumab.

Mr Whitehurst received two infusions of tocilizumab 12 hours apart from nurses.

Before the infusion, his oxygen saturation was 75 per cent. A normal reading should be between 80 and 100.

After the infusion, Mr Whitehurst's clinical conditions and his oxygen saturation improved very quickly, and then kept improving gradually and steadily over the subsequent days.

His oxygen requirement decreased gradually over time.

'At the time, we were at the very beginning of the COVID-19 crisis in the UK and the national lockdown had just been declared. So, it is quite possible that the RCHT has been the first NHS trust in the UK to successfully treat a patient with tocilizumab,' added Dr Gentile.

Mr Whitehurst was discharged from hospital last week 'smiling and overjoyed', having spent more than a month in the hospital.

Dr Gentile stressed that although tocilizumab worked for his patient, further evidence from rigorous randomised controlled trials is necessary to fully establish the role of the drug in COVID-19 pneumonia.



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