Drug that calms 'cytokine storm' associated with 45 percent lower risk
of dying among COVID-19 patients on ventilators

Date:
July 13, 2020
Source:
Michigan Medicine - University of Michigan
Summary:
Patients who received single intravenous dose of tocilizumab
were also more likely to leave the hospital or be off ventilator
within a month, despite double the risk of additional infection,
according to a new study.



FULL STORY ========================================================================== Critically ill COVID-19 patients who received a single dose of a drug
that calms an overreacting immune system were 45% less likely to die
overall, and more likely to be out of the hospital or off a ventilator
one month after treatment, compared with those who didn't receive the
drug, according to a new study by a team from the University of Michigan.


==========================================================================
The lower risk of death in patients who received intravenous tocilizumab happened despite the fact that they were also twice as likely to develop
an additional infection, on top of the novel coronavirus.

The study is published in the peer-reviewed journal Clinical Infectious Diseases after being available as a preprint last month.

It suggests a benefit from timely and targeted efforts to calm the
"cytokine storm" caused by the immune system's overreaction to the
coronavirus.

Tocilizumab, originally designed for rheumatoid arthritis, has already
been used to calm such storms in patients receiving advanced immunotherapy treatment for cancer.

The researchers base their conclusions on a thorough look back at data
from 154 critically ill patients treated at Michigan Medicine, U-M's
academic medical center, during the first six weeks of the pandemic's
arrival in Michigan from early March to late April. The analysis looked
at patients' records through late May.

During that time, when little was known about what would help COVID-19
patients on ventilators, about half of the studied patients received tocilizumab and half did not. Most received it within the 24-hour period surrounding their intubation.



==========================================================================
This created a natural opportunity for comparing the two groups' outcomes
in an observational study, though clinical trials are still needed to
truly see if the drug provides a benefit, the authors say.

Promising result Lead author Emily Somers, Ph.D., Sc.M., an epidemiologist
who has studied both rheumatologic and immunologic diseases, says the
research team went into their analysis uncertain whether they would
find a benefit, a risk, or no clear effect associated with tocilizumab
in the patients with life-threatening COVID- 19. But they knew it was
a critically important question that they were uniquely positioned to
answer at that point in the pandemic.

"One role of epidemiology is to rigorously evaluate real-world data on treatment effects, especially when evidence from clinical trials is not available. We kept trying to prove ourselves wrong as signals of benefit emerged in the data, both because of the immediate implications of these
data, and in part because of concern about the supply of the medication
for other patients," she says. "But the difference in mortality despite
the increase in secondary infection is quite pronounced, even after
accounting for many other factors." Somers is an associate professor
in the U-M Medical School's Department of Internal Medicine and member
of the U-M Institute for Healthcare Policy and Innovation. She co-leads
the COVID-19 Rapid Response Registry, which is supported by the Michigan Institute for Clinical and Health Research.



==========================================================================
The paper's co-first author is Gregory Eschenauer, Pharm.D., a clinical pharmacist at Michigan Medicine and clinical associate professor at the
U- M College of Pharmacy. He and senior author Jason Pogue, Pharm.D.,
are members of the Michigan Medicine Antimicrobial Stewardship Program.

The ASP group developed treatment guidelines provided to Michigan Medicine physicians in mid-March that identified tocilizumab as a potentially
beneficial therapy for the most severely ill COVID-19 patients. Those guidelines also pointed out its risks and the lack of evidence for its
use in COVID-19, and recommended a dose of 8 milligrams per kilogram.

This led some physicians to choose to use it, while others did not --
setting the stage inadvertently for a natural comparison.

More research needed Pogue, clinical professor at the U-M College of
Pharmacy and an infectious disease pharmacist at Michigan Medicine,
notes that more robust data released in June from a large randomized
controlled trial in the United Kingdom has led him to recommend the
steroid dexamethasone as the first choice to treat critically ill
COVID-19 patients.

"For a retrospective, single-center study, our data are robust. But at
this time, due to the lack of randomized controlled trial data and the
much higher cost, we recommend reserving tocilizumab for the treatment of select patients who decompensate while on or after receiving dexamethasone
or in patients where the risks of adverse events from steroid therapy
outweigh the potential benefits" says Pogue.

"Further studies of tocilizumab, which is more targeted than dexamethasone
in addressing the hyperinflammatory process, could include combining
these agents or comparing them head-to-head," he adds.

Pogue notes that a single dose of tocilizumab is roughly 100 times more expensive than a course of dexamethasone. He also notes that another
drug that aims to treat cytokine storm by targeting the interleukin-6
(IL-6) receptor - - one called sarilumab -- appears to have failed to
improve outcomes in a clinical trial in COVID-19 patients including
those on ventilators.

Michigan Medicine had been participating in the sarilumab study at
the time the patients in the current study were treated, but not all
patients qualified because of the timing of their admission or issues
around testing for COVID-19.

The current study does not include any patients who received sarilumab.

If the evidence around IL-6 targeting bears out in further studies,
the authors note that it will be important to select the dose and timing carefully, to address the cytokine storm without interfering with IL-6's
other roles in activating the body's response to infections and its
processes for repairing tissue.

More about the study The majority of the patients were transferred to U-M
from Detroit-area hospitals after diagnosis with COVID-19, and those who received tocilizumab were less likely overall to have been transferred
while already on a ventilator.

By the end of the 28-day period after patients went on a ventilator, 18%
of those who received tocilizumab had died, compared with 36% of those
who had not. When adjusted for health characteristics, this represents
a 45% reduction in mortality. Of those still in the hospital at the end
of the study period, 82% of the tocilizumab patients had come off the ventilator, compared with 53% of those who didn't receive the drug.

In all, 54% of the tocilizumab patients developed a secondary infection,
mostly ventilator associated pneumonia; 26% of those who didn't receive tocilizumab developed such infections. Such "superinfections" usually
reduce the chance of survival for COVID-19 patients.

Hydroxychloroquine was included in the treatment guidelines for COVID-19 inpatients at Michigan Medicine for the first two and a half weeks of the
study period, before being removed as evidence of its lack of benefit
and risks emerged. In all, it was used in one-quarter of the patients
who received tocilizumab and one-fifth of those who didn't. Similar
percentages of the two patient groups received steroids, though none
received dexamethasone.

The patients in the two groups were similar in most ways except for
a slightly higher average age in the non-tocilizumab group, and lower
rates of chronic obstructive pulmonary disease and chronic kidney disease
among the tocilizumab patients.

The study was supported by the National Institutes of Health
[UL1TR002240, 1K12HL133304]; the Centers for Disease Control and
Prevention [U01IP000974]; and an American Society for Transplantation
and Cellular Therapy New Investigator Award.

The COVID-19 Rapid Response Registry is supported by the Michigan
Institute for Clinical and Health Research (MICHR), and uses the
International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) Clinical Characterization Protocol to standardize the clinical characterization of patients with COVID-19 so their data can be studied.

In addition to Somers, Pogue and Eschenauer, the study's authors are
from several departments of the U-M Medical School, and from the U-M
College of Pharmacy, School of Public Health, and MICHR. They are:
Jonathan P Troost, PhD, Jonathan L Golob, MD PhD, Tejal N Gandhi, MD,
Lu Wang, PhD, Nina Zhou, MS, Lindsay A Petty, MD, Ji Hoon Baang, MD,
Nicholas O Dillman, PharmD, David Frame, PharmD, Kevin S Gregg, MD, Dan
R Kaul, MD, Jerod Nagel, PharmD, Twisha S Patel, PharmD, Shiwei Zhou,
MD, Adam S Lauring, MD PhD, David A Hanauer, MD MS, Emily Martin, PhD,
Pratima Sharma, MD MS, and Christopher M Fung, MD.


========================================================================== Story Source: Materials provided by
Michigan_Medicine_-_University_of_Michigan. Original written by Kara
Gavin. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Jason M Pogue, Christopher M Fung, Pratima Sharma, Emily Martin,
David A
Hanauer, Adam S Lauring, Shiwei Zhou, Twisha S Patel, Jerod Nagel,
Dan R Kaul, Kevin S Gregg, David Frame, Nicholas O Dillman, Ji
Hoon Baang, Lindsay A Petty, Nina Zhou, Lu Wang, Tejal N Gandhi,
Jonathan L Golob, Jonathan P Troost, Gregory A Eschenauer, Emily
C Somers. Tocilizumab for treatment of mechanically ventilated
patients with COVID-19. Clinical Infectious Diseases, 2020; DOI:
10.1093/cid/ciaa954 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200713120016.htm

--- up 24 weeks, 6 days, 2 hours, 34 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1337:3/111)