Drug
That Calms ‘Cytokine Storm’ Associated with 45% Lower Risk of Dying among
COVID-19 Patients on Ventilators
By Kara Gavin
University of
Michigan Health Lab -- July 13, 2020 -- Patients who received single
intravenous dose of tocilizumab were also more likely to leave the hospital or
be off a ventilator within a month, despite double the risk of additional
infection.
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
also had twice the risk of developing 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
experiment.
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
had 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.
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