From the Journals

Combination therapy quells COVID-19 cytokine storm


Treatment with high-dose methylprednisolone plus tocilizumab (Actemra, Genentech) as needed was associated with faster respiratory recovery, a lower likelihood of mechanical ventilation, and fewer in-hospital deaths compared with supportive care alone among people with COVID-19 experiencing a hyperinflammatory state known as a cytokine storm.

Dr. Sofia Ramiro, Leiden (the Netherlands) University Medical Center

Dr. Sofia Ramiro

Compared with historic controls, participants in the treatment group were 79% more likely to achieve at least a two-stage improvement in respiratory status, for example.

“COVID-19-associated cytokine storm syndrome [CSS] is an important complication of severe acute respiratory syndrome coronavirus-2 infection in up to 25% of the patients,” lead author Sofia Ramiro, MD, PhD, said in an interview.

Furthermore, CSS often leads to death in this population, said Dr. Ramiro, a consultant rheumatologist and senior researcher at Leiden University Medical Center and Zuyderland Medical Center in Heerlen, the Netherlands.

Results of the COVID High-Intensity Immunosuppression in Cytokine Storm Syndrome (CHIC) study were published online July 20 in Annals of the Rheumatic Diseases.

Contrary to guidance?

The World Health Organization (WHO) cautions against administering corticosteroids to some critically ill patients with COVID-19. “WHO recommends against the routine use of systemic corticosteroids for treatment of viral pneumonia,” according to an interim guidance document on the clinical management of COVID-19 published May 27.

Dr. Ramiro and colleagues make a distinction, however, noting “the risk profile of such a short course of glucocorticoid for treatment of CSS needs to be separated from preexisting chronic use of glucocorticoid for conditions like rheumatic and musculoskeletal diseases.”

Participants in the current study tolerated immunosuppressive therapy well without evidence of impaired viral clearance or bacterial superinfection, they added.

Other experts disagree with recent recommendations to use corticosteroids to treat a hyperimmune response or suspected adrenal insufficiency in the setting of refractory shock in patients with COVID-19.

Information about immunosuppressive therapy and CSS linked to COVID-19 remains anecdotal, however, Dr. Ramiro and colleagues noted.

The researchers assessed outcomes of 86 individuals with COVID-19-associated CSS treated with high-dose methylprednisolone plus/minus tocilizumab, an anti-interleukin-6 receptor monoclonal antibody. They compared them with another 86 patients with COVID-19 treated with supportive care before initiation of the combination therapy protocol.

Participants with CSS had an oxygen saturation of 94% or lower at rest or tachypnea exceeding 30 breaths per minute.

They also had at least two of the following: C-reactive protein > 100 mg/L; serum ferritin > 900 mcg/L at one occasion or a twofold increase at admission within 48 hours; or D-dimer levels > 1,500 mcg/L.

The treatment group received methylprednisolone 250 mg intravenously on day 1, followed by 80 mg intravenously on days 2-5. Investigators permitted a 2-day extension if indicated.

Those who failed to clinically improve or experienced respiratory decline could also receive intravenous tocilizumab on day 2 or after. The agent was dosed at 8 mg/kg body weight during a single infusion from day 2-5 up to a maximum of 800 mg.

In all, 37 participants received tocilizumab, including two participants who received a second dose 5 days after initial treatment.

Except for one patient in the treatment group, all participants also received antibiotic treatment and nearly 80% received chloroquine.

Mechanical ventilation and mortality

The primary outcome of at least a two-stage improvement in respiratory status on a WHO scale associated with treatment yielded a hazard ratio (HR) of 1.79. The treatment group achieved this improvement a median 7 days earlier than controls.

Mechanical ventilation to treat respiratory deterioration was 71% less likely for the treatment group versus controls (HR, 0.29).

The treatment group were also 65% less likely to die in hospital (HR, 0.35) than were controls.

The researchers also reported a significant difference in the number of deaths at day 14 in the treatment vs. control group, at 10 vs. 33 patients (P < .0001).

Glucocorticoid sufficient for many

In a sensitivity analysis excluding patients who received tocilizumab, the benefits of treatment remained statistically significant, “suggesting that a clinically relevant treatment effect can be reached by high-dose glucocorticoids alone,” the researchers noted.

This finding suggests “that the timely administration of high-dose glucocorticoids alone may provide significant benefit in more than half of the patients, and that tocilizumab is only needed in those cases that had insufficient clinical improvement on methylprednisolone alone,” they added.

“This is an important finding given the limited availability of tocilizumab in many countries and tocilizumab’s high costs.”

Complications were fairly balanced between groups. For example, bacterial infections during hospitalization were diagnosed in eight patients in the treatment group versus seven in the control group.

In addition, cardiac arrhythmias occurred in both groups, but slightly less frequently in the treatment group (P = .265), and there was a trend towards more pulmonary embolisms in the treatment group (P = .059).

Strengths and limitations

“A treatment with high-dose glucocorticoids is a convenient choice since glucocorticoids are safe, widely available, and inexpensive,” the researchers noted. “Longer follow-up, however, is needed to give final resolution about the safety and efficacy of the strategy.”

A strength of the study was “meticulous selection of those patients more likely to benefit from immunosuppressive treatment, namely patients with a CSS,” she added.

The study featured a prospective, observational design for the treatment group and retrospective analysis of the historic controls. “Methodologically, the main limitation of the study is not being a randomized controlled trial,” she noted.

“Ethically it has shown to be very rewarding to consciously decide against a randomized control trial, as we are talking about a disease that if only treated with supportive care can lead to mortality up to almost 50% from COVID-19-associated CSS,” Dr. Ramiro said.

Going forward, Dr. Ramiro plans to continue monitoring patients who experienced CSS to assess their outcome post-COVID-19 infection. “We want to focus on cardiorespiratory, functional, and quality of life outcomes,” she said. “We will also compare the outcomes between patients that have received immunosuppression with those that haven’t.”

‘Quite interesting’ results

“We desperately need better evidence to guide the management of patients hospitalized with COVID-19,” Nihar R. Desai, MD, MPH, who was not affiliated with the study, said in an interview.

“These data from the Netherlands are quite interesting and provide another signal to support the use of corticosteroids, with tocilizumab if needed, among hospitalized patients with COVID-19 to improve outcomes,” added Dr. Desai, associate professor of medicine and investigator at the Center for Outcomes Research and Evaluation, Yale University, New Haven, Conn.

“While these data are not randomized and have a relatively small sample size, we had recently seen the results of the RECOVERY trial, a UK-based randomized trial demonstrating the benefit of steroids in COVID-19,” he said.

“Taken together, these studies seem to suggest that there is a benefit with steroid therapy.” Further validation of these results is warranted, he added.
“While not a randomized clinical trial, and thus susceptible to unmeasured bias, the study adds to mounting evidence that supports targeting the excessive inflammation found in some patients with COVID-19,” Jared Radbel, MD, a pulmonologist, critical care specialist, and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School, New Brunswick, N.J., said in an interview.

Dr. Radbel added that he is part of a multicenter group that has submitted a manuscript examining outcomes of critically ill patients with COVID-19 treated with tocilizumab.

Dr. Ramiro, Dr. Desai, and Dr. Radbel have disclosed no relevant financial relationships.

A version of this article originally appeared on

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