Patient selection is key to better COVID-19 treatments: Optimal analysis is important

Researchers from Osaka University have found that repeated high-dose treatment, known as pulse therapy, with the steroid methylprednisolone reduces in-hospital deaths in COVID-19 patients who receive invasive mechanical ventilation, but not in patients who don’t receive invasive mechanical ventilation. These findings were only possible using appropriate statistical methods to remove bias from the data, which originally seemed to show that the opposite was true. These results can improve patient treatment and reduce COVID-19-related deaths worldwide.

Fig. 1
※Without bias control: Univariate in-hospital mortality in patients prescribed or not prescribed methylprednisolone pulse therapy, stratified by the presence or absence of invasive mechanical ventilation (iMV)

Researchers from Osaka University find that a treatment for COVID-19, consisting of repeated administration of high-dose steroids, improves patient outcomes under specific circumstances

Osaka, Japan – Although steroid treatment for COVID-19 is reportedly beneficial in some cases, details—such as the upper dosing limits and safety of this method—have not yet been clarified. Now, Japanese researchers have used a large dataset and complicated statistical methods to iron out the specifics of this treatment.

In a study published last month in Critical Care, researchers from Osaka University revealed that when repeated high doses (known as pulse therapy) of steroid methylprednisolone were given to patients receiving invasive mechanical ventilation, the patients were more likely to die; however, the opposite was true when the researchers corrected the data for underlying bias.

Steroid pulse therapy can reduce inflammation in many diseases and improve patient outcomes but can also cause fatal complications. Previous studies have reported different and sometimes conflicting results with pulse steroid therapy, which may be because many patients receive the treatment as a kind of “Hail Mary” —the situation is so grave that doctors and family members are willing to try anything to save the patient. This can distort the associations between treatment and outcome, something that the researchers from Osaka University wanted to tackle head-on.

“We were lucky that we had access to data from 67,348 hospitalized COVID-19 patients across 438 hospitals in Japan,” says Professor Yasuharu Tokuda, corresponding author of the study. “This large dataset allowed us to use a relatively new statistical model, known as marginal structural model analysis, to look at the outcomes of pulse therapy in different kinds of COVID-19 patients in an unbiased manner.”

When the data were analyzed without the bias control, the researchers found that methylprednisolone pulse therapy was clearly associated with increased in-hospital mortality in patients receiving invasive mechanical ventilation, from 24.7% to 28.6%. In patients who didn’t receive invasive mechanical ventilation, pulse therapy also increased the in-hospital mortality rates, from 2.3% to 19.5% (Fig. 1). However, when the research team taken into account “Hail Mary bias” (there is also named time-dependent bias) at the data using the cutting edge analysis, steroid pulse therapy was associated with a lower risk of mortality among COVID-19 patients receiving invasive mechanical ventilation but an increased risk among patients not receiving ventilation (Fig. 2).

“Optimal assessment methods are important when analyzing the results of COVID-19 studies. Here, we found that appropriate patient selection is key when considering methylprednisolone pulse therapy for hospitalized patients,” explains primary co-author, Dr. Ryoto Sakaniwa. “We also found that higher doses of methylprednisolone and a relatively short interval between patient intubation and the start of pulse therapy were associated with better outcomes in patients receiving ventilation, which will further improve COVID-19 treatments.”

Measures must be taken to stop COVID-19 from taking more lives. This study adds valuable new information on the treatment of COVID-19, which can be potentially applied globally to reduce in-hospital mortality associated with COVID-19. Better knowledge of the optimal conditions for pulse methylprednisolone therapy will improve outcomes for all future COVID-19 patients.


The article, “Intravenous methylprednisolone pulse therapy and the risk of in-hospital mortality among acute COVID-19 patients: Nationwide clinical cohort study,” was published in Critical Care at DOI:

Fig. 2
※With bias control: Forest plots of hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the risk of in-hospital mortality among acute COVID-19 patients with or without invasive mechanical ventilation (iMV) after doses of 40, 80, 125–250, 500, and 1000 mg and more of intravenous methylprednisolone

About Osaka University

Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan's most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.


Published: 27 Mar 2023


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Global Strategy Unit

1-1 Yamadaoka, Suita,Osaka 565-0871, Japan

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The Japan Institute for Policy Research
Tokyo Foundation