By Kathryn Radigan, MD, MSCI

Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago

Dr. Radigan reports no financial relationships relevant to this field of study.

SYNOPSIS: A study of adults admitted with COVID-19 pneumonia revealed risk factors associated with developing acute respiratory distress syndrome (ARDS) and progression from ARDS to death included older age, neutrophilia, organ dysfunction, and coagulation derangement.

SOURCE: Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020;180:1-11.

Researchers continue scrutinizing risk factors for COVID-19. Wu et al performed a retrospective cohort study among 201 adults admitted to Jinyintan Hospital between Dec. 25, 2019, and Jan. 26, 2020, to describe the clinical characteristics and outcomes of COVID-19 patients with pneumonia. Of the 201 patients, 84 developed acute respiratory distress syndrome (ARDS), and approximately half of those died. When compared to non-ARDS patients, ARDS patients complained more often of dyspnea (59.5% vs. 25.6% patients; difference, 33.9%; 95% confidence interval [CI], 19.7%-48.1%). ARDS patients also had more comorbidities, including hypertension and diabetes.

Through a bivariate Cox regression analysis, researchers showed risk factors associated with ARDS and progression from ARDS to death, which included: older age (hazard ratio [HR], 3.26; 95% CI, 2.08-5.11; HR, 6.17; 95% CI, 3.26-11.67, respectively), neutrophilia (HR, 1.14; 95% CI, 1.09-1.19; HR, 1.08; 95% CI, 1.01-1.17, respectively), and organ and coagulation dysfunction based on higher lactate dehydrogenase (HR, 1.61; 95% CI, 1.44-1.79; HR, 1.30; 95% CI, 1.11-1.52, respectively) and D-dimer (HR, 1.03; 95% CI, 1.01-1.04; HR, 1.02; 95% CI, 1.01-1.04, respectively). Although high fever (≥ 39°C) was associated with higher likelihood of ARDS (HR, 1.77; 95% CI, 1.11-2.84), it also was associated with a lower likelihood of death (HR, 0.41; 95% CI, 0.21-0.82). ARDS patients treated with methylprednisolone were at a lower risk of death (HR, 0.38; 95% CI, 0.20-0.72).

Researchers concluded older age, hypertension, and diabetes are associated with worse outcomes. Although high fever was associated with ARDS development, it also was associated with better outcomes among patients with ARDS. In addition, treatment with methylprednisolone may be beneficial for patients who develop ARDS.

COMMENTARY

Learning more about how to treat COVID-19 optimally is not only profoundly important but has reached a state of emergency. COVID-19-related mortality in the United States is progressing rapidly to more than 147,000 patients, and proven treatments are bleak.1 Shortly after there was evidence that cytokine storm syndrome was associated with the severity of ARDS in COVID-19,2 corticosteroids became a treatment of great interest, mainly because of their profound anti-inflammatory and immunoregulatory properties. This study is one of the first that references the use of steroids in COVID-19 and boasts giving methylprednisolone to patients with ARDS may lower death risk.

Of course, these findings and statements must be interpreted cautiously based on this study. The authors openly discussed their concerns that the small sample size and observational nature of the study subject it to potential bias and residual confounding. Furthermore, there also is concern that patients who died in this study population were less likely to be treated with antiviral therapy, and the authors did not separate which patients received steroids and/or antivirals. There also was no information on the timing, dosage, or duration of steroids, and whether there were any corticosteroid-related complications observed in the patients who received them.

Although this study is fraught with concerns, the results of the RECOVERY trial are promising.3 This study, conducted in the United Kingdom, was a randomized controlled trial that included 2,104 COVID-19 patients given dexamethasone 6 mg once daily by mouth or intravenously for 10 days. When compared to 4,321 patients who received standard care, dexamethasone reduced the death rate in mechanically ventilated patients by 35% and in oxygen-dependent patients by 20% without a benefit in patients who were not receiving respiratory support. In contrast to the RECOVERY trial, the only other studies available are extremely limited. Another retrospective cohort study by Wang et al, limited to 46 patients, showed that low-dose and short-term methylprednisolone was associated with a shorter time to defervescence along with a more rapid improvement in oxygenation and radiographic abnormalities.4 Patients on methylprednisolone were weaned off oxygen at a median of eight days vs. 14 days (P < 0.001) in the standard care group. Zhou et al validated the potential benefits of low-dose corticosteroids in a subset of critically ill patients with COVID-19 pneumonia. Interpretation of these data is extremely limited since there were only 15 patients and no control group.5

Expert opinion may be used to guide clinicians further but have not been updated since news of the RECOVERY trial. Currently, both the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recommend glucocorticoids should not be administered routinely to patients with COVID-19, except in the setting of an evidence-based indication, such as asthma or chronic obstructive pulmonary disease exacerbation, refractory septic shock, and adrenal insufficiency.6,7

In addition to the recommendations by the CDC and WHO, the Society of Critical Care Medicine (SCCM) provides a conditional, weak recommendation in favor of glucocorticoids for the sickest COVID-19 patients who are intubated with severe ARDS (PaO2/FiO2 ratio < 100).8 If clinicians choose to administer glucocorticoids, the SCCM suggests they should begin within the first 14 days, doses should be low, and courses should be short. The Surviving Sepsis Campaign aligns with the SCCM, while the infectious disease guidelines recommend steroids should be restricted to randomized controlled trials.9

The initial rationale for not administering glucocorticoids routinely in the COVID-19 ARDS population is that there is evidence of potential harm for patients with other viral pneumonias (i.e., Middle East respiratory syndrome, influenza, and severe acute respiratory syndrome). The data supporting any benefit did not include a sufficient proportion of patients with viral pneumonia to inform safety.10-12 In contrast, Fang et al demonstrated low-dose corticosteroid therapy did not delay viral clearance in COVID-19 patients.13 Keeping the administered dose low also may alleviate concerns about secondary bacterial or fungal infections. It will be interesting to observe how these recommendations will be updated after these groups reconvene, and the RECOVERY trial is discussed further.3

REFERENCES

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