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Early But Not Late Interferon Linked to
Lower COVID Mortality in Hubei
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Mark Mascolini
Compared with COVID-19 inpatients who did not receive interferon(IFN)-α2b, those who got IFN-α2b within 5 days of admission had lower in-hospital mortality in this retrospective study in Hubei, China [1]. In contrast, patients who received IFN-α2b later ran a higher risk of dying in the hospital than people who got no IFN-α2b.
Interferons see wide use in treating viral infections, now including COVID-19. Hypothetically, early IFN administration could slow viral proliferation in a person and thus the inflammation and consequent cytokine storm that threatens many people with poorly controlled COVID-19. But recent work suggests that ACE2, the COVID-19 virus receptor on target cells, may proliferate if stimulated by IFN-α2b [2].
To assess the impact of IFN-α2b in COVID-19 patients admitted to the hospital in China’s Hubei province, the initial epicenter of the pandemic, researchers at Sun Yat-sen University and colleagues at other centers conducted this retrospective two-center cohort study. The analysis took advantage of disparities in access to IFN-α2b in 2 Hubei hospitals during the early days of the pandemic to compare people who received IFN-α2b early (within 5 days of hospital admission, late (after 5 days), or not at all. All participants had PCR-confirmed SARS-CoV-2 infection and got admitted to 1 of 2 COVID-19-designated hospitals from January 15 through March 31, 2020.
All 446 patients included in this analysis were discharged from the hospital or died by May 22, 2020. Age ranged from 8 to 96 years (median 50), and 47% of participants were female. Median
time from symptom onset to admission stood at 6 days and median hospital stay at 19 days.
During this period China introduced and often modified treatment guidelines for COVID-19. Patients received recommended therapy on a first-come-first-served basis. If the preferred medication was not available, they received alternative agents. Thus some study participants received IFN-α2b within 5 days of hospital admission, some received it later, and some did not receive it. About two thirds of study participants received IFN-α2b within 2 days of admission, and 89% got it within 5 days.
The researchers counted 216 people who received early IFN-α2b, 204 who received no IFN-α2b, and 26 who received it late. Women made up a higher proportion of the no-IFN group (53.4%) than the early group (43.1%) or the late group (30.8%) (P = 0.024). Median age (50 years overall) did not differ much across the three groups.
Median hospital stay was significantly longer in the late-IFN group (28 days) than in the no-IFN group (19.5 days) or early-IFN group (18 days) (P = 0.001). Median time from admission to CT scan improvement was also longer in the late-IFN group (14 days) than in the other two groups (10 days in both) (P = 0.001). Time from symptom onset to hospital discharge was significantly longer in the late-IFN group (32.5 days) than in the no-IFN group (26 days) or the early-IFN group (25 days) (P = 0.025). Finally, the proportion of people who died in the hospital was significantly greater in the late-IFN group (15.4%) than in the no-IFN group (4.9%) or the early-IFN group (0.9%) (P < 0.001).
To identify independent predictors of mortality, logistic regression analysis and Cox proportional hazards models adjusted for gender, age, hypertension, diabetes, oxygen saturation at admission, symptom count at admission, and symptom onset to admission greater than 7 days. Compared with no IFN-α2b, early IFN-α2b sliced chances of in-hospital death 95% (adjusted odds ratio [aOR] 0.05, 95% confidence interval [CI] 0.01 to 0.37) or 90% (adjusted hazard ratio [aHR] 0.10, 95% CI 0.02 to 0.50). In contrast, compared with no IFN-α2b, late IFN-α2b boosted chances of in-hospital death about 7-fold or 2-fold, depending on the type of analysis (aOR 6.82, 95% CI 1.14 to 40.8; and aHR 2.30, 95% CI 0.64 to 8.27).
The authors point out that the clinical benefits seen with early IFN-α2b in this study involved patients with severe or critical COVID-19, not moderate disease. (No one with mild or moderate disease died.) They observe that acute inflammation often seen in critically ill patients could reflect repressed type I IFN expression, a resulting imbalanced IFN response, and ultimately the often deadly cytokine storm. Treating appropriate patients with IFN, they propose, could halt this progression.
Why didn’t the threat of ACE2 proliferation with IFN seem to affect clinical outcomes in the early-IFN group, especially since IFN went directly to airways via aerosol nebulizer? The researchers speculate that “critically ill patients often have a high viral load that could already saturate airway cells.” As a result, IFN-incited ACE2 expression might not pose as high a risk as it does in moderately ill patients.
References
1. Wang N, Zhan Y, Zhu L, et al. Retrospective multicenter cohort study shows early interferon therapy is associated with favorable clinical responses in COVID-19 patients. Cell Host Microb. 2020;July 22. https://doi.org/10.1016/j.chom.2020.07.005
2. Ziegler CGK, Allon SJ, Nyquist SK, et al. SARS-CoV-2 Receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell. 2020;189:1016-1035. https://www.sciencedirect.com/science/article/pii/S0092867420305006
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