Guideline recommendations on steroid use in COVID are contradictory.  For example, the Surviving Sepsis Campaign recommends steroid for intubated patients with COVID and ARDS,^​1​ whereas the IDSA guidelines recommend that steroid should be restricted to randomized controlled trials.  Reviewing these documents shows that they often lean on data from influenza and MERS, which may not be applicable to SARS-CoV-2.  This chapters starts with some theoretical background information before reviewing more pertinent data from SARS-CoV-1 and SARS-CoV-2.

theory

It appears that COVID-19 infection passes through multiple phases.  An initial phase involving viral replication is often marked by relatively mild symptoms.  Subsequently, adaptive immunity is stimulated, leading to an increase in illness severity.

This model would suggest that the effect of steroid should vary depending on timing:

• Stage I:  Administration of steroid during the early infection could increase viral replication and perhaps delay development of adaptive immunity.  This might be expected to be detrimental.
• Stage II:  Low-dose steroid administration during the pulmonary phase might be expected to be beneficial (by blunting the severity of inflammation and thereby preventing a severe hyper-inflammation phase).
• Stage III:  For those patients who develop a marked hyper-inflammation phase, low-dose steroid might be inadequate to treat this.  Higher doses of steroid or targeted immunosuppressives (e.g. tocilizumab) could be necessary to treat established hyper-inflammation.  However, higher doses of steroids have greater side-effects – so delaying steroid administration until Stage III could result in missing the window of optimal intervention. 

Even before delving into the data, we begin to see how complex it will be to unpack this evidence.  The question isn’t whether steroids are good or bad in COVID – that would be a gross over-simplification.  The question is whether timed and titrated steroid could be beneficial. 

evidence: steroid in SARS-CoV-1 (a.k.a. “SARS”)

Lee et al. 2004:  Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients.

This is a prospective, randomized, double-blinded, placebo-controlled trial of early steroid (within 7 days of illness initiation).^​2​  The primary endpoint was blood levels of SARS RNA. 

Exclusion criteria included:

• Presentation more than five days after symptom onset
• Presence of any comorbidity
• Evidence of respiratory failure on admission (defined as saturation <90% on room air)

The steroid regimen used was 100 mg hydrocortisone IV q8hr for a total of 12 days.  For patients in either group, pulse-dose methylprednisolone (500 mg IV daily for three days) was used for patients with persistent fever plus radiographic progression of lung opacities.  (Using such high doses of steroid for mildly ill patients is pretty nutty.) 

Seventeen patients were recruited, who were young and healthy.  Over half received pulse doses of methylprednisolone (including six of seven patients in the placebo group). 

The primary endpoint was viral titers, which were higher in patients treated with early steroid:

However, no differences were observed between patients who received salvage pulse-dose methylprednisolone (n = 10) versus those who didn’t (n = 6)(p > 0.05). 

Very little detail is provided regarding clinical outcomes in these patients (most patients recovered nicely).  However, from Table 1 we can see that salvage pulse-dose methylprednisolone was used in 4/9 patients given early hydrocortisone compared to 6/7 patients provided with placebo.  This may suggest that early steroid administration caused some clinical improvement (avoiding the indication for salvage pulse-dose methylprednisolone). 

This is a tiny study including patients who are very different from our current patients (note the exclusion criteria – none of the patients I’m seeing would meet these criteria!).  However, the following conclusions might be drawn:

• Early steroid administration did increase viral levels.  However, patients treated with early steroid were also less likely to deteriorate clinically.
• Delayed administration of pulse-dose methylprednisolone had no discernable effect on viremia. 
• This study has been widely cited as evidence that steroid is dangerous.  However, a close reading of the study suggests that patients treated with steroid may have done better clinically (despite having higher viral titers).  This emphasizes an extremely important point – viral titers are an appropriate endpoint for trials of antiviral chemotherapy, but not trials of immunosuppressive treatment (for which clinical improvement is a more appropriate endpoint). 

Chen RC et al.  2006  Treatment of severe acute respiratory syndrome (SARS) with glucosteroids: The Guanghou experience

This is a retrospective study of 401 patients with SARS.^​3​  All patients with less severe SARS survived, so the analysis focuses on 152 patients with critical disease. 

Among patients with more severe, steroid use didn’t correlate with outcome.  However, multivariable regression analysis to correct for illness severity did find that steroid use correlated with reduced mortality and shorter length of stay (table below).  Additionally, steroid use wasn’t associated with a risk of superinfection.

As a correlative study, this cannot prove anything.  However, it’s notable that steroid correlated with improved endpoints, given that steroid was generally given to sicker patients (e.g. 59% of non-critical patients received steroid compared to 80% of critical patients). 

Long Y et al.  Clinical recommendations from an observational study on MERS:  glucocorticoids were beneficial in treating SARS patients

This is a retrospective study evaluating the largest SARS database in China (including 5,327 patients).^​4​  Patients initially treated with an average of ~80 mg methylprednisolone daily seemed to have the best survival: 

Multivariable regression found that steroid use remained an independent predictor of survival.  Treatment with average doses of steroid between 0-80 mg/day methylprednisolone equivalent carried a hazard ratio for mortality of 0.47 (with a 95% confidence interval of 0.24-0.56). 

There appeared to be interactions between disease severity and steroid dose.  Severe disease was defined here as any patient with tachypnea >30 breaths/minute, PaO2 < 70 mm, saturation below 93%.   

• Among patients with non-severe disease, steroid use was generally nonbeneficial.  Use of >160 mg/day methylprednisolone equivalent correlated with increased risk of death.
• Among patients with more severe disease, steroid correlated with improved survival (even at relatively high doses and extended courses):  

evidence: steroid in SARS-CoV-2 (COVID-19)

Fang X et al.  Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19

This is a retrospective study describing 78 patients admitted with COVID (55 with mild disease and 23 with more severe disease).^​5​  The median dose of steroid was low (~40 mg methylprednisolone daily).  Steroid use had no observable impact on time to COVID-19 clearance from pharyngeal PCR:

This study shows the opposite results compared to the study by Lee et al. above, which showed that steroid delayed viral clearance.  The difference may result from steroid timing.  Lee et al. found that early steroid administration (during the viral replicative phase) prolonged viral shedding.  Alternatively, this study by Fang et al. involved patients who had been ill for about a week and were moving into an adaptive immune phase.  At this later timepoint in the disease course, there is a more robust immune response against the virus.  Consequently, steroid doesn’t appear to affect viral titers. 

Wang Y et al.  Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia:  single-center experience from Wuhan, China

This is a retrospective study describing 46 admitted patients with COVID pneumonia.  26 patients received methylprednisolone at a dose of 1-2 mg/kg/day for 5-7 days, whereas the remaining patients did not.  Patients treated with steroid had a bit more tachypnea, but overall the groups were surprisingly similar:

Patients treated with steroid defervesced faster than other patients.  This shouldn’t be too surprising, given that steroid has antipyretic properties.  More importantly, steroid therapy correlated with more rapid improvement in oxygenation and radiographic abnormalities (figure below).  Patients treated with methylprednisolone were weaned off oxygen earlier (median of 8 days vs. 14 days, p<0.001):

This isn’t a blinded RCT, so results cannot demonstrate causality.  For example, it’s possible that steroid use correlated with the application of additional therapies in a more aggressive treatment package. 

Wu C et al.  Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. 

This is a retrospective study of 201 patients with COVID pneumonia.^​6​  42% of patients developed ARDS, of whom about half died.  Steroid was preferentially given to sicker patients, so within the entire patient cohort steroid use correlated with worse outcomes.  However, among the subgroup of patients with ARDS, steroid use correlated with reduced mortality:

This is a single-center, correlational study which cannot show causality.  Nonetheless, it’s notable that steroid correlated with better outcomes (despite generally being used on the sickest patients). 

steroid in COVID: where should we go from here?

To sum up the above studies: 

• There are no prospective RCTs available, so it’s premature to reach any definitive conclusions.
• Steroid may increase viral titers if given early within the disease course (e.g. <5 days).  However, even in this scenario, steroid administration appears to correlate with clinical benefit.  When administered later on in the disease course, steroid didn’t appear to affect viral titers. 
• Steroid is usually administered to the sickest patients.  Nonetheless, steroid administration generally correlated with improved outcomes.  This suggests that steroid may be causing benefit (or, at the least, it seems unlikely that steroid is causing harm).

What should we do currently?  Opinions are divided, for example:

• The Surviving Sepsis Campaign recommends steroid administration for intubated patients with ARDS.^​1​
• The Infectious Disease Society of America recommends steroid only within the context of an RCT (not a workable solution for most clinicians who lack access to such a study). 

Currently, it may be reasonable to judiciously provide low-dose steroid (e.g. 1 mg/kg methylprednisolone or ~10 mg dexamethasone daily) to some patients, judged on a patient-by-patient basis.  The following factors may be relevant:

• Timing since disease onset (steroid benefit may be greatest ~5-10 days after onset, during the beginning of the adaptive immunity phase).
• Contraindications to steroid (if present).
• Level of inflammatory markers, if known.
• Severity of illness, for example:
  • Outpatients probably are too healthy to benefit from steroid.
  • Inpatients who are hypoxemic but not yet intubated could represent the opportunity of maximal intervenability (with a view towards avoiding further deterioration).
  • Inpatients who are intubated with ARDS are the patients who may have the strongest indication for steroid.  However, delaying therapy until the patient is intubated could result in missed therapeutic opportunities.

Going further: Are we missing the optimal treatment window? 

The combination of happy hypoxemia plus reticence to go to the hospital is causing many patients to present at a very late stage in their disease course.  Some patients are presenting with established multi-organ failure (often including profound hypoxemia and acute kidney injury). 

Based on his experiences at Bellevue, Richard Levitan is promoting home monitoring of pulse oximetry, to detect decompensation earlier and facilitate intervention at an earlier timepoint.  This could allow patients to present to the hospital with less developed organ failure, which would be more amenable to conservative therapies.  Earlier presentation could conceivably represent an optimal time window when low-dose steroid might be effective in avoiding the need for intubation and for more aggressive immunosuppressive therapies (e.g. tocilizumab):   

related:

• COVID-19 IBCC chapter: immunomodulation section
• DEXA-ARDS trial (PulmCrit)

Image credit: Photo by Will Truettner on Unsplash

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Josh Farkas

Josh is the creator of PulmCrit.org. He is an associate professor of Pulmonary and Critical Care Medicine at the University of Vermont.

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