COVID-19 / MEDICINE / HEALTH
Are Corticosteroids Contraindicated in COVID-19 Patients?
In short, it depends, really.
Even before the results of the U.K. RECOVERY trial on dexamethasone were published, researchers and doctors, including a few in the United States, had already been advocating for steroid use in COVID-19 treatment. Two months into my own battle with COVID-19, I was also prescribed a short, high-dose course of prednisone, which temporarily ameliorated my breathing distress enough to allow me to pitch the following story idea:
Unfortunately, after completing my short course of corticosteroids, my symptoms returned with a vengeance, resulting in ten more months of worsening hypoxemia (low blood oxygen levels), shortness of breath, bradycardia and tachycardia, excruciating chest pain, ataxia (loss of balance and coordination), nerve pain, depression, delirium, hydronephrosis (kidney swelling), and gastrointestinal bleeding.
In my case, oral corticosteroids ended up being a misstep, allowing for viral dissemination to other organs. As we’ll see, appropriate clinical indications for corticosteroid use depend on context.
A Bit of Background Information
Corticosteroids come in two types — glucocorticoids and mineralocorticoids — and differ from the anabolic steroids sometimes abused by body builders and athletes to gain a competitive advantage. Prednisone is a synthetic glucocorticoid and mimics the action of cortisol, a hormone released by the adrenal glands in response to inflammation and stress.
Four times more potent than cortisol, prednisone reduces inflammation by suppressing the immune system, and five milligrams daily is considered the physiologic dose in adults. Dexamethasone, another synthetic corticosteroid, is 25 times more potent than cortisol.
The corticosteroids are widely used in medicine for many conditions, including asthma, lupus, rheumatoid arthritis, psoriasis, inflammatory bowel disease, cancer, and Addison’s disease, and may be taken orally, topically, by injection, or by inhaler.
A Pharmocokinetics Primer
The elimination half-life of prednisone is around 3 to 4 hours. The half-life is the time required for the body to reduce plasma levels by half. It usually takes around 5.5 half-lives for a drug to be completely eliminated from your system, so prednisone would be out of your system in 16.5 to 22 hours.
Side Effects Associated with Steroid Use
Steroids are not without their fair share of side effects. Oral corticosteroids, in particular, can cause glaucoma, fluid retention, weight gain, high blood pressure, mood swings, memory deficits, confusion or delirium.
Steroids may also trigger or worsen diabetes, increase the risk of bacterial, viral, and fungal infections, and suppress production of adrenal gland hormones, leading to symptoms such as severe fatigue, nausea, vertigo, loss of appetite, and muscle weakness. Additionally, steroid-induced psychosis is a well-documented, dose-dependent phenomenon.
Even short-term use can cause side effects, such as changes in sleep, mood, and appetite. A 2017 study involving 327,452 adults found that short term use of oral corticosteroids (defined as less than 30 days) was associated with an increased risk of sepsis, blood clots, and bone fracture. The authors note,
Even short durations of use, regardless of dose, were associated with increased risks of adverse events and that few patients were using very low doses. Only 6.3% of the prescriptions were for a prednisone equivalent dose of less than 17.5 mg/day, and 1.0% of prescriptions were for less than 7.5 mg/day…A major reason for the higher than expected doses was the widespread use of “fixed dose” methylprednisolone dosepaks that are tapered over a short period. These dosepaks offer ease of use but do not permit the individualization of drug dosing to minimize exposure.
According to a large study from Taiwan published in the Annals of Internal Medicine in September 2020, corticosteroid bursts of 2 weeks or less were still linked to severe adverse events, even among relatively healthy users. The case series included 2.6 million individuals between the ages of 20 and 64 who had received a steroid burst between January 2013 and December 2015.
The average age of the patients was 38, 55.3% were women, and 85% had no co-morbid conditions. The most common indications for the steroid prescriptions were skin disorders and respiratory tract infections.
For those taking oral steroids over a median of three days, rates of GI bleeding, sepsis, and heart failure significantly increased in the 5 to 30 days following steroid therapy.
In response to this data, Beth Wallace, MD, and Akbar Waljee, MD, both of the VA Ann Arbor Healthcare System and Michigan Medicine, shared their thoughts in an accompanying editorial entitled “Burst Case Scenario: Why Shorter May Not Be Any Better When It Comes to Corticosteroids.”
The authors told MedPage Today, “We are now learning that bursts as short as 3 days may increase risk for serious AEs [adverse events], even in young and healthy people. As providers, we must reflect on how and why we prescribe corticosteroids to develop strategies that prevent avoidable harms.”
It is useful to note the many parallels between use of corticosteroid bursts and that of other short-term medications, such as antibiotics and opiates. All of these treatments have well-defined indications but can cause net harm when used — as they frequently are — when evidence of benefit is low.
Apart from duration, dosage is another consideration to take into account. When taken in very high doses, prednisone can kill off lymphocytes, a type of white blood cell. “Prednisone is very dose-dependent, and 5 mg is very different than 40 mg,” says Vinicius Domingues, MD, a rheumatologist in Daytona Beach, Florida. “You’re going to have far more impairment if you’re taking higher doses.”
To mitigate some of the side effects associated with steroids, doctors may prescribe low-dose courses and use inhaled corticosteroids instead of oral forms when appropriate. Because inhaled corticosteroids deliver medicine directly to the lungs, much smaller doses are needed to control respiratory symptoms compared to what would be required if the same medication was taken orally.
This approach prevents systemic exposure and reduces the risk of side effects. Some inhalers do not contain steroids but beta-agonists, such as albuterol, fometerol, and salmeterol. Beta-agonists are bronchodilators, medications that relax muscles around the airways to allow for easier breathing.
Taking calcium and vitamin D supplements may reduce the risk of osteoporosis associated with long-term corticosteroid therapy. When discontinuing therapy, gradually tapering the dose can help your adrenal glands recover their function and prevent any potential dizziness, fatigue, and body aches associated with steroid withdrawal.
Corticosteroids and COVID-19
Are synthetic steroid medications appropriate to use in the setting of COVID-19 infection? Since these steroids significantly dampen immune responses, the World Health Organization has expressed concern that these medications may prevent an individual from successfully clearing the virus.
However, critics argue that the most severe complications of COVID-19 arise due to overactive immune responses and the production of inflammatory molecules. For this reason, some health experts believe the use of steroids is justified in order to suppress the inflammatory response and prevent potentially fatal damage.
Paul Marik, MD, Chief of Pulmonary and Critical Care Medicine at Eastern Virginia Medical School, opines that “the historically high levels of morbidity and mortality from COVID-19 is due to a single factor: the widespread and inappropriate reluctance amongst intensivists to employ anti-inflammatory and anticoagulant treatments, including corticosteroid therapy early in the course of a patient’s hospitalization.” Marik elaborates,
The systematic failure of critical care systems to adopt corticosteroid therapy resulted from the published recommendations against corticosteroids use by the World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC), and the American Thoracic Society (ATS) amongst others….Their erroneous recommendation to avoid corticosteroids in the treatment of COVID19 has led to the development of myriad organ failures which have overwhelmed critical care systems across the world.
Marik stresses that it is not the virus that is killing the patient but the patient’s overactive immune system. “The flames of the ‘cytokine fire’ are out of control and need to be extinguished. Providing supportive care (with ventilators that themselves stoke the fire) and waiting for the cytokine fire to burn itself out simply does not work,” he says.
Recommendations from the World Health Organization
The original WHO statement recommending against the routine use of corticosteroids rested on incomplete evidence. One of the referenced studies reported delayed viral clearance among MERS (Middle East respiratory syndrome) patients who received corticosteroid therapy. However, as Jesús Villar, MD, PhD and colleagues point out in a commentary published in Critical Care Explorations,
What “kills” COVID-19 patients is dysregulated systemic inflammation. There is no evidence linking delayed viral clearance to worsened outcome in critically ill COVID-19 patients, and it is unlikely that it would have a greater negative impact than the host’s own “cytokine storm.”
The WHO report also cited a systematic review on effective treatments for SARS (severe acute respiratory syndrome). A commentary coauthored by a member of the WHO panel on clinical management for 2019-nCoV referenced the same review, erroneously concluding that “only four studies provided conclusive data, all indicating harm.” In a response to the commentary, Shang and colleagues clarified,
These four studies were not definitive and only showed evidence of possible harm, whereas the results of 25 other studies were inconclusive, leading the original authors to state that the totality of data are inconclusive, and because of methodological limitations, it was not possible to make any recommendation. Inconclusive clinical evidence should not be a reason for abandoning corticosteroid use in 2019-nCoV pneumonia.
Moreover, the original review also included the results of three clinical trials that examined the effect of corticosteroids on ARDS outcomes:
In two trials, high-dose methylprednisolone given for approximately 2 d was not effective for early ARDS. One small RCT that used a regimen of lower dose methylprednisolone (2 mg/kg per day), tapered after 2 wk, showed possible evidence of ARDS improvement.
The latter approach is the one for which Marik advocates.
Early Clinical Trial Data
Several studies on SARS and COVID-19 support the use of corticosteroids at low-to-moderate dose in patients with coronavirus infections:
- In a study of 5,327 patients with SARS, glucocorticoid therapy was found to decrease the risk of death by 47%-72% in severe cases.
- A retrospective study of 401 patients with SARS similarly found that proper use of corticosteroids reduced mortality and shortened the length of hospitalization stay for critically ill patients. Unlike trends observed with intensive ventilation, the use of corticosteroids was not associated with a greater risk of secondary lower respiratory infections or other complications.
- A 2005 review on SARS concluded that “the initial use of pulse methylprednisolone therapy appears to be more efficacious and equally safe when compared with regimens with lower dosage and should therefore be considered as the preferred steroid regimen in the treatment of SARS. A further preliminary, uncontrolled study of patients with SARS, reported that the use of interferon alfacon-1 plus steroids was associated with reduced disease-associated impaired oxygen saturation and more rapid resolution of radiographic lung abnormalities.”
- A study out of Wuhan, China reported that early, low-dose, short-term administration of intravenous methylprednisolone in patients with severe COVID-19 pneumonia was associated with earlier resolution of clinical symptoms, shorter duration of fever, and significantly faster improvement in oxygen saturation levels.
- A propensity score matching analysis evaluated data from 70 French patients with severe COVID-19 pneumonia (requiring at least 3 liters of oxygen) and found that corticosteroid therapy significantly diminished the risk of intubation.
- Data from the Henry Ford COVID-19 Management Task Force in Detroit, Michigan concluded that early, short courses of methylprednisone in patients with moderate to severe COVID-19 reduced clinical care escalation and improved clinical outcomes.
Results of the RECOVERY Trial
In June 2020, preliminary results from the Randomized Evaluation of COVID-19 Therapy (RECOVERY) Trial, which included 6,000 patients in the United Kingdom, were released.
Researchers found that dexamethasone reduced deaths by one-third among patients on mechanical ventilators, and by one-fifth among patients receiving only supplemental oxygen. There was no benefit among those who did not require respiratory support, and the study did not include patients outside the hospital setting.
University of Oxford Professor Peter Hornby, one of the chief investigators for the trial said: “The survival benefit is clear and large in those patients who are sick enough to require oxygen treatment, so dexamethasone should now become standard of care in these patients. Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide.”
Following these positive results, the National Institutes of Health revised its guidelines to recommend dexamethasone 6 mg/day for up to 10 days (the same dose administered in the RECOVERY trial) in COVID-19 patients requiring mechanical ventilation (dexamethasone is not recommended for people not requiring supplemental oxygen).
Marik opined, “Notwithstanding the very important and impressive results of the Recovery-Dexamethasone study, methylprednisolone is the corticosteroid of choice for the pulmonary phase of COVID-19. This is based on pharmacokinetic data (better lung penetration), genomic data specific for SARS-CoV-2, and a long track record of successful use in inflammatory lung diseases.”
Additional Clinical Trials on Corticosteroids in COVID-19 Treatment
The Covid-19 Dexamethasone (CoDEX) multicenter, open-label trial randomized almost 300 Brazilian patients with COVID-19 and moderate to severe acute respiratory distress syndrome (ARDS) to receive either standard care alone or daily intravenous dexamethasone in addition to standard care.
Dexamethasone use resulted in a statistically significant increase in the number of ventilator-free days and reduced risk of organ failure. However, unlike in the RECOVERY trial, CoDEX showed no impact on all-cause mortality although this difference could be chalked up to early termination of the trial.
A few additional limitations were present: the providers were not blinded as to whether the patients did or did not receive dexamethasone, and 35 percent of patients in the control group received steroids as part of the standard of care, which makes the marked difference observed between the treatment arms even more surprising.
A randomized, double-blinded study involving 149 French patients with confirmed or suspected COVID-19 found that hydrocortisone did not prevent death or need for respiratory support compared to placebo.
A meta-analysis sponsored by the WHO and published in JAMA found that dexamethasone, hydrocortisone, and methylprednisolone reduced 28-day mortality by a relative 34% compared with controls.
Corticosteroids for COVID-19 Patients in Clinical Practice
Since a trend towards harm was seen in the sub-group of patients with the RECOVERY trial who were not on oxygen, the COVID-19 treatment guidelines set forth by Massachusetts General Hospital specifically state: “Do not start dexamethasone unless the patient progresses to oxygen requirement (severe disease) or has an alternate indication for corticosteroids.”
Because systemic corticosteroids increase the risk of reactivation of latent infections (e.g., hepatitis B virus, herpesviruses, strongyloidiasis, tuberculosis), Mass General also advocates for infectious disease screening in foreign-born patients prior to steroid administration.
“There is good data that prednisone makes you more susceptible to a variety of infections, maybe even more so than biologics and methotrexate,” according to Joseph E. Huffstutter, MD, a rheumatologist in Hixson, Tennessee.
In early May, I was prescribed 40mg of oral prednisone daily for a total of four days. Although my lungs were inflamed, the fact that I did not require oxygen support likely made steroid treatment inappropriate in my case. As previously alluded to, the dose of 40mg was also quite high and may have contributed to the harrowing experiences that followed.
Summary
Corticosteroids generally appear to reduce the risk of death in cases of severe COVID-19 (those requiring respiratory support in the form of supplemental oxygen or mechanical intubation). Moreover, steroids should be used with caution in patients with milder disease or those who might harbor latent tropical infectious diseases, as the risks may outweigh potential benefits in this population. When steroids are required, lower doses for shorter durations are typically associated with fewer side effects.
Marik concludes, “It is important to acknowledge that there is no known therapeutic intervention that has unequivocally been proven to improve the outcome of COVID-19. This, however, does not mean we should adopt a nihilist approach and limit treatment to ‘supportive care.’ Furthermore, it is likely that there will not be a single ‘magic bullet’ to cure COVID-19. Rather, we should be using multiple drugs/interventions that have synergistic and overlapping biological effects that are safe, cheap and readily available.”
