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JCI - Corticosteroids, COVID pneumonia, and acute respiratory distress syndrome
Commentary Free access Address correspondence to: Michael A. Find articles by Matthay, M. Find articles by Wick, K. Published September 25, - More info. We performed a propensity score PS matching analysis to control confounding factors. RESULTS Of eligible patients, patients received corticosteroids, with a median time from hospitalization to starting corticosteroids of 1. As compared with usual care, treatment with corticosteroids was associated with increased rate of myocardial After PS matching, corticosteroid therapy was associated with day mortality adjusted HR 1.
Although corticosteroids dampen the dysregulated immune system and sometimes are prescribed as an adjunctive treatment for pneumonia, their effectiveness in the treatment of coronavirus disease COVID remains controversial. The authors assessed subjects retrospectively for cardiac and liver injury, shock, ventilation, mortality, and viral clearance. Here, we consider how to reconcile the negative effects of corticosteroids revealed by Liu and Zhang et al. We posit that treatment timing, dosage, and COVID severity determine immune response and viral outcome.
Patients with moderate-to-severe COVID pneumonia are likely to benefit from moderate-dose corticosteroid treatment when administered relatively late in the disease course. The effects of corticosteroids in the treatment of viral pneumonia and the acute respiratory distress syndrome ARDS have been the subject of controversy over decades, including several studies through the last 15 years.
The majority of studies report a detrimental effect of corticosteroids for the treatment of influenza viral pneumonia, including studies during the H1N1 influenza outbreak of — 12 and subsequent studies with H5N1 influenza pneumonia 3.
Most studies were retrospective, though the analyses were adjusted for baseline differences between the corticosteroid-treated and untreated patients 4. Others showed either no benefit or evidence of harm 6. Notably, viral RNA clearance was delayed in patients who received early corticosteroids 7. In a retrospective study of corticosteroids in critically ill patients with Middle East respiratory syndrome, unadjusted mortality was higher among patients who received corticosteroids, and RNA viral clearance was delayed 8.
Notably, patients who received corticosteroids were substantially different from those who did not by several criteria. The steroid-treated group included fewer smokers, fewer patients with diabetes, and fewer patients with chronic cardiac or renal disease, but the baseline acute physiology and chronic health evaluation APACHE II score severity of illness measure was higher 12 vs.
To account for these differences, a propensity analysis based on multiple variable regression was done that matched patients who received steroids versus patients who did not. This adjusted analysis reinforces the primary findings. However, it is still possible that the patients who received corticosteroids differed in some meaningful ways that cannot be fully captured by propensity matching.
Traditionally, this is termed confounding by indication; in other words, the steroid-treated patients could have been sicker than patients not treated with steroids. There was, however, a strong trend for greater mortality in patients who received dexamethasone and who were not requiring oxygen therapy. In a prespecified subgroup analysis, patients who received corticosteroids more than seven days after symptom onset had reduced day mortality rate ratio [RR] 0.
Some patients were excluded because their treating physician determined that corticosteroids were contraindicated, although the reasons for such a determination were not recorded. Also, there were no measurements of viral clearance in this pragmatic trial. Can the negative results of the Liu and Zhang et al. The timing of corticosteroid administration could be a major factor.
In the Liu and Zhang et al. Earlier corticosteroid administration might impair clearance of SARS—CoV-2, as suggested by delayed viral clearance in the steroid-treated patients. The dose of corticosteroid treatment is likely a second important factor. The median dose of corticosteroids in the study by Liu and Zhang et al.
The detrimental effects of steroids on mortality were driven by patients in the higher-dose group, whereas there was no statistically significant difference in the odds of death in the lower-dose group. Thus, the results from Liu and Zhang et al. These findings match reasonably well with the RECOVERY trial 10in which corticosteroid administration was associated with different mortality rates by severity of illness. Coronaviruses have developed various mechanisms to evade detection and targeting by the host response early after infection Corticosteroid treatment in the early stage of viral infection can suppress host antiviral activity 1314enhancing viral replication and cytopathic damage to the alveolar epithelial cells Uptake of virus by the ACE-2 receptor on alveolar epithelial type 2 cells with enhanced cell injury and death would impair surfactant secretion needed for alveolar inflation and stability and inhibit vectorial alveolar fluid clearance, the main pathway for resolution of pulmonary edema The degree of alveolar epithelial injury is a major determinant of the severity of ARDS In contrast, corticosteroid therapy given to COVID patients after the host has controlled viral replication could have a favorable effect by reducing proinflammatory cytokines, enhancing antiinflammatory cytokines and proresolving lipids, decreasing lung vascular permeability, improving epithelial barrier integrity, and promoting alveolar edema fluid clearance 18 — We posit that there are potential deleterious and beneficial effects of corticosteroids at different stages of infection, lung injury, and ARDS Figure 1.
Antigens are presented to T cells and a targeted cytotoxic response ensues. B In worsening illness, corticosteroid treatment can delay pathogen recognition and control. Dampened danger signaling leads to impaired IFN release, unchecked viral replication, and consequent alveolar and lung damage.
C In severe illness with COVID without corticosteroid treatment, viral propagation to the alveoli amplifies danger signals and worsens alveolar epithelial and endothelial damage. D In severe cases of COVID corticosteroid treatment may decrease proinflammatory cytokine burden and help resolution. Corticosteroids promote a proresolving macrophage phenotype that can clear cellular debris. Corticosteroids also reduce capillary permeability and increase alveolar edema fluid clearance, resulting in improved barrier function.
In conclusion, the findings of Liu and Zhang et al. Early treatment in milder disease seems harmful. Prospective studies are needed that include more data on SARS—CoV-2 viral shedding in the presence of both corticosteroid treatment and antiviral therapy with remdesivir 21 correlated with the specific level of oxygen support nasal oxygen versus high-flow nasal oxygen and ventilatory support noninvasive ventilation versus invasive ventilationand detailed information regarding comorbidities that may increase susceptibility to harm from corticosteroid treatment.
The complex immune response to SARS—CoV-2 infection is still being fully characterized, including comprehensive lymphocyte profiles in patients with severe disease Ongoing studies of the immune activation pattern in patients with COVID should provide additional insights into the timing and therapeutic effects of corticosteroids and help determine which COVID patients will benefit or be harmed.
Reference information: J Clin Invest. See the related article at Corticosteroid treatment in severe COVID patients with acute respiratory distress syndrome.
Go to JCI Insight. Email the journal. Published September 25, - Version history. Text PDF. Abstract Although corticosteroids dampen the dysregulated immune system and sometimes are prescribed as an adjunctive treatment for pneumonia, their effectiveness in the treatment of coronavirus disease COVID remains controversial.
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❾-50%}Is treatment with corticosteroids beneficial and safe for people with pneumonia? | Cochrane.
The effects of corticosteroids in the treatment of viral pneumonia and the acute respiratory distress syndrome ARDS have been the subject of controversy over decades, including several studies through the last 15 years. The majority of studies report a detrimental effect of corticosteroids for the treatment of influenza viral pneumonia, including studies during the H1N1 influenza outbreak of — 1 , 2 and subsequent studies with H5N1 influenza pneumonia 3.
Most studies were retrospective, though the analyses were adjusted for baseline differences between the corticosteroid-treated and untreated patients 4. Others showed either no benefit or evidence of harm 6. Notably, viral RNA clearance was delayed in patients who received early corticosteroids 7.
In a retrospective study of corticosteroids in critically ill patients with Middle East respiratory syndrome, unadjusted mortality was higher among patients who received corticosteroids, and RNA viral clearance was delayed 8. Notably, patients who received corticosteroids were substantially different from those who did not by several criteria. The steroid-treated group included fewer smokers, fewer patients with diabetes, and fewer patients with chronic cardiac or renal disease, but the baseline acute physiology and chronic health evaluation APACHE II score severity of illness measure was higher 12 vs.
To account for these differences, a propensity analysis based on multiple variable regression was done that matched patients who received steroids versus patients who did not. This adjusted analysis reinforces the primary findings. However, it is still possible that the patients who received corticosteroids differed in some meaningful ways that cannot be fully captured by propensity matching. Traditionally, this is termed confounding by indication; in other words, the steroid-treated patients could have been sicker than patients not treated with steroids.
There was, however, a strong trend for greater mortality in patients who received dexamethasone and who were not requiring oxygen therapy. In a prespecified subgroup analysis, patients who received corticosteroids more than seven days after symptom onset had reduced day mortality rate ratio [RR] 0.
Some patients were excluded because their treating physician determined that corticosteroids were contraindicated, although the reasons for such a determination were not recorded. Also, there were no measurements of viral clearance in this pragmatic trial.
Can the negative results of the Liu and Zhang et al. The timing of corticosteroid administration could be a major factor. In the Liu and Zhang et al. Earlier corticosteroid administration might impair clearance of SARS—CoV-2, as suggested by delayed viral clearance in the steroid-treated patients.
The dose of corticosteroid treatment is likely a second important factor. The median dose of corticosteroids in the study by Liu and Zhang et al. This research was published in the Journal of Hospital Medicine in Rather, severity of hypoxemia is used as a surrogate for inflammation in lieu of any measurement of an individual's inflammatory response.
This approach introduces substantial imprecision from patient to patient, with some patients receiving a greater than necessary corticosteroid dose or duration and others potentially receiving inadequate therapy. To address these knowledge gaps, an individualized, biomarker-guided corticosteroid dosing approach using C-reactive protein CRP was recently evaluated in hospitalized patients with COVID pneumonia and acute hypoxemic respiratory failure in a pilot randomized controlled trial at Mayo Clinic in Minnesota.
Study results were published in Critical Care in Odeyemi and fellow researchers hope to inform future clinical trials evaluating corticosteroid use in community-acquired pneumonia, regardless of the infectious pathogen, by identifying the following:.
Odeyemi concludes. Torres A, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: A randomized clinical trial. Keller MJ, et al. Journal of Hospital Medicine. Corticosteroids significantly reduced mortality in adults with severe pneumonia RR 0. Early clinical failure rates defined as death from any cause, radiographic progression, or clinical instability at day 5 to 8 were significantly reduced with corticosteroids in people with severe and non-severe pneumonia RR 0.
Corstocosteroids reduced time to clinical cure, length of hospital and intensive care unit stays, development of respiratory failure or shock not present at pneumonia onset, and rates of pneumonia complications.
Among children with bacterial pneumonia, corticosteroids reduced early clinical failure rates defined as for adults, RR 0. Hyperglycaemia was significantly more common in adults treated with corticosteroids RR 1. There were no significant differences between corticosteroid-treated people and controls for other adverse events or secondary infections RR 1.
Is treatment with corticosteroids beneficial and safe for people with pneumonia? Review question We looked at the effects of treating people with pneumonia using corticosteroids also called steroids or glucocorticoids on numbers of deaths, response to treatment, treatment complications, and side effects.
Background Acute pneumonia is a lung infection treated with antibiotics that target the bacteria that caused the infection. Search date The evidence is current to 3 March Study characteristics We included 17 studies evaluating systemic corticosteroid therapy given intravenously or by tablets for people with pneumonia participants; adults and children.
Study funding sources Eight trials did not report funding sources; seven were funded by academic sponsors; one was funded by a pharmaceutical company; and one reported receiving no funding. Quality of the evidence We downgraded the quality of the evidence due to issues with study design, unclear results, or results that were not similar across studies. Authors' conclusions:. To assess the efficacy and safety of corticosteroids in the treatment of pneumonia.
Search strategy:. Selection criteria:. Data collection and analysis:. Main results:.
Pneumonia remains one of the most significant public health problems, with even more prominence in the ongoing COVID pandemic. Its impact on the health care system includes increased outpatient and emergency room visits, hospitalization rates, organ support, intensive care need, post-hospitalization risk, and mortality. However, the impact of pneumonia and acute respiratory distress syndrome ARDSa related severe complication, on patient outcomes remains substantial.
Odeyemi, M. Odeyemi explains: "The use of adjunct anti-inflammatory therapy to potentially improve outcomes has been the most explored strategy. Inflammation is a hallmark pathologic feature of pneumonia regardless of the underlying infectious pathogen.
The increased concentrations of pro-inflammatory mediators have been associated with increased need for respiratory support and mortality in patients with community-acquired pneumonia, including COVID pneumonia.
This result has prompted multiple scientific investigations into the role of specific anti-inflammatory treatment strategies. Corticosteroids are by far the most often studied.
Odeyemi continues: "Despite multiple studies over the last three decades, the use of adjunctive corticosteroid treatment to curb excessive inflammation in pneumonia remains controversial and undefined, with four key knowledge gaps: optimal patient selection, optimal timing, optimal dosing regimen and duration. Corticosteroid use has been variable in both clinical practice and trials, with arbitrary dosing regimens irrespective of individual patient characteristics and degree of inflammation.
In those past trials, reduction in mortality was most pronounced in patients with severe pneumonia, as defined by multiple criteria, including the pneumonia severity index, CURBthe Infectious Diseases Society of America and American Thoracic Society criteria without consideration for markers of inflammation.
A study using C-reactive protein CRP alone as an enrichment strategy, published in JAMA indid observe decreased treatment failure rates in the corticosteroid arm. This research was published in the Journal of Hospital Medicine in Rather, severity of hypoxemia is used as a surrogate for inflammation in lieu of any measurement of an individual's inflammatory response. This approach introduces substantial imprecision from patient to patient, with some patients receiving a greater than necessary corticosteroid dose or duration and others potentially receiving inadequate therapy.
To address these knowledge gaps, an individualized, biomarker-guided corticosteroid dosing approach using C-reactive protein CRP was recently evaluated in hospitalized patients with COVID pneumonia and acute hypoxemic respiratory failure in a pilot randomized controlled trial at Mayo Clinic in Minnesota.
Study results were published in Critical Care in Odeyemi and fellow researchers hope to inform future clinical trials evaluating corticosteroid use in community-acquired pneumonia, regardless of the infectious pathogen, by identifying the following:.
Odeyemi concludes. Torres A, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: A randomized clinical trial. Keller MJ, et al. Journal of Hospital Medicine. Odeyemi YE, et al. Critical Care. Refer a patient to Mayo Clinic. This content does not have an English version. This content does not have an Arabic version.
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Medical Professionals Steroid use in pneumonia.
"More recently, corticosteroid use in pneumonia has been associated with improved clinical outcomes, including decreased mortality in patients with SARS-CoV Steroid therapy may reduce the mortality rate of severe pneumonia (7,8), with corticosteroids mainly administered as prednisolone mg/day or hydrocortisone. Steroid therapy may reduce the mortality rate of severe pneumonia (7,8), with corticosteroids mainly administered as prednisolone mg/day or hydrocortisone. Overall, the findings suggest that steroid treatment could reduce death rates among pneumonia patients from about 9 percent to10 percent now, to. We found good-quality evidence that corticosteroids reduced clinical failure rates in children with pneumonia, but the data were based on a. Critical Care. Corticosteroid therapy reduced morbidity, but not mortality, for adults and children with non-severe CAP. People treated with corticosteroids had higher blood glucose levels hyperglycaemia than those not treated with corticosteroids. All trials limited inclusion to inpatients with community-acquired pneumonia CAPwith or without healthcare-associated pneumonia HCAP. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: A randomized clinical trial.Jump to navigation. We looked at the effects of treating people with pneumonia using corticosteroids also called steroids or glucocorticoids on numbers of deaths, response to treatment, treatment complications, and side effects. We compared treatment with corticosteroids in addition to antibiotics with placebo or no treatment. Acute pneumonia is a lung infection treated with antibiotics that target the bacteria that caused the infection.
Pneumonia is quite common, and despite adequate antibiotic treatment, complications and sometimes death can occur. Corticosteroids are hormones produced naturally in the adrenal gland. Corticosteroids have been found to be beneficial in the treatment of some infections. However, their beneficial effects are often offset by serious side effects, mainly when used at high doses and over the long term.
This is an update of a review published in We included 17 studies evaluating systemic corticosteroid therapy given intravenously or by tablets for people with pneumonia participants; adults and children.
We included 12 new studies in this update and excluded one previously included study. All included studies evaluated people who had acquired pneumonia in the community community-acquired pneumonia CAP being treated in the hospital; no studies assessed people who had developed pneumonia while in hospital or who were on breathing machines mechanically ventilated.
Eight trials did not report funding sources; seven were funded by academic sponsors; one was funded by a pharmaceutical company; and one reported receiving no funding.
Eighteen adults with severe CAP need to be treated with corticosteroids to prevent one death. People with CAP treated with corticosteroids had lower clinical failure rates death, worsening of imaging studies, or no clinical improvement , shorter time to cure, a shorter hospital stay, and fewer complications. We found good-quality evidence that corticosteroids reduced clinical failure rates in children with pneumonia, but the data were based on a small number of children with different types of pneumonia.
People treated with corticosteroids had higher blood glucose levels hyperglycaemia than those not treated with corticosteroids. Corticosteroid treatment was not associated with increased rates of other serious adverse events. Corticosteroids were beneficial for adults with severe CAP. People with non-severe CAP may also benefit from corticosteroid therapy, but with no survival advantage.
We downgraded the quality of the evidence due to issues with study design, unclear results, or results that were not similar across studies. For the outcomes of death and clinical failure in adults, we graded the quality of the evidence as moderate.
For the outcomes of clinical failure in people with severe CAP, non-severe CAP, and in children, we graded the quality of the evidence as high. Corticosteroid therapy reduced morbidity, but not mortality, for adults and children with non-severe CAP. Corticosteroid therapy was associated with more adverse events, especially hyperglycaemia, but the harms did not seem to outweigh the benefits. Pneumonia is a common and potentially serious illness. Corticosteroids have been suggested for the treatment of different types of infection, however their role in the treatment of pneumonia remains unclear.
We also searched three trials registers for ongoing and unpublished trials. We included randomised controlled trials RCTs that assessed systemic corticosteroid therapy, given as adjunct to antibiotic treatment, versus placebo or no corticosteroids for adults and children with pneumonia. We used standard methodological procedures expected by Cochrane. Two review authors independently assessed risk of bias and extracted data.
We contacted study authors for additional information. This update included 12 new studies, excluded one previously included study, and excluded five new trials.
One trial awaits classification. All trials limited inclusion to inpatients with community-acquired pneumonia CAP , with or without healthcare-associated pneumonia HCAP. We assessed the risk of selection bias and attrition bias as low or unclear overall. We assessed performance bias risk as low for nine trials, unclear for one trial, and high for seven trials. We assessed reporting bias risk as low for three trials and high for the remaining 14 trials. Corticosteroids significantly reduced mortality in adults with severe pneumonia RR 0.
Early clinical failure rates defined as death from any cause, radiographic progression, or clinical instability at day 5 to 8 were significantly reduced with corticosteroids in people with severe and non-severe pneumonia RR 0. Corstocosteroids reduced time to clinical cure, length of hospital and intensive care unit stays, development of respiratory failure or shock not present at pneumonia onset, and rates of pneumonia complications.
Among children with bacterial pneumonia, corticosteroids reduced early clinical failure rates defined as for adults, RR 0. Hyperglycaemia was significantly more common in adults treated with corticosteroids RR 1. There were no significant differences between corticosteroid-treated people and controls for other adverse events or secondary infections RR 1.
Is treatment with corticosteroids beneficial and safe for people with pneumonia? Review question We looked at the effects of treating people with pneumonia using corticosteroids also called steroids or glucocorticoids on numbers of deaths, response to treatment, treatment complications, and side effects.
Background Acute pneumonia is a lung infection treated with antibiotics that target the bacteria that caused the infection.
Search date The evidence is current to 3 March Study characteristics We included 17 studies evaluating systemic corticosteroid therapy given intravenously or by tablets for people with pneumonia participants; adults and children. Study funding sources Eight trials did not report funding sources; seven were funded by academic sponsors; one was funded by a pharmaceutical company; and one reported receiving no funding.
Quality of the evidence We downgraded the quality of the evidence due to issues with study design, unclear results, or results that were not similar across studies.
Authors' conclusions:. To assess the efficacy and safety of corticosteroids in the treatment of pneumonia. Search strategy:. Selection criteria:. Data collection and analysis:. Main results:. Health topics:. Our evidence Featured reviews Podcasts What are systematic reviews?
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