Systemic Corticosteroids

NO features of severe or critical illness (see below).

• Symptomatic (any acute COVID-19 related symptoms)
• AND respiratory rate <24/min
• WITHOUT pneumonia or hypoxia

In patients with persistent fever and high inflammatory markers(e.g., CRP > 10 times ULN)  in the second week of the illness we accept there is some equipoise and that some doctors may wish to prescribe this when these markers are present.

NO features of severe or critical illness (see below).

• • Pneumonia (clinical or radiological)
• AND respiratory rate ≤30/min
• AND SpO2 ≥94% on room air

We recommend dexamethasone base 6mg once daily (this is 8mg sodium phosphate salt), oral or IV depending on available route of administration, until discharge or sustained normalization of oxygen saturation, up to a maximum of 10 days.

Drug: This is the drug used in most trials. However, if dexamethasone is not available methyl prednisolone 32mg/day, prednisolone 40mg or hydrocortisone 150mg /day can be used at an equivalent dose.

Moderate illness with hypoxia

NO features of severe or critical illness (see below).

• Hypoxia (SpO2 <94% on room air)
• AND respiratory rate ≤30/min
• AND SpO2 ≥90% on room air

Severe illness

Pneumonia with ANY ONE of the following:

• Respiratory rate >30/min
• Severe respiratory distress
• SpO2 <90% on room air
• NO invasive or non-invasive respiratory support needed

Critical illness:

• Requirement for high-level respiratory support: noninvasive ventilation, high-flow oxygen (≥20 litres per minute) or invasive mechanical ventilation
• OR acute respiratory distress syndrome (PaO2/FiO2 ratio of <300)
• OR sepsis
• OR shock

The evidence from the RCTs indicates that systemic steroids were associated with decrease in the all-cause mortality and need for mechanical ventilation to a moderate extent. This benefit was observed in patients with severe or critical COVID-19, who had need for oxygen therapy. There was evidence against the use of systemic steroids in non-hypoxic patients; subgroup analysis from a large trial did not show any benefit and there was also concern about potential increase in mortality.

No significant increase in the adverse events, especially secondary infections, was observed in the trials. The panel believes that appropriate and responsible use of systemic steroids with strict sugar control would lead only to a small risk of undesirable effects but the same could be moderate if used in high doses or for longer duration.

There was no statistically significant difference in terms of mortality, progression to mechanical ventilation, serious adverse events, nosocomial infections, or hyperglycemia, with respect to the use of equivalent doses of different classes of steroids. The data available on the outcomes, with respect to the timing of steroids after the symptom onset (≤7 days vs. 7 days or more), the dose (< or ≥ 10 mg of dexamethasone or equivalent) as well as the total duration of steroids ( 7 days) was weak. However, no statistically significant difference was observed amongst these different subgroups suggesting that using steroids too early in higher doses or longer duration was not proven to be beneficial and may be contributing to harm like hyperglycemia, higher risk of nosocomial infections and mucormycosis where inappropriate use of steroids is emerging as an important risk factor.

The panel concluded that moderate amount benefit of systemic steroids supports their use in severe to critically ill COVID-19 patients, who have hypoxia.

Date of latest search: 28^th April 2021.

Date of completion of Summary of findings table and presentation to Expert Working Group: 29^th May 2021.

Date of planned review: 27th November 2021

Evidence synthesis team:  Anupa Thampy, Richard Kirubakaran, Bhagteshwar Singh and Priscilla Rupali

Problem

COVID 19 infection produces significant morbidity and mortality and this is well known. Hence low cost accessible therapeutic interventions for clinical management are a priority. Today with the oxygen needs climbing and paucity of intensive care beds everywhere in the country, we need resources and drugs which will prevent progression of disease and in turn reduce the duration of severe and critical disease. Steroids have been shown to be beneficial in multiple trials, however gaps in evidence exist with regard to dose, duration, drug choice and optimal timing of steroids in the hypoxic patients. There are also concerns about inappropriate use in the non-hypoxic patients, and questionable benefit with higher doses and prolonged courses (>10 days) in the hypoxic patients. The burgeoning epidemic of mucormycosis has been variably attributed to the immunosuppressive effect of steroids and the ensuing hyperglycemia even if given for a shorter duration as steroids have a long half-life.

Desirable effects

The group felt that in the moderate, severe & critical illness COVID19 categories there were moderate desirable effects in terms of reduction in mortality and progression to invasive ventilation in the group given steroids. The group debated at length whether this would be small vs. moderate desirable effects considering the results are likely to vary according to drug choice, even though this is not reflected in the available evidence. The group also noted that since most of the evidence comes from the Recovery trial, in which most received dexamethasone it would be heavily weighted towards giving Dexamethasone rather than Hydrocortisone or methylprednisolone. This choice was also felt to reflect biological plausibility as the latter two drugs have more mineralocorticoid effect than dexamethasone and the anti-inflammatory effect of steroids is mostly from the glucocorticoid component.

For non-hypoxic patients, the evidence for desirable effects is limited. Subgroup analysis did not show benefit in this group in the recovery trial, and there was concern about potential increase in mortality and need for invasive mechanical ventilation (not statistically significant). Hence at present no desirable effects have been noted in this category. In exceptional circumstances if a decision was made to give the drug, that decision should left to the treating physician based on inflammatory markers and patients clinical condition and attendant comorbidities.

 Undesirable effects

In the hypoxic group pf patients in the moderate, severe and critical categories there seems to be no increase in secondary infections or adverse events. The group felt that this could vary; appropriate and responsible use with strict sugar control would lead to perhaps a small risk of undesirable effects but could be moderate if inappropriate use with higher doses or longer duration. Main concerns were that steroids in unnecessary high doses and duration with hyperglycemia could contribute to an increased risk of mucormycosis. Secondary bacterial infections though a theoretical risk were not seen in the studies evaluated, however there are anecdotal reports of increased incidence of nosocomial and community acquired secondary bacterial, viral and fungal infections after steroids were given for management of COVID19 infection. Therefore, the risk of undesirable effects will be higher in certain groups, such as those with diabetes mellitus.

Very few patients without hypoxia were included and hence a reasonable conclusion cannot be drawn with regard to undesirable effects in this group.

Certainty of evidence

There was consensus regarding moderate certainty of evidence for steroids preventing mortality and progression to invasive mechanical ventilation in moderate, severe and critical categories of illness. There was low/very low certainty of evidence for serious adverse events. The non-hypoxic patients were assessed as a subgroup in one trial. A separate summary of findings table was not made for this population, but likely to be very low certainty in the evidence overall.

Values

Outcomes considered for steroid recommendations were mortality, progression to invasive mechanical ventilation, serious adverse events, hyperglycemia and secondary infections, all of which were considered clinically relevant and important. The group felt there was no important uncertainty regarding the value applied to these outcomes by key stakeholders

Balance of effects

The group considered and acknowledged the overwhelming evidence of benefit of steroids among hypoxic patients producing a reduction in mortality & progression to invasive mechanical ventilation. When serious adverse events were evaluated there was no increase noted and there was very low certainty of evidence regarding hyperglycemia as well. Hence in this category of patients, the group favoured the intervention.

In the non-hypoxic group of patients, there was very low certainty of evidence but overall the group felt that the potential harms that are well-established for steroids are likely to outweigh benefits in this category of patients. The panel discussed that there are no trials focused on mucormycosis and the balance here favoured the intervention in hypoxic patients but did not favour in the non hypoxic patients.

Resources required

Clinicians in the group felt that considering the reduction in mortality and progression to mechanical ventilation this cheap intervention was lifesaving and would lead to large overall cost savings.

In non-hypoxic patients, the harms or benefits were unclear as it is not normally indicated in this category and hence it was not possible to comment on savings or costs. However, the potential for abuse was high and it is likely that there may be costs due to treatment required for secondary bacterial or opportunistic fungal infections.

Certainty of evidence of required resources

Experienced clinicians in the group felt that there was high certainty of evidence of required resources in implementing steroid use in hypoxic patients with COVID-19 as this was a drug widely used and available and clinicians were well aware of its benefits and harms.

In the patients with COVID-19 but no hypoxia, though the intervention itself was of low cost but there was an unclear indication for its use in this category of patients and potential harm outweighing the benefits here.

 Cost effectiveness

Among the hypoxic patients, the panel feel that even though no cost effectiveness analyses were performed in the studies included, we can safely conclude that the intervention is cost effective considering its low cost and high savings from efficacy on mortality and progression to ventilation.

Among the non-hypoxic patients, it is unclear if there would be cost savings from efficacy as there is little evidence for efficacy in this category and possible harm when used inappropriately at high dose and longer duration in the absence of a clear indication.

Equity

This is an intervention that is cheap, widely available, equitable and accessible to all. However caution should be exercised towards its use due to the attendant side effects.

Acceptability

The group felt that the intervention was acceptable in hypoxic patients with COVID19 due to the overwhelming evidence that it saves lives, if it is given at the appropriate dose and duration with close monitoring for adverse effects.

In patients with mild disease with no hypoxia, in the absence of high-certainty evidence the group felt that the use should be strongly discouraged in this category. However, the group did recognize there are some situations where in the presence of intense systemic inflammation even without hypoxia clinician judgment may be exercised for use.

Feasibility

This is an oral and cheap intervention which could be easily implemented in hypoxic patients in any setting provided the indication was right and guidelines given for appropriate and responsible use. This should not be encouraged in patients without hypoxia.

Use of systemic corticosteroids in hypoxic patients was backed with significant data support from various trials, however risk of worsening hyperglycemia and risk of secondary infections needs equal consideration due to the attendant morbidity and sometimes mortality. In hypoxic patients, steroids even with or without evidence of systemic inflammation saves not just lives but resources. Though by itself this intervention is cheap, the ensuing side effects leading on to secondary bacterial nosocomial or opportunistic fungal infections are likely to be expensive and resource intensive taking up hospital beds and personnel that could be better used elsewhere. Hence steroid use in all hypoxic patients though warranted must be tempered with optimal and strict sugar control and stringent infection control precautions in definitely all but most especially in the immunocompromised individuals. India has an extremely high prevalence of diabetes and chronic invasive mucormycosis and hence steroid use or abuse when not indicated is likely to be detrimental.

There is no supportive evidence for use of steroids in non-hypoxic patients, however in the presence of overwhelming systemic inflammation with persistent fever and high inflammatory markers and change in high resolution computed tomography score judicious consideration with the input from a senior physician may be appropriate.

Extensive interrogation of potential differences in effect between subgroups was performed using an indirect between-trial approach, for mortality, progression to invasive mechanical ventilation, serious adverse events, infections and hyperglycemia. A detailed analyses of subgroup differences revealed that Methylprednisolone and Hydrocortisone had the same efficacy as Dexamethasone when equivalent doses were given. When equivalent doses of steroids were given, 10mg/day of equivalent doses of Dexamethasone no subgroup difference was found suggesting no superiority of higher vs lower dose. Longer vs shorter courses of steroids were also evaluated and again no subgroup difference was noted suggesting that longer duration had no benefit over shorter duration. Optimal timing of initiation of steroids 7 days after symptom onset was evaluated and no obvious differences were identified. Most of this evidence came from large trials like Recovery, REMAP-CAP etc which recruited large number of patients suggesting that in the arms where these trials were represented likely skewed the data to that side during a subgroup analysis. Principles of good clinical practice suggest that a steroid which has the maximal efficacy (glucorticoid rather than mineralocorticoid activity) with the minimal side effects, given in as low a dose as possible, for as short duration as possible and initiated when it is likely to be of maximal benefit (i.e., period of hyperinflammation) would be appropriate. A subgroup that is under-represented in trial evidence is patients who have raised inflammatory markers or persistent fever but not requiring oxygen and hence we were unable to draw conclusions or provide a suitable recommendation in these patients and at this point, may be left to clinician discretion to use steroids in this scenario in a very narrow subgroup of patients where the potential benefit likely outweighs the risk.

Pregnancy

The concerns over medications in pregnancy are the changes in physiology in the three trimesters and the degree of placental transfer of the active component of the drug and its effect on the foetus. Inhaled and systemic steroids in respiratory disease and pregnancy have mainly been studied in the context of Bronchial asthma. Use of oral Prednisolone and parenteral Hydrocortisone, both are considered safe in all trimesters as they undergo degradation by theplacental 11 β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Dexamethasone however is not metabolized by 11β-HSD2 and readily crosses the placenta and is useful for use in preterm labour to facilitate lung maturity. This raises the concern for use of Dexamethasone in hypoxic pregnant patients with Covid 19 however there is paucity of data on the use of steroids in pregnant patients

Hence Dexamethasone is recommended in the second, third trimesters of pregnancy and in post-partum patients with severe or critical Covid 19 pneumonia as rapid progression to severe disease is often seen in these patients.Oral prednisolone can be used in hypoxic pregnant patients in first trimester and second trimester for moderate Covid 19 pneumonia and in the first trimester only in severe Covid 19 pneumonia. Severe disease is often not encountered in the first trimester of pregnancy.

In all subjects, steroid doses, duration and preparation must follow as in the recommendation. Pulse steroids or higher dose or duration beyond the recommended doses are unlikely to be beneficial and perhaps even harmful even in hypoxic subjects. Higher doses and longer duration are not beneficial and can lead to toxicities like uncontrolled diabetes mellitus and superadded secondary infections like mucormycosis.

In non-hypoxic subjects, treating physician’s judgment should be strictly guided by the evidence and irresponsible use of steroid discouraged. Clinical features like fever, persistent cough, raised CRP and ground glass infiltrates on High Resolution Computed Tomography are non-specific and can be seen with other differential diagnoses like Influenza, Dengue fever etc. Steroids must be discouraged in 1^st week of illness as cytokine storms / hyperinflammation is unlikely then.

Above all, close monitoring and strict control of blood sugar in all subjects, whether diabetics and nondiabetics is warranted, as many prediabetics may be pushed to diabetes even with this short course of steroids) on a daily basis. In those with leucopenia, apart from the diabetics; extra watch for superadded or opportunistic infections is a must.

Though corticosteroids have been unequivocally been shown to reduce mortality and progression to respiratory failure, there exist uncertainties with regard to the best steroid to be used, optimal dose, timing and duration of corticosteroid therapy. Steroids have been used for decades and the side effects whether in the short term or long term are well known. They are well known to produce increased susceptibility to infection, believed to be the most likely reason for the epidemic of covid associated mucormycosis. Though it is fairly certain that initiation of steroids in hypoxic COVID19 individuals is lifesaving, utility of steroids in non-hypoxic individuals with evidence of systemic inflammation is still unknown. In addition, the use of biomarkers like CRP, Ferritin in initiation, prognostication or discontinuation of steroids is still unknown.

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Covid Management Guidelines India Group - Anti-inflammatory Working Group. Systemic Corticosteroids. Covid Guidelines India; Published online on July 15, 2021; URL: https://indiacovidguidelines.org/systemic-corticosteroids/ (accessed ).