4 Febr 2021 Episode 108 Immune modulatory treatment Part 1 gluco-corticosteroids

Dear colleagues,

In this episode, I will focus on the various immune-modulatory treatments that have been tried.

Part 1 is on systemic and local (inhaled) glucocorticosteroids. Part 2 will be on more targeted approaches (e.g. anti-IL6)  

Equivalence: 100 mg hydrocortisone (HC)    = 20 mg methyl-prednisolone (MP)   = 4 mg dexamethasone (Dexa)

1. A recent paper by Mao et al in Front Endocrinol (Ep 108-1) suggests that the adrenal cortex could be a target for SARS-CoV-2 (receptor and TMPRSS2 present slide 2), which might explain why cortisol levels in critically ill COVID patients are lower than in comparable critically ill patients without COVID  (slide 3), though this is a very small series. 

2. The RECOVERY trial showed already in July that 6 mg Dexamethasone (≈ 150 mg HC) daily for 10 days was associated with a 36 % lower 28-day mortality rate in critically ill patients (requiring mechanical ventilation), while the effect was only 22 % in those requiring oxygen and absent in those without oxygen need (Ep 108-2 and slide 4).

3. A WHO Working group performed a meta-analysis of 28 mortality in 7 RCT with corticosteroids: there were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95%CI, 0.53-0.82];  P < .001).  The effect was comparable for dexa and HC, but much less in the MP group (which was small (slide 5). The effect was independent on age, sex and duration of symptoms (< or > 7 days), it was absent in patients taking vaso-active medication (slide 6).  

4. In a prospective observational study amongst 318 mostly severely ill  patients (Ep 108-4), Lopez-Zuniga et al show that high dose corticosteroid pulse therapy (HDCPT) 1.5mg/kg/24h  (= 105 mg  for a 70 kg person) of methylprednisolone or dexamethasone equivalent is associated with increased survival (slide 7).  By longitudinal analysis of a number of potentially predictive inflammatory markers (slide 8), they propose IL-6 > = 40 pg/ml, and/or two of the following: C-reactive protein > = 100 mg/L, D-dimer > = 1000 ng/ml, ferritin > = 500 ng/ml and lactate dehydrogenase > = 300 U/L) to identify patients at risk for hyperinflammation, hence eligible for this therapy.  Clearly, a RCT is needed to confirm these results

5. An RCT with low-dose hydrocortisone (Ep 108-5) was stopped because of futility. In this case the dosage was 200mg/d until day 7 and then decreased to 100 mg/d for 4 days and 50 mg/d for 3 days. (hydrocortisone is 25 times less potent than dexamethasone).  Clearly, however, the 21 days mortality was 12.7 % lower ( p=0.57) in the treatment group (slide 9).  As can be calculated the dose was indeed lower than in RECOVERY, but not that much (6 mg Dexa = 150 mg HC).  Interestingly, there was no increase in nosocomial infections in the treatment group.  

6. Another paper by Fadel shows that a short (3 days) course of methylprednisolone 0.5 to 1 mg/kg/day (35-70 mg MP = 175 – 350 mg HC) in moderate and severe patients was associated with lower death and respiratory failure (Ep 108-6 and slide 10).  However, this was not an RCT

7. Importantly, a recent meta-analysis by Pasin (Ep 108-7) of 5 RCT involving 7,692 patients: .

• Overall mortality of patients treated  with systemic corticosteroids (CS) was lower than controls (26% v 28%, relative risk {RR} = 0.89
• This beneficial survival was, however, limited to patients, requiring mechanical ventilation (RR = 0.85); while CS increased mortality in those not requiring oxygen (RR 1.23)
• On the other hand again, patients treated with CS had a significantly lower need for mechanical ventilation!!

Clearly, these results are rather consistent and indicate that systemic corticoids can have a beneficial effect in critically ill patients, but they certainly do not provide a “cure”.  The treatment is limited in time, but could have systemic metabolic and cardiovascular side effects, especially in patients with pre-existing predisposition (pre-diabetes, hypertension).  There is also an increased  risk for other infections.  Therefore one wonders of local (inhalation) corticoids could be an alternative.

In fact “early descriptions of patients admitted to hospital during the COVID-19 pandemic showed a lower prevalence of asthma and chronic obstructive pulmonary disease (COPD) than would be expected for an acute respiratory disease like COVID-19, leading to speculation that inhaled corticosteroids (ICSs) might protect against severe acute respiratory syndrome coronavirus 2 or the development of serious sequelae.” (Schultze  et al Ep 107-8)

There are two possible bits of information on the effect of ICS: population studies and RCT

1. UK population study (Ep 108-8) was on almost 150,000  COPD over 800,000 asthma patients with various medications

• People with COPD and ICSs were at increased risk of COVID-19-related death compared with those non-steroid medication (adjusted HR 1·39 [95% CI 1·10–1·76]).
• Also asthmatics with ICS were at an increased risk of death (1·55 [1·10–2·18]), whereas those given a low or medium dose were not (1·14 [0·85–1·54]).

However: Sensitivity analyses showed that the apparent harmful association observed could be explained by relatively small health differences between people prescribed ICS and those not prescribed ICS

Interpretation:

• No major role for regular ICS use in protecting against COVID-19-related death
• Observed increased risks of COVID-19-related death can be plausibly explained by unmeasured confounding due to disease severity.

2. Korean study (Ep 108-9) is much smaller and focuses on 7341 patients hospitalized with COVID, where ICS, asthma and COPD are analyzed.  The conclusion is “Prior ICS use was not significantly associated with COVID-19 in patients with COPD or asthma, nor with clinical outcomes among patients with COVID-19.

3. Randomized controlled use of ICS in COVID-19?  At the end of an equally inconclusive comment in Lancet Resp Med Sept 2020 (Ep 108-10),  Nicolau mentions 6 ongoing RCT registered at ClininalTrial.Gov.  Unfortunately, none has communicated results until now, as far as I could see (I looked in several places)….

General conclusion:  

It is clear that systemic corticosteroids can have a beneficial effect for critically ill COVID patients. It is limited in size, but could make a difference between life and death.

In view of the complexity of the syndrome, with advanced age, co-morbidity, frailty etc, it is quite possible that systemic corticoids are in fact only indicated in a subset of patients and might be deleterious in others.

The conditions of overwhelmed intensive care units and complex individualized therapeutic schemes, we cannot expect final answers; but, most probably they will become available in the next period, when things will return to a more normal situation and focused trials in subgroups of patients can be planned.

The role of inhalation corticosteroids remains very unclear today.  

Best wishes,

Guido