Question 5

College Answer

Rationale / Indications

Conventional & generally accepted indications include:

• Pneumonia complicating exacerbated COPD
• PJP infection with lung infiltrates (data from HIV population, and by extrapolation to other immunosuppressed groups)
• Patients who are on long term corticosteroids or otherwise have adrenal suppression
• (With less certainty) those with shock states and vasoplegia as a catecholamine sparing strategy

Outside of these groups, in a general population with CAP:

• The basis for use is as an adjunctive therapy in hospitalised patients to reduce inflammation and improve morbidity or mortality.
• Some patients with CAP fail to resolve, and progress to cryptogenic organising pneumonia, (COP) with case series showing response to corticosteroids (and relapse on early cessation 
• Conflicting evidence in the fibro-proliferative phase of ARDS
• Now several studies randomising patients to early use in uncomplicated CAP

Potential adverse effects

• Super-added infection
• Muscle weakness / Proximal myopathy / Critical illness polyneuromyopathy
• Difficulty weaning from ventilatory support

Evidence

A 2015 Meta-analyses (Siemieniuk et al, 2015):

•   3% decrease in all-cause mortality, 
•   5% decrease rate of mechanical ventilation
•  Reduced hospital length of stay by 1 day.
•  Critique of metanalysis
  • Trials included in metanalyses have been small
  • had high heterogeneity
  • Insufficient power to analyse mortality.
  • Many exclusions
    •  (e.g. immunocompromised patients at risk of superinfection, pregnant women, GI bleeding within 3 months as well as patients with neuropsychiatric conditions prone to psychotic side effects of steroids)
  • Small overall effect

A recent RCT (Blum et al, Lancet 2015, 392 pt per group) showed a shorter time to reach a composite endpoint of ‘clinical stability’ with Prednisolone 50mg daily for 7 days.  

Another RCT (Torres et al, JAMA 2015, 60 pt per group) showed that Methylprednisolone 0.5mg/kg 12h for 5 days reduced risk of “treatment failure” compared with placebo in patients with severe CAP and high CRP levels

Practical (Translational) Issues

• No clear data on exact steroid and regimen
  • There is no definitive data on what type of steroid to give and whether to give continuously or in a tapering regimen and for how long.
  •  In the idiopathic pneumonia group (COP) steroid tapering can be associated with abrupt relapse
• Pathogen dependent response to steroids
  • Pneumonia due to pathogens like the influenza virus and aspergillus may be associated with worse outcomes with steroid use, PCP better
• Studies in progress that may help
  • The ESCAPE study by the Department of Veterans affairs is assessing the role of steroids in CAP with either placebo, methyl prednisolone 40 mg per day or 20 mg per day for 7 days followed by tapering over 13 days on all cause 60 day mortality.

Summary statement (For example)

• Subgroups where steroids would be conventional therapy (COPD, PJP)
• Not yet accepted therapy
• Treatment effect small
• But no evidence of adverse effect and demonstrated safety.
• Listed as practice changing update in Up-to-Date
• Should ideally be a conjoint decision with clinician responsible for post ICU management

Additional comments:

Candidates were lacking in knowledge relating to the evidence for steroids in severe CAP. The detail in above template was not required for a pass mark. Satisfactory answer for a pass mark was expected to include:

• Accepted indications for steroids in CAP
• Some reference to rationale for use in other groups with CAP
• Potential adverse effects
• Some reference to evidence

Discussion

Rationale  for the use of steroids

• Much of the organ system effects of pneumonia may be related to the inflammatory reaction
• Anti-inflammatory drugs like steroids may reduce the release of cytokines, thereby dampening the SIRS response
• Modulation of the pro-inflammatory response should lead to a more rapid resolution of clinical features
• Similar rationale has been successfully applied to other infectious illnesses, for instance in the use of dexamethasone for pneumococcal meningitis
• Other pulmonary infections benefit from corticosteroids:
  • COPD complicated by pneumonia: patients with pneumonia may have underlying COPD or asthma which may be unrecognised in the community, and which will improve with steroids as a "collateral benefit".
  • Pneumocystis jirovecii pneumonia (PJP): even in non-HIV patients, around 30mg/d of prednisone seems to reduce ICU stay and duration of mechanical ventilation (Pareja et al, 1998).
  • Cryptogenic organising pneumonia (1mg/kg/day of prednisolone, according to a multinational guideline from 2008)
  • Fibro-proliferative phase of ARDS - but the evidence is not convincing; there may be some sort of effect if the steroids are given between 7 and 1 days following onset, accroding to Steinberg et al (2006)
  • Acute eosinophilic pneumonia ( Davis et al, 1986)
• Other extrapulmonary pathology will benefit from steroids:
  • Adrenally suppressed patients (eg. chronic steroids)
  • Relative adrenal insufficiency in septic shock: this is discussed elsewhere

Arguments against the use of steroids

• The systemic inflammatory response to pneumonia has constructive facets, as it mobilises the immune retaliation against the pathogens
• The metabolic side effects (eg. hyperglycaemia, hypernatremia, adrenal suppression) may be a disadvantage to severely septic patients
• The possibility of exacerbating muscle weakness may be a disadvantage with using corticosteroids in mechanically ventilated patients
• Some forms of pneumonia are known to get worse with steroids, eg. Influenza where mortality is doubled (Rodrigo et al, 2015 ) and Aspergillus  (Parody et al, 2009 - although this was a study of bone marrow transplant patients)

Evidence regarding use of steroids

• Torres et al : compared methylprednisolone (n = 61) or placebo (n = 59) for 5 days.
  • Less treatment failure with steroids (13% vs 31%)
  • No difference in mortality
  • Major criticism:
    • The placebo group has more intubated patients, and more septic shock
    • Only ~ 20-25% of the patients received proper dual antibiotic therapy
    • Only 57% of the patients had a CRP above 15
    • The study recruited over 8 years, an average of 5 patients per center per year.
    • The primary treatment difference between groups was radiographic progression between days 3 and 5, which may represent something completely clinically irrelevant.
• Blum et al: 785 patients randomised to 50mg prednisolone or placebo
  • "Median time to clinical stability was shorter in the prednisone group" - 3.0 days vs. 4.4
  • Not specifically ICU patients - all CAP admissions were enrolled
  • "Clinical stability" was a composite endpoint
• The college answer has quoted a 2015 meta-analysis by Siemieniuk et al, who (including the above data) suggested that the use of corticosteroids may reduce
  • mortality by 3%
  • need for mechanical ventilation by 5%
  • hospital stay by 1 day
• Since this SAQ had been used, DEXA-ARDS has come out (2020), which - though ostensibly ARDS-oriented - enrolled patients of whom 53%  had pneumonia, and which demonstrated an almost implausible-sounding 15.3% mortality difference with 10-20mg of dexamethasone.
• It is difficult to know whether COVID-19 data belongs in this section, but the reader is owed some mention of it, as the use of steroids certainly revolutionised the management of this condition. 

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