The document discusses a case of empyema in a 63-year-old male who experienced worsening respiratory symptoms and significant health decline after a pneumonia diagnosis. It provides an overview of pleural infections, detailing the rising incidence, distinct microbiological patterns, clinical presentation, and stages of empyema, alongside treatment challenges and recent clinical trial results. Additionally, it outlines future research directions and potential advancements in the management of pleural infections.

1. Empyema
IAN BITTINER
ST5

2. 63 male
Normally F&W, no regular medications
Became unwell 7th Dec 2020 – cough, yellow sputum
Saw GP 23rd Dec – oral doxy
No real improvement – Clarithromycin 6/1/21
Again no improvement
Progressive loss of appetite and weight over a couple of months – given fortisip, which stopped
weight loss, but poor appetite continued
Progressive right shoulder pain and inability to lie on left side due to dyspnoea

3. SH
Works for government in IT
Ex-smoker, 5-10/day for 10-15 years
Lives with step daughter and her partner
Bottle wine/night up until December – nil since

4. On examination
OE: Acutely distressed, in significant pain and sats dropped to 80% when sat forwards, but 98%
when reclined at 60 degrees
Chest – no air entry right side

6. If an empyema does not rupture, death will
occur - Hippocrates

15. Results
Fluid LDH >50000
pH unable due to viscosity
Protein 63
Glucose <0.6
Fluid grew Streptococcus anginosus

16. Pleural infections - overview
From Greek, Empyein – pus producing
Incidence of pleural infection is rising
Rising most in elderly, where mortality is highest
Microbiology is inherently different from pneumonia
There has been improvement of non surgical drainage over the past decade
Surgical drainage continues to play an important role

17. Pleural infections - overview
Up to 57% of patients with pneumonia develop pleural effusion
The majority do not develop empyema
Simple effusions lead to increased admission, longer stays and antibiotic durations and higher
mortality
Pleural infection (complicated parapneumonic, empyema) require prompt drainage and
prolonged courses of antibiotics

18. Clinical presentation
Can be diverse – fevers with effusion and non-resolving pneumonia
Another pattern (more elderly) – Malaise, anorexia, weight loss (as in the case) can end up on
malignant diagnostic pathways, leading to delays
Mortality 10-20%

19. Risk factors
Age
Pneumonia
Alcohol/drugs
Diabetes
GORD
Poor oral hygiene
Immunosuppression
(Pleural intervention)

20. 3 stages of Empyema
Exudative
Fibrino-purulent
Organising
These are not necessarily linear and are dependant on innumerate host-pathogen factors
Eg: patient with heavily loculated, but serous appearing effusion

21. Stages of Empyema
Exudative Fibrino-purulent Organising
0-14 days 7 days to 6 weeks From 2 weeks

22. Exudative stage (1-7 days) –
“parapneumonic effusion”
Bacterial invasion of lung parenchyma
Parenchymal inflammation leads to visceral pleural membrane permeability and leakage of
interstitial fluid
Mesothelial lining further disrupted by neutrophil infiltration, leading to mesothelial cells
releasing pro-inflammatory cytokines such as IL6, IL8 and TNF-alpha
High level of endogenous fibrinolytic enzymes
Anatomical distortion occurs, leading to increased fluid
Normal pH, glucose and culture negative
Important to recognise these early and treat

23. Fibrino-purulent stage (4 days – 6 weeks)
Bacteria transcend the pleural membrane
High fibrinolytic levels start to be suppressed by a rise in plasminogen activator inhibitors - PAI-1
and PAI-2
PAI-1 levels now correlate with residual pleural thickening
Progressive leukocytosis and fibrin accumulation initially at the pleural surfaces
Progressive tendency towards loculation
Bacterial and neutrophil phagocytic activity use glucose and produce lactate
LDH rises due to release from polymorphs and mononuclear cells

24. Organising stage (2-6+ weeks)
Fibroblasts grow onto pleural surfaces
Formation of inelastic membrane “pleural rind”
Platelet-derived growth factor and transforming growth factor beta can lead to pleural fibrosis
Pleural thickness inhibits antibiotic penetration further
Microbial biofilm occur further reducing antibiotic effectiveness
Collagen deposition in this phase reduces the effectiveness of fibrinolysis and surgery becomes
essentially inevitable

25. Late complications
Destruction of lung tissue, bronchopleural fistulae/pyopneumothorax
Spontaneous entry into chest wall “empyema necessitans”
Rupture into abdominal cavity

26. Limitations of understanding
Animal models have been largely dependant on artificial inoculation of bacteria into the pleural
space, thus bypassing the predominant route of bacterial translocation to the pleural space
Study: IV vs intranasal inoculation of S. pneumoniae in mice – intranasal formed empyema much
more quickly and reliably, suggesting direct mesothelial penetration rather than haemotogenous
spread was predominant

27. Microbiology
Distinct from pneumonia
Staph aureus has overtaken Strep viridans gr
Polymicrobial in estimated 23%, likely underestimate from current culture techniques
Recent metagenomics DNA studies show that primary pleural infection (without pneumonia) is more
likely polymicrobial (60%) than secondary to pneumonia (25%)

28. Microbiology
Gram +ve aerobes predominant in CA
Gram –ve aerobes in HA
Anaerobes hard to culture, but suited to the hypoxic pleural environment
Atypical pathogens rarely cause pleural infection

29. Aims of treatment
Control of infection
Expansion of lungs

30. Antibiotics
Penicillin and metronidazole most rapidly formed equilibrium of serum and pleural
concentrations, flowed by ceftriaxone and clindamycin (rabbit models)
It remains unclear how effective antibiotics are at preventing bacterial replication in an infected
pleural space

31. Drain size
Evidence suggest small drains with adequate flushing are probably non-inferior to larger drains
I’d still put in an 18Fr

32. 2nd Multicentre Intrapleural Sepsis Trial
(MIST2)
NEJM 2011
210 patients with empyema
Randomised to 1 of 4 arms: double placebo, tpa 10mg bd, dnase 5mg bd, tpa and dnase
Primary outcome measure was reduction of opacification of hemithorax on day 7 CXR compared
to baseline
Secondary outcomes: referral for surgery, duration of hospital stay and adverse events

33. Eligibility
Evidence of infection (fever/high inflammatory markers)
AND one of
Purulent fluid macroscopically
Positive gram stain or culture
pH <7.2

34. Outcomes
Only tpa and DNase group shows significance
-29.5% vs -17.2% change in opacification of chest radiograph
77% reduction in referrals for thoracic surgery
6.7 day reduction in inpatient stay

35. Challenges
Rapid inactivation of enzymes by inhibitors inc plasminogen activator inhibitor 1. High levels of
this increase loculation, and dramatically effect outcome of MIST2 protocol
Future
◦ Personalised dosing of enzymes based on pleural fluid inhibitor levels?
◦ PAI-1 neutrolising antibodies?
◦ LTI-01 – a single chain urokinase plasminogen activator activator resistant to PAI-1 shows bioavailability
beyond 24 hours

36. Better prevention? – STOPPE trial.
Steroid therapy and outcome of parapneumonic pleural effusions
Hypothesis: Initial exudative stage could be due to exaggerated pleural inflammatory response
Rationale: Paediatric trial which showed reduced time to recovery in simple parapneumonic
effusions in children with viral pneumonia
Rationale 2: Observation of reduced numbers of empyema in patients with COPD ?steroid effect
Currently recruiting RCT looking at their role

37. Alternative strategies
Pleural irrigation Trial (2015) – single centre in Bristol 250ml saline infused via gravity tds vs 30ml
flush tds via 12Fr tube for 3/7
All patients put on suction (up to 20cmH20)
This showed a reduction in effusion size on CT and a reduction in referral for surgery
Multicentre RCT planned
◦ Role could be in patients who are not fit for surgery and in whom fibrinolysis is contraindicated

38. Surgery - VATS
RCTs show 80% can be managed medically
VATS has widened the number of patients suitable for surgery
Current guidance is for usage in treatment failure or advanced cases
In advanced cases VATS treatment failure increases with conversion to decortication up to 61%
VATS decortication mortality 2-6%
Complication rate 9-40%
Persistent air leak, pain, bleeding, infection, residual pleural space
No data for best time for surgery

39. Fibrinolysis v VATS
Multiple trials ongoing to investigate
MIST 3 – cannot see protocol
DICE – IR guided drain + fibrinolysis vs VATS as primary treatment for empyema

41. v

42. How long are fibrinolytics retained in the
pleural space?
1-2 hours
2-4 hours
4-6 hours
6-8 hours
8-12 hours

43. How long are fibrinolytics retained in the
pleural space?
1-2 hours
2-4 hours
4-6 hours
6-8 hours
8-12 hours

44. References
Bedawi EO, Rahman NM. Pleural infection: moving from treatment to prevention. In Maskell
Nam Laursen CB, Lee YCG et al. eds Pleural Disease (ERS Monograph). Sheffield, European
Respiratory Society, 2020; pp. 155-171