A talk by Adam Linder at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine. All available content from SSAI2017: https://scanfoam.org/ssai2017/ Content delivered in collaboration between scanFOAM, SSAI & SFAI.

1. Sepsis
-A neglected global public health
problemIncidence, long-term outcome, awareness, and diagnostics
SSAI, Malmö Sept 8th 2017
Adam Linder, MD, Clin for Infect Dis, Lund University Hospital

2. Disclosures
• Hansa Medical has filed a patent on
the application of HBP as a sepsis
biomarker and A.L. is listed as one
of the inventors.

3. There is an unmet need to improve sepsis care and
management– WHO Sepsis resolution 2017
• In May 2017 WHO declared a Sepsis resolution recognizing sepsis as a global
health problem and urging their member states to address this issue (Reinhart
2017 NEJM):
What needs to be done:
• Increased public awareness of sepsis
- Campaigns, patient organizations
• Early identification and determine the “inflammatory” stage
– Novel biomarkers predictive of disease progression and outcome.
• Rapid identification of bacteria from patient samples
– Influence treatment decisions (only 20-30% blood culture positive)
• Subdivision of Sepsis (akin to cancer)
– Targeted therapies “personalized medicine”.
• Improved long-term follow-up
- Post-Sepsis Clinics?

4. Sepsis can affect anyone!

5. Incidence

6. Is Sepsis common?
• 50-300/100 000 based on ICD diagnos
• Sepsis incidence is underestimated using ICD
• Henriksen 457/100 000 ED visits
• Mellhammar 670/100 000 – the incidence of
community and nosocomial sepsis.
Angus 2001 CCM, Gaeiski 2013 CCM
Johansson 2014 Läkartidningen
Henriksen 2014 Crit Care Med
Mellhammar 2016 OFID

7. Is Sepsis common?
• Appr. 40 000 adult sepsis cases
(infection+ organ dysfunction) every year
in Sweden
• The 4 most common forms of cancer
affects 27 000 individuals every year
(prostate, breast, skin and bowel cancer).
Mellhammar OFID 2016
Henriksen CCM 2015

8. 20-30 Million sepsis cases/year
Fleischmann C. et al CCM 2015
15.3 million cancer cases/year

9. Is Sepsis dangerous?
Wellcome Trust

10. Sepsis 28-d mort 10-30%
mortality AMI 7.5%
Is Sepsis dangerous?
Deaths from traffic accidents 275/y
Deaths from Sepsis – appr 5000/y

11. Long-term
outcomes

12. Long term consequences
• Cardiovascular events - more common after severe sepsis
hospitalization than other and a 1.9 fold higher risk compared to matched population
controls – (Yende 2014 AJRCCM, Bergh et al 2017 Eur J Prev Card)
• Cognitive impairment - 3.3 fold increased risk after severe sepsis
(Iwashyna 2010 JAMA)
• Dementia - 1 in 5 ICU survivors develop dementia within 3 years (Guerra Crit
Care 2012
• Impaired Quality of life - significantly lower physical functioning,
vitality (P=0.03), mental health (P=0.04) (Zhang Anaesthesist 2013)
• Renal dysfunction - ICU survivors (28-day) with mild AKI have an increased
10-year mortality (Linder AJRCCM 2014)
• Lower life expectancy – Younger severe sepsis 1-year survivors have 17
fold increased risk of dying within 10 years compared to the normal population (Linder CCM
2014)

13. Is Sepsis expensive?
• Sepsis is the most expensive disease condition in US and European
hospitals.
• One day in intensive care costs about 5 000 USD, ward 1 000 USD
• A sepsis cases costs an average of 40 000 USD in emergency care
• The majority of the economic burden of severe sepsis occurs after hospital
discharge; initial inpatient costs represent only 30 % of the total cost
• Earlier detection and treatment of sepsis patients would reduce deaths by
92 000 / year and reduce spending by 1.5 billion / year in the United
States.
• No Swedish numbers are available

14. So Sepsis seems to be ..
• The most common disease
• The most dangerous disease
• The most expensive disease
• Is Sepsis the most well-known disease?

15. Awareness

16. A Swedish Awareness survey
21%
90%
92%
95%
95%
96%
96%
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Sepsis
COPD
Leukemia
Prostate cancer
Stroke
Breast cancer
Acute Myocardial Infarction
N= 1001
Which of the following medical conditions have you heard of?
21% of adult
Swedes have
heard about
SepsisMellhammar et al OFID 2015

17. Awareness of sepsis is low around the world
World Sepsis Day org

18. Diagnostics

19. What can we do about this?
• The role of the doctor is to amuse the
patient, while nature takes it course.
Voltaire 1700

20. 20-30% of sepsis patients progress to
organ dysfunction within the first 24 hours
in hospital
24 hours
Glickman et al 2010
Shapiro et al 2009
Linder et al 2009

21. Early identification of Sepsis is difficult
Shahrzad wasn’t feeling well and contacted the emergency
unit, the ambulance came and suggested an anxiety attack
• But it was meningococcal
sepsis

22. Early identifcation of sepsis is vital
Diagnostics in the ED
Triage systems Biomarkers

23. How do we identify Sepsis in
Sweden?
• 88% of EDs use RETTS as triage system (5%
use qSOFA)
• 32% do not have routines for contacting an
Intensivist or ID-specialist if suspicion of sepsis
• 30% lack standardized guidelines for the
treatment of septic patients in the ED
Ulfsson Ms 2017

24. Sepsis Alert – Early and equal sepsis care?
Sepsis alert –prehospital or in the ED
Infectious disease physician is summoned to the ED
Guidelines for sepsis care bundles are equal for the whole province
Rosenqvist et al 2016

25. Is the Sepsis Alert perfect?
Pros
• Sepsis is highlighted
• High specificity (>70-80%
have sepsis)
• Rapid detection and
treatment of the most
severe cases (28d mortality
>20%, 1y mort >50%)
• ID physician is summoned
early
Cons
• Early antibiotics necessary
in non-shock sepsis?
• Risk that early antibiotic
stress gives poor microbial
culture quality
• Low sensitivity (36% of
community acquired sepsis)
• Resource demanding – 2-3
alerts/24hr in Lund

26. Where should we look for an early biomarker?
Sepsis Progression:
Infection
Neutrophil
activation and
TNF release
Increased micro-
coagulation begins
to be excessive
Damaged
vascular
endothelium
Edema and
hypovolemia
Vasodilation hypotension
Decreased tissue
perfusion
Organ failure
HBP
Lactate

27. Heparin Binding Protein (HBP)
-an early sepsismarker with biological plausibility
• Stored in neutrophils which are the first line of defense.
• Pre-fabricated (not produced after stimuli)
• The only neutrophil protein stored in secretory vesicles which are the
first to exocytose.
• Induces vascular leakage (a key feature in sepsis)
• Bacterial structures can induce the release of HBP

28. Previous findings: plasma-HBP is elevated in sepsis with organ dysfunction
Validation in an international multicenter setting
HBP was the best predictor of
progression to organ dysfunction
HBP levels are elevated before clinical signs of organ
dysfunction in >80% of patients with suspected sepsis
Linder CID 2009
Linder CCM 2015
HBP

29. 0
10
20
30
40
50
60
70
80
90
100
0 20 40 60 80 100
Sens
Spec
Sepsislarm 2qSOFA qSOFAinklHBP
qSOFAinkllaktat sepsislarm/HBP
Sepsis Alert + HBP
2 qSOFA + HBP
Sepsis Alert
2 qSOFA + lactate
2 qSOFA
Adding HBP to the triage system may improve
sensitivity of identification of sepsis in the ED
Mellhammar et al Ms 2017

30. Conclusions
• Sepsis is a (serious) public health problem
• Incidence of sepsis is higher than previously
anticipated
• Awareness of sepsis is low
• Long-term outcomes should be better explored –
post-sepsis clinics?
• Sepsis guidelines in the ED is not equal in Sweden
• HBP is a promising biomarker that may aid in
early identification of sepsis already in the ED

31. Sepsisambassadörer
Magnus Samuelsson
AKA Världens starkaste man
Shahrzad Kiavash
Triathlet och
paralympics
Styrelseledamot
Anders Åkesson
Regionråd i Skåne
Sveriges förste politiker som
är sepsisambassadör
• Grundades september 2015 i Lund
• En ideell insamlingsstiftelse med 90-konto
• Målsättningen är att öka kännedom om
sepsis bland befolkning och makthavare
samt att samla in pengar till
sepsisforskning
24/5 antog WHO en Sepsis Resolution som uppmärksammar
Sepsis som ett globalt folhälsoproblem och World Sepsis Day
den 13 September skall bli den 8de världshälsodagen

32. • Tack!

33. Sepsis is a complex syndrome
• Infecting pathogen
• Site of infection
• Disease spectrum
and sample timing
Streptococcus pyogenes Staphylococcus aureus Escherichia coli
Salmonella spp.

34. Research funding for Sepsis is low

35. Sepsisincidensen högre med Sepsis-3?
• Via infektionsverktyget identifierades vuxna som ordinerades iv antibiotika I Skåne
och Halland under 4 datum 2015 (Jan, Apr, Juli, Okt).
• Journalerna granskades manuellt efter tecken till organskada 12h före o 12 efter
insättande av ab
• 2425/100,000 (95% CI 2167-2683) som behandlas årligen för infektion
med iv antibiotika.
• 687/100,000 (95% CI 549-824) med svår sepsis (Sepsis-2)
• 780/100,000 persons (95%CI 633-926) med Sepsis-3.
Fördel: alla specialiteter samt både samhällsförvärvad och nosokomiala.
Noggrann genomgång av varje patient.
Nackdel: Relativt liten studie, 4 datum utspridda över året
Mellhammar et al OFID Oct 2016

36. The qSOFA criterion
Vital signs Criteria
Two or more of:
Blood Pressure SBP ≤100 mm Hg
Respiratory Frequency RF ≥22
Mental Awareness GCS <15
Fulfilling 1 criteria = 1 point.
Parameters 0 qSOFA 1 qSOFA 2 qSOFA 3 qSOFA
Number % (n) 27.9 (77) 50.4 (139) 18.5 (51) 3.3 (9)
Outcome, % (n)
72h mortality 0 (0) 1.4 (2) 17.6 (9) 44.4 (4)
In hospital mortality 5.2 (4) 4.3 (6) 19.6 (10) 55.6 (5)
ICU-admission 1.3 (1) 4.3 (6) 11.8 (6) 22.2 (2)
Admission 62.3 (48) 71.2 (99) 94.1 (48) 100 (9)
Organ dysfunction*** 32.5 (25) 65.5 (91) 96.1 (49( 100 (9)
Multi organ dysfunction **** 10.4 (8) 29.5 (41) 76.5 (39) 100 (9)
Hospital stay, median (quartiles) 1.0 (0.3 , 5.6) 3.7 (0.3 , 7.0) 6.0 (4.0 , 11.0) 10.8 (6.1 , 14.1)
Outcome within Groups with different qSOFA points - Entire cohort
Korrelerar qSOFA med dålig prognos även
hos svenska akutpatienter?
• Ökat antal qSOFA poäng hos akutpatienter verkar
korrelera med sjukdomens allvarlighetsgrad

37. Akut CNS påverkan=hög dödlighet!
Parameters GCS <15 p-value* SBP ≤100 p-value* RF ≥ 22 p-value*
Number 33 26 86
Outcomes, % (n)
In hospital mortality 30.3 (10) 0,000 15.4 (4) 0.288 11.6 (10) 0.541
72 h mortality 24.2 (8) 0,000 11.5 (3) 0.194 7.0 (6) 0.714
ICU-admission 15.2 (5) 0.011 7.7 (2) 0.625 4.7 (4) 0.691
Hospital admission 90.9 (30) 0.113 96.2 (25) 0.033 86.0 (74) 0.074
Multi Organ Dyfunction** 84.8 (28) 0,000 73.1 (19) 0.001 51.2 (44) 0.015
Hospital stay, median
(quartiles) 6.0 (4.2 , 9.0) 0.226 7.1 (5.0 , 12.6) 0.018 6.0 (2.1 , 10.5) 0.064
Patients with infection diagnosed
Table 5. Outcomes when fulfilling different qSOFA-criterions
**1 of dysfunctions likely to be the fullfilled qSOFA-criterion in groups GCS <15 and SBP <100
* Statistic tests performed: Pearson Chi-Square for Hospital admission and Multi organ dysfunction. Fisher's exact test
for ICU-admission, In hospital mortality and 72h mortality. Mann-Whitney U Test for Hospital Stay.
Hadorn T10 arbete Lund 2016

38. Sepsis incidence is underestimated in registries
- Correct Sepsis diagnosis only in 20%!
Johansson et al Läkartidningen Sept 2015