SEPSIS – and the role of the autopsy

Sebastian Lucas

Dept of Cellular Pathology

GSTT

March 2019 national news

• “Sepsis kills over 52,000 every year – each death a preventable tragedy”

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tweeted Matt Hancock, UK Secretary of State for Health & Social Care

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ISSUE: is ‘sepsis’ being over-diagnosed?

Public opinion driven by uncommon cases of true preventable sepsis deaths

Sepsis hysteria: excess hype and unrealistic expectations

• Mervyn Singer et al at UCLH ITU; Lancet letter 26^th Oct 2019
• >75% of ‘sepsis’ deaths in those older than 75 years
• Frailty, co-morbidities more important
• Most in DNAR category

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• Osler’s ‘pneumonia as the friend of the aged’ – now reclassified as ‘sepsis’?

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• Most patients with infection and substantial organ dysfunction receiving full active management: - 70% survive
• [sepsis epidemiology complicated and hard data difficult to come by]

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Contents

• Case definition of sepsis
• Doctrinal issues
• Causes of sepsis and sepsis-like clinical syndromes
• Pathogenesis of SIRS
• Autopsy features
• The crucial role of histology

Dictionary definition

a serious condition resulting from the presence of harmful microorganisms in the blood or other tissues

and the body’s response to their presence, potentially leading to the malfunctioning of various organs, shock, and death.

What is sepsis? – old version��

• “a severe infection associated with organ dysfunction”

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• ie SIRS + infection

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• SYSTEMIC INFLAMMATORY RESPONSE SYNDROME (SIRS)
• Not liked by sepsis clinicians now
• But very useful in pathological discourse
• There are visible histological features

• Systemic Inflammatory Response Syndrome (SIRS)
• Temperature >38 deg C or <36 deg C
• Heart rate >90/min
• Respiratory rate >20/min or PaCO₂ <32mmHg
• Blood white cell count >12x10⁹/L or <4x10⁹/L, or >10% immature band forms.

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Practical problem

A majority of ill people in hospital would, by case definition, be considered as having sepsis.

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But they have not got overwhelming infections:

Group A Streptococcus

Staphylococcus bacteraemia

E.coli

Meningococcal infection

etc

3^rd International Consensus Definition for Sepsis and Septic Shock [SEPSIS-3] - 2016

SEPSIS:

“Life threatening organ dysfunction resulting from dysregulated host responses to infection”

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[intermediate stage of SEVERE SEPSIS now eliminated]

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SEPTIC SHOCK:

“a subset of SEPSIS in which underlying circulatory, cellular and metabolic abnormalities are profound enough to substantially increase the risk of mortality”

3^rd International Consensus Definition for Sepsis and Septic Shock [SEPSIS-3]. SOFA: Sequential Organ Failure Assessment score�

Recent case

• Male 70
• Long term care
• Diabetes type 2, hypertension
• Peritoneal dialysis

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• 4 months ago
• Private podiatrist trimmed foot
• ALLEGATION: cut too much skin; sepsis; considering legal action for negligence

• Proposed clinical MCCD by GP

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• 1a. Cellulitis of rt foot caused by Staph aureus – recent foot podiatry
• 1b. End stage renal disease and frailty
• 2. Hypertension, AF, diabetes

Autopsy

• Ht 169cm, Wt 56kg: BMI = 19
• Heart 440g = 0.78% TBWt; old infarction, coronary arteries <1mm
• Severe systemic atherosclerosis – aorta and main branches
• Emphysema
• No PD peritonitis/serositis
• Liver – early cirrhosis?
• Pancreas small
• Left kidney small, scarred; right kidney multicystic
• Bone osteoporotic
• Brain - ventricles dilated

The foot and leg in question

Cellulitis??

Active infection?

Femoral artery atheroma + thrombosis

• My draft MCCD:
• 1a. MOF
• 1b. Multisystem and peripheral atherosclerosis
• 2. frailty, diabetes, multi-cystic kidney

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• Histology:
• Foot ulcer + local viable skin = no active infection, no bacteria

So what can we morbid anatomists do?

• Be aware of OVER and UNDER-DIAGNOSIS of sepsis and septic shock

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• Think about risk factors for sepsis [next slide]

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• Complete autopsy – do not cut corners
• Especially if relatives threatening legal action and inadequate care

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• Histology set

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• Microbiology data – pre-mortem and post-mortem

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• THINK…………………………………

Risk factors for infection and sepsis

• Generic
• Host genetics – receptor polymorphisms
• Genetic immunosuppression (T/B cell)
• Extremes of age
• HIV, transplantation, cancer chemotherapy, diabetes, alcohol
• Cirrhosis of liver
• Hyposplenism

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• Primary blood stream
• Indwelling catheters
• Parenteral nutrition

• Chest infection
• COPD
• Intubation
• Surgery
• Aspiration

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• Urinary tract
• Catheter
• Immobility
• Female sex

Practical autopsy outcomes in clinical sepsis

Focal sepsis evident

• Lung
• Peritoneum & gut
• Kidneys
• Bladder
• Brain
• Heart valves

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• ISSUE: is this significant sepsis?

‘Negative’ autopsy

• Bacteraemia, fungaemia, viraemia, parasitaemia?

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• The many non-infective causes of SIRS

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• ISSUE: multi-organ failure ?cause

Typical Fatal Sepsis Case

Clinical

• Male 64, obese, hypertensive, diabetic
• D0: morning - felt cold and shaky
• GP diagnosis = gastroenteritis
• D0: evening, admitted after collapse
• Hospital diagnosis = septic shock
• All tests negative
• Cultures, PCR for meningococcus
• ITU care: antibiotics, life support
• D1: dead within 24 hours of admission

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Autopsy

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• Lungs congested
• Large heart – 780gm, LVH

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• Fatty liver – 3,450gm
• Spleen 300gm, soft
• Gut normal

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• Large vague red ?bruise inside left arm

GAS Toxic Shock Syndrome

Spleen: congested, and white pulp atrophy

Bone marrow – haemophagocytosis (HPC)

CD68

Steatosis, and HPC of Kupffer cells

CD68

Lung

Lung - DIC

Lung – CD54+ [ICAM-1] endothelial cells

Skin – subcutis necrosis and cocci++. �a form of ‘necrotising fasciitis’

gram

Case conclusion

Diagnosis

• Toxic shock syndrome
• The most severe form of ‘septic shock’

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• Group A Streptococcus pyogenes (GAS) infection
• gram+ve cocci in chains
• histological diagnosis

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Pathogenesis

• Minor skin injury

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• GAS transfer from nose to skin

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• ? Host susceptibility factors
• Defence capacity - genetic
• Obesity?
• Steatosis of liver

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Key features for SIRS

• Large soggy organs
• Spleen white pulp atrophy

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• Upregulated ICAM-1 on endothelia – LUNG
• Haemophagocytosis in MARROW & LIVER
• In spleen but more difficult to see

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• Critical role of IHC – CD68 macrophage marker; CD54 (ICAM-1)

‘Diffluent’ spleen – most are p-m autolysis

For diagnosis of SIRS, is the key feature haemophagocytosis?

yes

HPS in bone marrow

CD68

Haemophagocytosis (HPC)

• What is it?
• Case definitions
• Causation & pathogenesis
• Overlap with other clinical syndromes
• Diagnosis
• Autopsy pathology evaluation

CLINICAL

MORPHOLOGY

GENES

Pathologists’

knowledge

Are these labels the same thing?

• Haemophagocytic syndrome (HPS)
• Macrophage activation syndrome (MAS)
• Haemophagocytic lymphohistiocytosis syndrome (HLH)
• YES – they all mean the same entity

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• SIRS with septic shock
• Multi-organ dysfunction syndromes
• Associated with MAS/HPC

�Histiocyte Society�Revised classification of histiocytosis and neoplasms of the macrophage-dendritic cell lineages.�Blood 2016, vol 127�

• L (Langerhans cell histiocytosis)
• C (cutaneous and mucocutaneous non-LCH)
• R (Rosai-Dorfman disease and related histiocytosis)
• M (malignant histiocytosis)
• H (haemophagocytic lymphohistiocytosis and macrophage activation syndrome)

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• Also: relationship between LCH and Erdheim-Chester disease

Causes of HPS – simpler version

Inherited

• Gene defects

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• Perforin genes
• MUNC genes
• Syntaxin gene

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• Partial phenotypes

Secondary

• Infections – severe sepsis
• Cancers
• Autoimmune/autoinflammatory diseases

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• Vasculitis syndromes
• Chemotherapies
• Sickle cell disease

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• Infection (1108)
• a) Viruses (762)
• • Epstein-Barr virus (330)
• • HIV (173)
• • Herpes viruses (74)
• • Cytomegalovirus (69)
• • Viral hepatitis (20)
• • Influenza (14)
• • Human parvovirus B19 (14)
• • Other viruses or not specified (68)

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• b) Bacteria (206)
• • Mycobacterium tuberculosis (78)
• • Rickettsia spp (17)
• • Staphylococcus spp (15)
• • Escherichia coli (11)
• • Other bacteria or not specified (85)

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• c) Parasites (53)
• • Leishmania spp (17)
• • Plasmodium spp (14)
• • Toxoplasma spp(10)
• • Other parasites (12)

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• d) Fungi (37)
• • Histoplasma spp (18)
• • Other fungi (19)

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• e) Infection not specified (50)

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• Neoplasms (1047)
• a) Haematological (981)
• • T-cell or natural-killer lymphoma (369)
• • B-cell lymphoma (333)
• • Leukaemia (67)
• • Hodgkin’s lymphoma (61)
• • Not specified lymphoma (35)
• • Castleman’s disease (22)
• • Other haematological neoplasms or not specified (94)
• b) Solid (32)
• c) Not specified neoplasm (34)

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• Autoimmune diseases (276)
• a) Systemic (244)
• • Systemic lupus erythematosus (133)
• • Adult-onset Still’s disease (54)
• • Rheumatoid arthritis (18)
• • Vasculitis (11)
• • Other or not specified (28)
• b) Organ-specific (32)
• • Inflammatory bowel disease (11)
• • Other diseases (21)

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• Other circumstances or diseases (184)
• a) Transplantation (95)
• • Kidney (53)
• • Haematological (29)
• • Other (13)
• b) Other circumstances (76)
• • Drugs (20)
• • Surgery or biopsies (11)
• • Vaccination or acute injuries (10)
• • Diabetes or chronic liver disease (14)
• • Pregnancy (11)
• • Haemodialysis (10)
• c) Other or not specified (13)

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• Idiopathic or unknown (81)

2197 published HLH adult cases. Ramos-Casals et al, Lancet 2014, 383: 1503-16

Highlighted conditions

• Epstein-Barr virus infection
• T-cell lymphoma
• B-cell lymphoma
• Systemic lupus erythematosus

Other features of SIRS - and sepsis

ALI

DIC

Lungs�Acute lung injury (ALI)

• Shock lung
• Hyaline membrane disease
• Adult respiratory distress syndrome
• Acute respiratory distress syndrome (ARDS)

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• NB – all histopathological definitions
• Not diagnosable by naked eye alone

• Also

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• DIC

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• And upregulated endothelial cell ICAM-1 expression

ALI progression: mural inflammation, haemorrhage, epithelial necrosis, hyaline membranes

Two solid ‘shock lungs’: which one is ALI/HMD?

Two solid ‘shock lungs’: which one is ALI/HMD?

COVID-19 + hyaline membrane disease

HIV + pneumocystis

pneumonia

An aside on shock lung

Case: Clinical history

• Female 58 years.
• Died on 2^nd Oct 2022 in A&E Dept.

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• Past history
• Ex-alcoholic and ex-IVDU
• HCV+ve
• But virus now cleared
• Cirrhosis and varices documented

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Clinical history - 2

• Had returned from holiday

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• 3 day history of SOBOE
• Feeling unwell, ‘generally rubbish’
• Confused
• Off her food
• “I’m not going to hospital!”

• Just before 4am
• Went to toilet
• Husband heard a crash
• Got her back to bed

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• Where she arrested at 4am
• By-stander CPR
• Paramedics arrived 0415
• Gave adrenalin and secured airway
• “Blood came up+++”

Cont’d

• ROSC achieved 0446
• Ambulance to hospital
• No pulse on admission to ED.

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• ALS continued
• Multiple attempts to obtain femoral vessel blood – failed
• No imaging attempted
• No other tests performed
• 2 more cycles of CPR

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• Declared dead at 0612 same day – 2 hours post-collapse.

Autopsy commanded by coroner

• BMI = 19
• Mildly jaundiced
• Tongue bitten

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• No recent external injury

• No blood in mouth
• No blood or gastric contents in the airways

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• Lungs 810 & 760gm
• ‘congestion and oedema only, no consolidation’
• No pulmonary thromboembolism

Autopsy

• Heart 360gm
• LV 2cm thick, RV 0.4cm [normal]
• Heart/body weight ratio = 0.73%
• Normal <0.5%

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• No visible muscle lesions
• Valves normal
• Coronary arteries patent

• Liver 1100gm
• Non-fatty micronodular cirrhosis
• Oesophagus – varices
• No blood in intestines

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Summary

• Sudden unexpected death
• Middle aged female with significant chronic co-morbidities
• ‘Negative autopsy?’

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• Full histology and toxicology screen

• My expectations:

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• Acute heart failure – cardiomegaly ?cause
• OR
• Alcohol +/- illicit drug toxicity
• OR
• SUDEP following previous brain injury

Liver

• Micronodular cirrhosis
• Chronic inactive
• No hepatitis
• No alcoholic steatosis etc

Heart & brain

• Mild LV hypertrophy only
• No scars
• No ischaemic damage
• No myocarditis etc

• Old brain gliotic scarring
• No active pathology

Kidney

• Mesangial sclerosis
• Arteriosclerosis
• Hyaline arteriolar sclerosis

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• = hypertension probably
• +/- diabetes

Lungs

Background emphysema

The main autopsy pathology

• Acute lung injury
• Interstitial pneumonitis
• Hyaline membranes

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• No organising pneumonia
• No bacterial sepsis

• CAUSES OF ALI:
• Chemical injury
• Systemic sepsis
• Acute infection

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• COVID-19
• Influenza

Fatal influenza [H1N1] usually has necrotising bronchiolitis as well as ALI

Conclusion – Sars CoV2 simulating sepsis

• Pathology very typical of acute COVID-19 lung failure
• Clinical story compatible

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• No imaging in life
• No Sars CoV2 virology
• Nose – in life – @ home, GP, ED
• Nose - in mortuary
• Lungs – at autopsy
• Lung – IHC identification?

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• No one thought to do it

• Co-morbidity influence:
• Emphysema
• Cirrhosis?
• Alcohol +/- HCV
• Hypertension?

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• Such Covid-19 presentations and deaths will continue – presumably – indefinitely into the future

Back to the pathology of SIRS and sepsis

Lung CD54 (ICAM-1) -�upregulated by TNFa & HMGBP-1

Dr M.Tsokos (Germany)

‘Endothelial cell up-regulation

= septic shock’’?

Kidney: disseminated intravascular coagulation (DIC)

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• Most frequently seen in
• Meningococcal infection
• E.coli infection
• Strep pyogenes (group A)

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• Fibrin & PLTs

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• [Platelets alone = TTP]

Also: acute tubular injury/necrosis & myoglobin casts

What about non-infectious simulators of sepsis?

A major problem for ITU and acute medicine

Two similar cases – clinically “MOF/sepsis”, dying on ITUs

#1: F 24yrs

• Phillipino
• No medical history
• Unwell, abdo pain
• Progress to MOF
• Liver
• Lung
• Kidney
• All imaging negative
• All microbiology negative
• Died on D8 of admission
• AUTOPSY – ENLARGED NODES IN MEDIASTINUM only

#2: F 30yrs

• African
• Recurrent joint pains – hands and knees
• Skin rash
• Seronegative for RhF etc

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• Similar history to other case
• Died on D14 admission
• AUTOPSY- GROSSLY NEGATIVE

Bone marrow – similar in both

CD68

Case #1: Hilar node

#1: Hilar node

CD3

Diagnosis – #1

• MOF
• Cytokine storm
• Haemophagocytosis
• Not sepsis (pre & post mortem studies = negative)

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• T-cell lymphoma – occult mediastinal nodes, not mass lesion
• ?diagnosable in life?

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Diagnosis – #2

• Haemophagocytosis

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• No lymphoma
• Not sepsis (pre & post mortem studies = negative)

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• ?

• Adult-onset Still’s disease [seronegative]

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• Can trigger fatal cytokine storm
• Mimicking septic shock

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• Personal experience – AOSD is more common in autopsy practice than SLE

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Practical

• Determine whether SIRS was present – pre-mortem clinical & lab data:
• No-nos include:
• No haemophagocytosis
• No ICAM-1/CD54 upregulation on endothelia
• Normal blood CRP/ESR/LDH/ferritin

• Determine if SIRS is due to infection or not

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• If not, consider alternative diagnoses
• Occult tumours – TCL, HD
• Autoinflammatory syndromes

Blood and tissue sampling for infection – another presentation

Taxonomy gets complicated - Wikipedia

• “Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. They are characterized by periodic or chronic systemic inflammation usually without the involvement of adaptive immunity.
• Autoinflammatory diseases are a separate class from autoimmune diseases.
• Both are characterized by an immune system malfunction which may cause similar symptoms, such as rash, swelling, or, fatigue, but the cardinal cause or mechanism of the diseases are different. A key difference is a malfunction of the innate immune system in AIDs, while in autoimmune diseases there is a malfunction of the adaptive immune system.”
• But the clinical picture, gross and histopathology are similar

More simply

• SEPSIS associated with infection
• More happening than just the diseased organ – all those systemic cytokine effects on cell function
• eg death from simple uni-lobar pneumonia = systemic sepsis [one can survive on 4 lobes of lung]
• Bacteraemic shock = systemic sepsis
• Malaria = systemic sepsis
• Meningococcal meningitis per is not necessarily sepsis, but meningococcaemia deaths are
• Consider co-morbidities as the main cause of death (eg case 1, atherosclerosis)

Meningococcal skin rash

Vasculitis with visible

blue bacterial cocci in

circulating monocytes

Skin – Brown-Hopps gram stain

Questions?