Roshan Lall Gupta’s Recent Advances in Surgery (Volume 17) Puneet
Page numbers followed by b refer to box, f refer to figure, fc refer to flowchart, and t refer to table.
Abdominal sepsis 147, 149
antimicrobial therapy for 149t
guidelines for empirical antibiotics therapy in 148
principles of management of 147
Abdominal surgery, antibiotics 137
Acardiac, cases of 40
Acinetobacter 142
Acland's test 222
Acral lentiginous melanoma 160f
Acute respiratory distress syndrome 275
Adenocarcinoma 77
Adsorbents 56
Ageusia 276
American College of Surgeons Oncology Group 174
American Joint Committee on Cancer 164, 166t, 232
American Medical System 64
American Society of Clinical Oncology 79
American Society of Gastrointestinal Endoscopy 123t
American Thyroid Association 256
Amitriptyline 56
Amniocentesis 39
Amniotic bands division 40
Amniotic cavity 45f
Amniotic fluid, complications of 46
Ampulla of Vater 118
stenosis 119
tumor 119
Amputated hand, replantation of 227f
Anal canal sensation 49
Anal manometry 55
Anal plug 57
Anal repair (post), result of 63t
Anal sphincter 66f
anatomy of 49f
artificial 64, 65t
complex, anatomy of 48
external 48
internal 48
Anastomosis 220
failure of 222
Angiogenesis inhibitors 73
Anidulafungin 149
Anomalous pancreatobiliary
junction 120
maljunction 119
Anorectal manometry 53
Anorectal surgery 50
Anosmia 276
broad spectrum 279
de-escalation of 6
resistance, emergence of 6
Anticoagulation agents 224
Antidiarrheals 56
Antimicrobial prophylaxis 140t
duration of 139
practice of 138
Antimicrobial therapy 148
duration of 149
Antireflux mucosectomy 112
Antityrosine kinase 82
Antrum, posterior wall of 16f
Aortic stenosis 39
Apatinib 73
Appendicitis, acute 139, 143 145
antibiotics for 143
antimicrobial prophylaxis for 145t
Appetite, loss of 14
Areolar, bilateral 269
Artificial intelligence, advent of 113
Aspire Assist System 112
Atraumatic technique 222
Atropine 56
Autofluorescence imaging 92
Autoimmune phenomenon 277
Avibactam 148
adenopathy 233
bilateral 269
Axillobilateral breast
approach 268
bilateral 268
Azoles 149
Bacterial infection
diagnosis of 5
differentiation of 5
Bacteroides 153
fragilis 143, 152
species accounts 148
Balanitis, chronic 194
Balloon dilatation 39
Barrett's esophagus 93
Basaloid carcinoma 199
biliary stricture 119, 130
follicular cells 262
phyllodes tumor 246
Beta coronaviruses 274
Bethesda system 261t
Bethesda System for Reporting Thyroid Cytopathology 258
Bevacizumab 73, 80, 83, 86
Bile duct dilatation 124f
causes of 129
Bile duct
polyp 120
radiological evaluation of 119
Bile salt binders 56
Biliary dilatation, causes of 120t, 125f
Biliary obstruction 129
Biliary procedures 141
antibiotics for 139
Biliary strictures 128
Biliary system 118
Biliary tract
cancer 86
imaging, recent advances in 130
procedures, antimicrobial prophylaxis for 142t
Biliary, type 120
Biofeedback training 56
Biomarkers 2
associated with phyllodes 249
newer 8
role of 132, 210
Biopsy 164
histopathologic examination 200
Tru-Cut 256
types of 165t
excisional biopsy 165
punch biopsy 165
shave biopsy 165
virtual 94
Bleomycin 210
Blood monocyte expression, circulating 10
Blumer's shelf 14
Body mass index 232
Bowel anastomosis 267
Bowel management 56
Bowel preparation 59
mechanical 150
Bowel sphincter, artificial 64f, 65t
Bowen's disease 195
Brachytherapy 107
Breast approaches 268
Breast cancer, inflammatory 232, 235, 238
clinical signs of 233f
differential diagnosis 237
genetics in 236
imaging 233
locoregional treatment for 238
pathology 235
prognosis 240
significance in 237
symptoms and signs 233
treatment 237
Breast cancer, surgery 288
Breast cancer syndromes 236
Breast erythema 232
Breast lesion 234f
Breast reconstruction 226f
Breslow's thickness 172
Bursectomy, role of 20
Buschke-Löwenstein tumor 195
Cabozantinib 211
Calcific pancreatitis, chronic 119
Calcitonin gene-related peptide 1 4
Candida glabrata 149
Capecitabine 78
Carbapenems 147
Carboplatin 238
Carcinogenesis, role in 74f
Carcinoma in situ 194, 203
Carcinosarcomas 244
Caspofungin 149
Cediranib 73
Cefazoline 138, 145
Ceftazidime 148
Ceftolozane 148
Ceftriaxone 138
Celiac disease 93
Celiac plexus neurolysis 100
Cell death-ligand 1 77
Cell free DNA 8
Cell membrane 74f
Cell pathways 70
Cell proliferation, signaling pathways 74f
Cell-mediated 4
Centers for Disease Control and Prevention 137
Cervical lymphadenopathy 258f
Cetuximab 7981, 86
Charged couple devices 92
Chemolabeled 71
Chemotherapy 69, 207
for advanced disease 210
Chimeric monoclonal antibody 70
Cholangiocarcinoma 119, 120
advanced 86
Cholangiography, intraoperative 125
Cholangiopancreatoscopy 131
Cholangioscopy 96
Cholecystitis 104
acute 141, 143, 143t
antibiotics for 141
mild acute 143
severe 143
Choledochal cyst 119, 120, 127, 128f
Choledochoduodenostomy 101103
Choledocholithiasis 122
presence of 123t
risk for 123
Chorion villus sampling 39
Chromoendoscopy, virtual 93
Cigarette smoking 193
Circumcision, role of 203
Cisplatin 210
Clindamycin 145
Clonorchis sinensis infection 119
Clostridium difficile infection 139
Clostridium species 141
Coagulase negative Staphylococci 137
Coagulation 223
Codeine 56
Coil and glue, combination of 106
Colonic mucus lining 151
Colonic transit time 49
Colorectal bowel malignancy 79
Colorectal cancer 79
advanced 80t
surgery 289
Colorectal, lateral spreading tumors 110
Colorectal surgery 150
antibiotic prophylaxis for 151
antibiotic therapy in 150
emergency antibiotics for 152
evolution of 150
Common bile duct 101, 103, 118, 120f, 124f
dilatation 122, 126, 128, 130
Community Health Centers 277
Continuous sutures 221
Contrast-enhanced computed tomography 256
Contrast-enhanced endoscopic ultrasound 99
Convoluted neural network 113
Cordocentesis 39
Corpora cavernosa 206f
Corticotrophin 82
Coupling devices 228
COVID-19 273289
adverse effects of 275
and surgical practice 281
changes to surgical systems 281
clinical manifestations of 276
control of infections 285
diagnosis 278
endoscopy 285
Indian guidelines 277
infection 283
laparoscopy 285
medical management of 278, 280
mitigating postoperative risks 286
on surgical education, training, and research 287
outpatient clinics and telemedicine 282
pandemic 281, 282f
prioritizing patients 282
procedural considerations in surgery 283
recovery of surgical services 287
reducing preoperative risks 283
risk of transmission 284
surgical practice in 273
surgical specialty guidelines 288
suspects 278
syndrome 277
tackling specific operative risk issues 285
treatment of 279
Cowden syndrome 257
C-reactive protein 3
Cutaneous melanoma, management of 176
Cystic adenomatoid malformation, congenital 44
Cytology 256, 261
Cytoreductive surgery 25
Cytotoxic chemotherapy 80, 177
Dacron-impregnated silastic sling 58
Damage-Associated Molecular Patterns 7
Deep inferior epigastric artery perforator flap 226f
Deep learning 113
Deep neural network 113
Defecography 54, 55
Dermal lymphatic
emboli, presence of 232
tumor emboli 236f
Dermal tumor emboli 233
Desmoplastic melanoma 161
Dexamethasone 279
Diaphragmatic hernia, congenital 34, 40, 43
Diarrhea-inducing foods 55
Diarrheal states 50
Diffuse pulmonary intravascular coagulopathy 275
Digital image analysis 132
Dilated bile duct, evaluation of 131
Diphenoxylate hydrochloride 56
Disseminated infection 3
Distal body 20
Distal fingertip replantations 225
Distal gastrectomy, open 26
Distal margin 24
Distal tumors 20
Distant metastases 198, 245
assessment for 200
Diverticulitis 139
DNA proliferation, digital image analysis 132
DNA repair mechanisms 86
Docetaxel 210
Dopamine 82
Doppler flow patterns 222
Ductal system 101
Duodenal 25
Duodenal bypass 28
Duodenal mucosal resurfacing 113
Duodenal obstruction 102f
Echinocandins 149
Edema 232
EGFR (HER-1), targeting 73
Elasticity index 260
Elastography 259
Electromyography 54
Electronic chromoendoscopy techniques 92
Electronic cylindrical phased array 132
Embolectomy 223
Emergency medical relief 277
Endoanal ultrasonography 53f
Endocrine neoplasia, multiple 257
Endocytoscopy 94
Endoplasmic reticulum processing 275f
Endorectal ultrasonography 52
Endoscopic bariatric, advances in 112
Endoscopic equipment 268
Endoscopic findings, correlation of 93
Endoscopic full thickness resection 111
Endoscopic imaging, advances in 92
Endoscopic mucosal resection 16, 112
Endoscopic myotomy
conventional 109
per oral 107109, 109f
per rectal 108
Endoscopic resection 16
Endoscopic retrograde cholangiopancreatography 95, 103, 121
advances in 95
guided photodynamic therapy 96
guided radiofrequency ablation 96
Endoscopic sleeve gastroplasty 113
Endoscopic submucosal dissection 16, 17, 110, 112
Endoscopic surgical approach to LND 209
Endoscopic tunneling, per oral 108
Endoscopic ultrasound 123
choledochoduodenostomy 102f
diagnostic, advances in 97
elastography 98f
elastography 98t
guided 107f
biliary drainage 100, 101
Endoscopic ultrasound-guided
biliary drainage, techniques of 103t
cancer therapy 106
elastography 97
gallbladder drainage 104
gastrojejunostomy 105
pancreatic duct drainage 104, 104f
tissue acquisition, advances in 99
vascular interventions 105
Endoscopic ultrasound, hepaticogastrostomy 101f
high-resolution, 93
magnification 92
recent advances in 92
role of 92
spectrum of “third-space” 107, 108fc
Endothelial proliferation 73
Enterobacter 142, 148
Enterobacteriaceae 148, 152
Enterococci 137, 140, 141
Enterococcus 143, 145
Enzyme-linked immunosorbent assay 9
Epidermal growth factor receptor 73, 74f, 236
Epidermis 159
Epithelial and stromal components 248
Epithelium, excision of 205
Equipment and accessories 108
Ergonomics 285
Erlotinib 81, 86
Erythrocyte sedimentation rate 3
Erythroplasia of queyrat 195
Escherichia coli 140
Esophageal cancer 76, 110
management of 77
Esophageal malignancy 76
Esophagus, restoration of 108
European Association of Urology 199, 201
Everolimus 83
Ex utero intrapartum treatment 36, 39, 41, 41t, 42
Extended resections, role of 25
Extracellular domains 83
Extracellular-signal-regulated kinases 75
Extrahepatic bile duct 121f
Extrahepatic ducts 118
Extrahepatic portal vein obstruction 119
Eye strain 218
Fecal incontinence 50
classification of 51
common causes of 50
diagnosis 51
etiopathogenesis 48
evaluation 51
investigation 55
management of 48
surgical treatment for 59
treatment 55
Fetal bleeding 43
Fetal, endoscopic surgery 39
Fetal, image-guided surgery 39, 39t
Fetal intervention
indication of 44
techniques of 38
Fetal skin biopsy 39
Fetal surgery 34
applications of 43
approach for 38f
challenges in 43
complication 43
components of 34
contraindications 38
diagnosis 35
history of 35t
indications 38
multidisciplinary approach in 37
open 39, 41, 42t, 43
potential of 43
types of 39
Fetal therapy, evolution of 34
Fetoendoscopic surgery 40t
Fetoscopic endoluminal tracheal occlusion 40f
Fibroadenomas 247
Fine needle aspiration cytology 146, 172, 200, 261, 265
Flexible spectral imaging color enhancement 92
Fluorescein angiography 222
Fluorescence in situ hybridization 132
Fluorescent intensity 267
Fluorodeoxyglucose 16
FNB needles, different kinds of 99f
Follicular lesion of 265
Follicular neoplasm 262
Food and Drug Administration 77
Food intolerance, source of 55
Free latissimus dorsi muscle flap 227f
Free radial forearm flap 225f
Free survival
progression 80, 82, 85
recurrence 84, 85
Free-hand technique 106f
Functional utility 186
Fusobacterium 153
Gallbladder cancer 86, 119, 120
proximal 19, 28
subtotal 19
total 19
Gastric cancer 13, 77, 110
advanced 17
clinical presentation 13
complications of 27
diagnosis and staging 14
early 16
endoscopic resection 17
histological classification of 13
management of 16, 27
neoadjuvant chemotherapy 23
perforation 28
postgastrectomy care 28
role of surgery 27
surgery for 13, 20
trastuzumab for 78
Gastric metaplasia 93
Gastric outlet obstruction 28
causing 15f
Gastric per oral endoscopic myotomy 108
Gastric plication and suturing 112
Gastric variceal coiling 107f
Gastric varices 105
endoscopic vision of 107f
Gastric wall thickening 15
Gastroenterology surgery, practice of 92
Gastroesophageal junction 14, 77
Gastroesophageal reflux disease 111
advances in management of 111
bleed, advances in management of 111
carcinoid tumors 82
stromal tumor 83, 85t, 99
surgery, practice of 92
Gastrojejunostomy 28
Gefitinib 81
Gene therapy 107
Genetic engineering 46
Genital warts 194
Genital warts, history of 194
Gentamicin 145
Giant condylomata acuminata 195
Glasgow Coma Scale 2
Glasgow revised seven point checklist 163
Glucose transporter-1 16
Gluteus maximus muscle 64
Glycosaminoglycans 7
Graciloplasty therapy study group, dynamic 63
Graciloplasty, dynamic 61, 63t
Gram-negative rods 137
Gram-positive bacteria 145
Granulocyte macrophage colony stimulating factor 175
Growth factor receptors 72
Growth factors, targeting 73
Haemobilia 120
Hand foot disease 82
Healing, mechanism of 219
Heat shock protein 7
Hedgehog pathway 86
Helicobacter pylori infection 93
Hemostasis 264
Heparin 224
Hepatic cyst 119
Hepaticogastrostomy 101, 103
Hepatitis B virus 72
Hepatitis C virus 81
Hepatobiliary ascariasis 119
Hepatocellular carcinoma 81, 106
advanced 82t
development of 72
Hepatocyte growth factor receptor 74f
HER-2, targeting 73
Heterogeneity of internal echo 131
blue 98
green 98
red and green 98
Heterozygosity, loss of 236
High-mobility group B1 7
Hilar block vs distal obstruction 129
Hilar cholangiocarcinoma 120
Hirschsprung's disease 50, 109
Histamine 82
Hodgkin's disease 257
blue 98
green 98
Hormonal evaluation 257
Hormone receptor 236
Hormone receptor expression 249
Host cell cytoplasm 275f
Human body's response 2
Human epidermal growth factor receptor 74f, 78
Human monoclonal antibody 70
Human papillomavirus infection 194
Humanized monoclonal antibody 70
Hydroxychloroquine 279
Hyperbaric oxygen therapy 224
Hyperthermic intraperitoneal chemotherapy 25
Hyperthermic isolated limb perfusion 174, 175t
Hyperthyroidism, etiologies of 263f
nadir of 266
predictors of 266
Hypothesis 151
Iatrogenic 59
Ifosfamide 210
Illness (acute), cause of 1
Immune checkpoint inhibitors 211
Immunotherapy 211
Immunotoxins 71
Incidental biliary dilatation, causes for 118, 119b
Indocyanine green 267
Infected pancreatic necrosis, therapeutic antibiotics for 146
Infectious diarrhea 50
Infectious Diseases Society of America 6
Inflammation 3
marker of 4
Inflammatory bowel disease 50
Inflammatory cytokines 237
Inflammatory process 9
Inguinal lymph node 199
dissection 208
Inguinal metastases 198
Inguinal nodes 204t
clinical staging 199
Injectable biomaterials 58
Injury, accidental 50
Intensive care units 182
Interleukin-27 8, 9
Interleukin-6 3
International Consensus Definitions for Sepsis and Septic Shock 147
International Fetal Medicine and Surgery Society 34
International Union for Cancer Control 232
Intestinal ischemia 152
occlusive type of 152
Intracellular domains 73
Intraductal cholangioscopy 131
Intraductal echogenic focus 125f
Intraductal papillary mucinous tumor 120
Intraductal stones 97f
Intragastric balloons 112
Intrahepatic biliary dilatation 128f
Intralesional therapies 175
Intrauterine procedures 38
Invasive penile carcinoma 194
Ipilimumab 211
Irish node 14
Isolated bile duct 118
Isolated limb infusion 175
Isotope scan 263
Jaundice, symptoms of
Jejunal loops, dilated 106f
Juxtamembrane domain 83
Juxtapapillary diverticulum 119
Kinase domains 83
Kinases 72
Klebsiella 148
pneumoniae 152
species 140142
Korean Laparoscopic Study Group 26
Krukenberg tumor 14
appendectomy 144
cholecystectomy 139, 140t
surgery 26
Laryngeal nerve
monitoring 267
recurrent, incidence of 264
Laser-assisted anastomosis 228
Laser coagulation of vessels 40
Laser Doppler flowmetry 267
Laser endomicroscopy, confocal 92, 94, 132
in evaluation of dilated bile duct 132
Laser endomicroscopy, needle-based confocal 100
Lauren classification, features of 14t
Lentigo maligna melanoma 160f
Lethal malignancy 212
Levatorplasty, anterior 62f
repair with 60
Lichen sclerosus 195f
Li-Fraumeni syndrome 244
Lobectomy 42
Local tumor staging 1
Locoregional radiation therapy 239
Low-molecular-weight heparin 224, 279
Lumen-apposing metal stents 100
Lung malformation 42
congenital 36
Lymph nodal dissection, extent of 21
Lymph node
disease 168
dissection 21f, 168, 200
enlarged 257
management of 172
metastasis, left axillary 170f
Lymphatic metastasis 166, 167
Lymphatic surgery 225
Lymphedema, management of 228
Lymphoma 120
Lymphovascular invasion, presence of 205
Macroscopic disease 173
Magnetic anal sphincter 65
Magnetic resonance cholangiopancreatography 121, 124f, 128f
Magnetic resonance imaging 37, 52
advantages of 37
risks of 37
Malignancy 86
Malignant lymphoma 119
Malignant melanoma 159
surgical management 169
surveillance after treatment 178
Malignant phyllodes 249
Mammograms, bilateral 234f
Matrix metalloproteins 75
Mean arterial pressure 2
Medigus ultrasonic surgical endostapler 112
Mega rectum 50
Megaloblastic anemia 28
Melanoma 159
ABCDE of 162f
advanced 176
amelanotic 161
clinical diagnosis 161
clinical progression of 159
difficult 163
excision specimen of 171f
in children 163
locoregional therapies in 174
management of 176fc, 169
pigment synthesizing (animal-type) 161
prognostic factors and staging 164
progression of 159f
subtypes of 160
acral lentiginous melanoma 161
lentigo maligna melanoma 161
nodular melanoma 160
superficial spreading 160
thickness 173
tumor-node-metastasis staging of 166t
various thicknesses of 172t
Meningomyelocele 42
surgery for 46f
Metabolic therapies, advances in 112
Metal stents 28
Metastases 120
Metastatic penile cancer (T4, N2-3, M1) 209
Metastatic phyllodes 251
Methotrexate 210
Methylcellulose 55
Methylprednisolone 279
Metronidazole 145, 148
Microcalcification 258, 259f
extensive 233
Microlithiasis 119
Microsatellite instability 77
Microsurgery 220, 223
contraindication of 223
failure of 223
field of 228
limitation for 225
masters of 218
refinement of 217
clamps 219f
procedure 222
surgery 217, 223
applications of 225
Minimally invasive fetal endo-surgery 40
Minimally invasive surgery 26
Minimally symptomatic biliary dilatation 129
Minimum inhibitory concentration 138
Ministry of Health and Family Welfare 277
Mirizzi's syndrome 120
Mitochondrial DNA 7
Mitogen activated protein kinase 73, 74f
Mitotic stromal, activity 247, 250
Mixed carcinoma 199
Mohs micrographic surgery 205
genetics 262
signatures 81
targets in cell pathway 74f
tests, types of 263
therapy 69
development of 86
Momab 70
Monoclonal antibodies 70, 71, 71f
mouse 70
production of 71f
Mucinous cystic neoplasm 119
Mucosa 226f
Mucosal incision 108
Multidrug resistance, development of 6
Multikinase inhibitors 83
Multisystem inflammatory syndrome 277
Multivisceral resections 25
Murine Int-1 gene 248
Muscle plasty, dynamic 63
Muscle transfer procedures 58
Myeloid cells-1 8, 10
Myotomy 108, 109f
N95 respirators 283
Narrow-band imaging 92, 93
Nasojejunal tube 28
National Cancer Registry Programme 13
National Comprehensive Cancer Network 23, 199, 201, 251
guidelines 173t
National Healthcare Safety Network 144
National Institute for Health Research 287
National Institute of Care and Excellence 138
Neural network, artificial 113
Neuroendocrine cells 82
Neuroendocrine tumor 119
Neurogenic integrity 49
Neurological conditions 50
Neurotensin 82
Neutralizing antibodies 73
Nipple retraction 245
Nitric oxide synthase 74f
Nivolumab 211
Nodular melanoma 160f, 164, 171f
Nonpalpable ILNs, surgical treatment of 207
Nucleocapsid protein 275f
rehabilitation 28
supplements 28
Obstetric trauma 50, 59
Obstetrical injury 50
Obstruction, level of 129
Obstructive pulmonary disease, chronic 279
Olaparib 86
Omentectomy, total 20
for early tumors 20
derivatives 56
tincture of 56
Optical biopsy 93, 94
concept of 92
Optical coherence tomography 94
Oral malignancy reconstruction 225f
Orbera Intragastric Balloon System 112
Oslen's theory 170
Ovarian masses 14
Overall survival 85
p53, expression of 249
p53 germline mutation 244
Paclitaxel 210
Paget's disease of penis 195
Palliative hemostatic radiotherapy 27
Palpable ILNs, surgical treatment of 208
Pancreas 104
head of 15f
Pancreatic cancer 84, 102f, 119, 120
familial 86
prognosis of 84
Pancreatic cyst 119
Pancreatic infiltration 25
Pancreatic necrosis 146
Pancreatic pseudocyst 120
Pancreatic rendezvous 104
Pancreaticobiliary malignancy 119
Pancreaticoduodenectomy 24, 25
acute 120, 144, 145
pathogenesis of infection in 145
chronic 119, 120
recurrent 128f
Pancreatoscopy 96
Panitumumab 79, 80, 81, 86
Papilla, accessibility of 101
Papillary carcinoma 199
Papillary stenosis 119, 120
Papillary surface 131
Parasites 120
Parathyroid detection 266
Parathyroid gland 266
in situ 267
intraoperative detection of 266
Parathyroid hormone 266
Parathyroidectomy, subtotal 267
Parenchymal edema 233
Parenchymal thickening 235f
Partial penectomy 206f
Peau d'orange 232, 233
Pelvic floor denervation 50
Pelvic INS, surgical treatment of 209
Pelvic lymph nodes 197, 198
Penile cancer 192, 195f197f, 207, 212, 213t
diagnosis of 198, 201t
epidemiology 192
etiopathology of 193
higher risk of 194
histological, subtypes of 199t
in situ, surgical treatment of 203
majority of 198
management of 192
palliation in advanced 212
risk factors 193
spread of 197
staging in 201t
Penile intraepithelial neoplasia 195
Penile stump 206
Penile trauma, chronic 194
Penis 194
Penoscrotal junction 206, 206f
Peptide receptor nucleotide therapy 83
Percutaneous transhepatic
cholangiography 121
drainage 100, 103
Periampullary cancer 120
Periampullary diverticulum 120, 126
sensation 52
examination 51
Peritoneal carcinomatosis 25
primary 149
secondary 149
tertiary 149
Personal protective equipment 283f
Pertuzumab 238
Phimosis 193
Phosphoinositide 3-kinase 74f
Phospholipase C 74f
Photodynamic therapy 96
Phyllodes 249
biology of 248
borderline 250
molecular classification of 249
tumor 250
borderline 247
breast of 244
chemotherapy 251
clinical presentation 245
diagnosis 245
epidemiology 244
grading of 246
histological grading of 247t
histopathology 246
hormone therapy 251
malignant 248
mammography 246
management 249
MRI of breast 246
radiology 246
radiotherapy 251
recurrence of 244, 245f
Plasma-bound ICG molecules 267
Plasma cell neoplasm 119
Platelet derived growth factor receptor 74f
Plate-reinforced suture 112
Pleural shunts 39
Polyadenosine diphosphate 86
Polydioxanone 59
Polyposis coli, familial 257
Polytetrafluoroethylene 112
Portal biliopathy 119
Portal vein 106
Positron emission test 235
Positron emission tomography 170f, 200
Postanal repair 61
Premalignant lesions 194
Premature rupture of membrane 41
Prenatal surgery 34, 38
Presepsin 8
Procalcitonin 4, 5
guidance study 6
in postoperative period 7
in renal failure 8
levels 8
interpretation of 5t
utility of 5
Prognostication 8
Programmed cell-death ligand-1 10
Proinflammatory cytokines, upregulation of 276
Prophylactic antibiotic
general principles 137
role of 145
Prophylactic measure 26
kinase B 73, 74f
main structural 275f
Proteus 148
Proteus mirabilis 152
Proton-pump inhibitor 27, 112
Pseudoepitheliomatous 195
Pseudointima 219
Pseudomembranous colitis 139
Pseudomonas 142
Psoralen plus ultraviolet therapy 161
Psychological motivation 49
Psyllium products 55
Public Health England, guidance 283f
Puborectalis muscle 48, 49
testing 52
Pudendal nerve terminal motor latency 54
Pulmonary airway malformation, congenital 44
Pulmonary epithelial cells 274, 275f
Pulmonary fibrosis 277
Pylorus 20
Qualitative assessment 98
Quinolones 147
Radial and linear scanning 132
Radial sector scan system, mechanical 132
Radiation 207
therapy 176, 177, 239
Radiation Therapy Oncology Group 84
Radical gastrectomy, principles of 18
Radioactive iodine 265
Radiofrequency ablation 39f, 71, 96
Radiolabeled 71
Radiotherapy 69
for advanced penile cancer 211
Ramucirumab 73
Rapamycin, mechanistic target of 74f
Rapidly accelerated fibrosarcoma 73, 74f
Rat sarcoma 74f
signals of 73
Reactive-oxygen species 96
examination 14
prolapse 50
sensory testing 54
Regional lymph node 179
surgical management of 207
Rendezvous 101, 103
Reservoir bags, high flow nasal cannula 279
Respiratory illnesses 274
Respiratory infections, antibiotic therapy in 7
Reverse transcriptase polymerase chain reaction 278
Rhinolophus affinis 274
Ribose polymerase inhibitor 86
Rituximab 70
RNA-binding proteins 84
RNA, single strand 275f
Robot-assisted thyroidectomy 268, 269
Robot face lift thyroidectomy 269
Robotic-assisted endoscopes 113
Robotic gastrectomy 27
Robotic surgery, surgeon console in 269f
Roux-en-Y reconstruction 19
Royal Surgical Colleges 284
Sacral nerve stimulation system 57, 58f
Sacrococcygeal teratoma 39, 39f, 42
Saga of development
advancing frontiers 217
giant leap in surgery 217
microsurgery everywhere 218
preparation 217
small stitch on tissue 217
Sarcomatoid carcinoma 199
infection 277
life cycle 275f
polyproteins 275f
Scanning electron microscopes 103
Sclerosing cholangitis, primary 119
SECCA procedure 65
Sentinel lymph node 177
biopsy 169, 173t
Sentinel node biopsy, dynamic 201, 207
technique of 207
Sepsis 3
biomarkers of 1
diagnosis of 5
Sequential organ failure, assessment score 2t, 147
Serotonin 82
Serum lactate dehydrogenase 167, 169
Severe acute respiratory syndrome coronavirus-2 273, 274
Shear-wave 260
elastography 259, 260
speed 260
Short gut syndrome 50
Sister Mary Joseph node 14
Skeletal muscle flaps 58
Skin flaps 267
Skin grafting 227f
Small bowel adenocarcinoma 81
Small bowel malignancy 79
Small intestinal malignancy 81
Small molecule inhibitors 72
Somatic mutations of KRAS 86
Sorafenib 73, 83
Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol trial 82
Sphincter, normal and damaged 49f
Sphincter of Oddi 118
dysfunction 127, 129
resulting in dilatation 122
Sphincter repair 58, 59
direct, result of 60t
Sphincteroplasty 58
overlapping 60, 60t, 62f
Spina bifida 45
Spindle cell metaplastic carcinomas 244
Spitzoid melanoma 161
Splenectomy 23
Squamous cell carcinoma 76, 192, 198, 199
pathogenesis of 194
Staphylococcus aureus 137
Staphylococcus spp. 143
Steatohepatitis, nonalcoholic 81
Steatorrhea 28
Stent placement, antegrade 103
Stone 120, 125f
Stool consistency 49
Strain elastography 259, 260f
Streptococcal species 137
Streptococci 143
Stromal atypia 247
Stromal cellularity 246, 247
Stromal overgrowth 247
Subepithelial connective tissue 205
bleb, formation of 108
endoscopy 107
injection 109f
tunneling 109
and myotomy 109
endoscopic resection 108
Subungual melanomas 164
Succinate dehydrogenase mutations 83
Sunitinib 73, 83
Supermicrosurgery 228
Surgical antimicrobial prophylaxis 137
Surgical margins, adequacy of 23
Surgical metastasectomy 176
Surgical Patient Safety System 184
Surgical preoperative pathway 284f
Surgical safety checklist 182, 185f
communication 185
compliance of 188
contents of 183
disadvantages of 188
history of 183
implementation 188
need for 182
teamwork enhancement 186
validity of 189
Surgical site infection 137
Surviving Sepsis Campaign 6
guidelines 148
Sutures, number of 220
Systemic inflammatory response syndrome 1, 1b
T2-T4 disease, surgical treatment of 206
Talimogene laherparepvec 175
Targeted agents 76, 177, 211
challenges 76
classes of 70
hepatocyte growth factor 75
in gastrointestinal malignancy 69
matrix metalloproteins 75
PI3K-Akt-mTOR pathway 75
targeting gene fusion 75
Taxane 238
Tazobactam 148
Therapeutic endoscopic ultrasound, advances in 100
Thiersch procedure 58
Thyroid cytopathology 261t
Thyroid imaging, reporting, and data system 256, 258
Thyroid malignant, mass of 257f
Thyroid nodule 259t
autonomous functioning 263f, 265
clinical examination 256
imaging 257
management of 256, 265fc
surgical management of 264
Thyroid ST 265
Thyroid stimulating hormone 256
Thyroidectomy technique produces 268
assessment 258
system 259t
Tissue injury 3
Tissue sampling techniques, advances in 132
TNM staging system 202
chewing 193
consumption 193
Toxic multinodular goiter 265
Trachea, balloon occlusion of 40
Tracheal stenosis 42f
Transabdominal ultrasonography 119
Transanal ultrasound 55
Transarterial chemoembolization 82
Transient, incidence of 266
Transluminal drainage 104
Transoral incisionless fundoplication 112
Transplant surgery 289
Trastuzumab 70, 238
Trauma surgery 289
Tricyclic antidepressant 56
Tropomyosin receptor kinase 75
bleeding 27
invades corpus cavernosum 202
necrosis factor alpha 4, 276
node metastasis 202
of papilla of vater 119
proximal margin for 23
superficial 159
surgery by site of 19
acardiac 40
anomalous 39
cord cauterization in 39
Twin-to-twin transfusion syndrome 40
Tyrosine kinase inhibitors 81
Tyrosine kinase pathway, targeting 84
Ugly duckling sign 163
advances, utility of 36
development in 36
limitation of 37
Umbilical nodule 14
dissection 206f
flap glanuloplasty 206f
stump 206f
valves, posterior 44
Urinary bladder 45f
Urinary tract obstructions, lower 44
Urological malignancies 198
Vaccines 72
Vaginal delivery 50
Vaginal introitus 61
Vascular endothelial growth factor receptor 17, 73
Vascular surgery 289
Vasculoendothelial growth factor receptor 74f
Vasopressin 9
Vasospasm 222
Vater's papilla 129
Venous thromboembolism 224
Ventral phalloplasty 206
Ventral urethral spatulation 206f
Verrucous carcinoma 199
Vesicoamniotic shunt 45f
Vessel repair, triangulation technique of 221f
Vessels, milking of 222
Video capsule endoscopy 95, 95f
Vinci Xi Surgical System 27
Viral entry 274, 275f
Viral genome 275f
Viral genomic RNA 275f
produced 275f
Viral infections, differentiation of 5
Viral transport media 278
Virchow node 14
Visual examination 162
Vitamin D supplementation 266
Vocal cord paralysis 257
Warm breast 232
Warty-basaloid carcinoma 199
Warty carcinoma 199
Weight loss 82
White blood cell 3
Wieberdink toxicity grading system 174t
Wnt gene 248
World Health Organization 70, 138, 244
melanoma program trial 171
surgical safety checklist 184f
World Society for Emergency Surgery 146
Wound infection, higher risk of 137
Ximab 70
Young's modulus 260
Yttrium-aluminum garnet 203
Yttrium-90 labeled 83
Zenker's diverticulum 109, 110f
Zumab 70
Chapter Notes

Save Clear

Biomarkers of SepsisCHAPTER 1

Nishanth Baliga,
JV Divatia
Sepsis remains the major cause of acute illness and death in all age groups worldwide. Early diagnosis and treatment influence the morbidity and mortality. The definition of sepsis has evolved over the years. In 1914, Schottmuller defined sepsis as a state which is caused by microbial invasion from a local infectious source into the bloodstream which leads to signs of systemic illness in remote organs. Subsequently, sepsis was defined as an uncontrolled host response to injury in the presence of infection. This systemic inflammatory response syndrome (SIRS) was diagnosed clinically by the presence of at least two features: tachycardia, tachypnea, leukocytosis or leukopenia, and fever or hypothermia (Box 1). This definition was neither sensitive nor specific for sepsis. Several of these features are present in patients in the hospital, especially in postoperative patients. Many noninfective conditions such as burns, pancreatitis, trauma, and ischemia-reperfusion may also have features of SIRS. However, the presence or absence of infection is difficult to prove in these patients. The major dilemma was the diagnosis of infection. In addition, several patients with SIRS and suspected infection (postoperative patient with fever, or a patient with influenza) fitted the definition of sepsis, but had an excellent outcome. Thus, the SIRS plus infection criteria did not identify patients at a higher risk of death.
In 2016, sepsis was redefined as life-threatening organ dysfunction caused by dysregulated host response to infection. The focus shifted from inflammation to organ dysfunction in the presence of infection. Organ dysfunction was defined in terms of sequential organ failure assessment (SOFA) score increase in 2 points from baseline (Table 1). One of the main components of this definition is the presence of infection.
TABLE 1   Sequential organ failure assessment (SOFA) score.
Points variables
≤200 with respiratory support
≤100 with respiratory support
Coagulation platelets (× 103 cells/mm3)
Bilirubin (mg/L)
Hypotension or
Vasopressor doses (μg/kg/min>1 h)
MAP ≥70 mm Hg
MAP <70 mm Hg
Dopamine <5
Dobutamine (any dose)
Dopamine 5.1–15
Or Adrenaline ≤0.1
or Noradrenaline ≤0.1
Dopamine >15 or
Adrenaline >0.1
or Noradrenaline >0.1
Central nervous system
Creatinine (mg/dL)
Urine output (mL/24 h)
(MAP: mean arterial pressure; GCS: Glasgow Coma Scale)
Present day methods for identification of pathogens such as blood culture take time and are not helpful for rapid recognition. Early and rapid recognition could lead to early institution of therapy, reduce morbidity and mortality and improve outcome. Hence, there is a role for biomarkers for early recognition of sepsis.1
The human body's response to sepsis is complex, comprising of inflammatory and anti-inflammatory processes, cellular and humoral responses. Biomarkers are naturally occurring molecules, genes, or other characteristics by which particular physiologic or pathologic processes can be identified. The characteristics of an ideal biomarker are: it should be an objective parameter, easy to measure, reproducible, inexpensive, have fast kinetics, high sensitivity and specificity, have a short turnaround time, show appropriate response to therapy (decline with response to therapy). However, no such ideal biomarker exists. Clinical biomarkers can be divided into two types: (1) diagnostic and (2) prognostic markers. Diagnostic biomarkers for sepsis are those which differentiate infectious from noninfectious causes as well as possible causative organisms or classes of organisms. Hence, diagnostic 3biomarkers can be used for prevention of unnecessary use of antibiotics. Prognostic biomarkers help in stratifying patients into risk groups and predict outcome. Biomarkers have also been used for differentiating local infection, disseminated infection and sepsis. They have been evaluated for the differentiation of viral and fungal from bacterial infection. Other potential uses of biomarkers include their role in prognostication, guidance of antibiotics, determine response to therapy, and prediction of organ dysfunction and complications.2
Initial biomarkers investigated in sepsis were white blood cell (WBC) counts, lactate, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The presence of leukocytosis or leukopenia was considered as response of infection and is a part of the SIRS criteria. However, noninfectious causes also lead to leukocytosis and hence it is not specific. Lactate, a byproduct of glycolysis has been investigated as a marker of sepsis. Several factors affect hyperlactatemia and lactate kinetics. Hypoperfusion leading to anaerobic glycolysis is an important mechanism. Currently, septic shock is defined as subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. It is clinically identified as sepsis with persisting hypotension requiring vasopressors to maintain mean arterial pressure >65 mm Hg and having a serum lactate level >2 mmol/L despite adequate volume resuscitation. Lactate levels are elevated in hypovolemia and hemorrhage during trauma and surgery. Lactate clearance is used as marker of adequate resuscitation. Thus, lactate levels are not useful biomarkers of sepsis, but are important indicators of the severity of shock and hypoperfusion, and the adequacy of resuscitation.
Erythrocyte sedimentation rate is an indicator of inflammation and utility as a marker of sepsis is limited. It can be influenced by the presence of anemia, immunoglobulins, and changes in erythrocyte size, shape and number. It can be elevated in malignant neoplasms, tissue injury, and in trauma. Hence it has limited utility in sepsis.3
C-reactive Protein
C-reactive protein (CRP) is an acute phase reactant protein which is synthesized in the liver in response to inflammation or tissue injury. Interleukin-6 (IL-6) upregulates the synthesis of CRP by hepatocytes. Normal CRP levels vary according to age, sex and race. CRP reference range varies from one laboratory to another. In general, levels less than 0.3–0.6 mg/L are considered normal. Its level can rise up to 1,000 times in response to an acute phase stimulus. CRP starts to rise after around 6 hours of the inciting stimulus, peaks at about 48 hours and has a plasma half-life of 19–20 hours. The role of CRP in acute inflammation is not clear. It has been found to bind to phospholipid components of microorganisms facilitating removal of necrotic 4and apoptotic cells by macrophages. CRP can also activate the complement system leading to binding to phagocytic cells and hence elimination. CRP levels can be elevated in both infectious and noninfectious inflammatory disorders. Modest elevations in CRP may be seen in noninflammatory or low-grade inflammatory conditions such as atherosclerosis, obesity, hypertension, diabetes and obstructive sleep apnea. Marked elevations in CRP are usually associated with infection, especially bacterial, however, modest elevations may be seen in viral infections. The primary drawback is its poor specificity although sensitivity is quite high. It appears to a better marker of inflammation rather than infection.4
Procalcitonin (PCT) is a 116 long amino acid peptide with a molecular weight of approximately 13 kDa. It is a precursor of calcitonin, produced by the C-cells of thyroid under the control of the calcitonin gene-related peptide 1 (CALC-1) gene. Under normal conditions C cells of thyroid secrete calcitonin after intracellular protoeolysis of the prohormone PCT. During microbial infections there is increase in CALC-1 gene expression in various extra-thyroid tissues and cells which is mediated by pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and IL-6. Parenchymal tissues such as lung, liver and kidney are the principal sources of circulating PCT in sepsis. Either microbial toxins directly or the host response by humoral or cell-mediated indirectly can lead to inflammatory release of PCT. Procalcitonin starts rising by 2 hours after a stimulus, peaks at around 6 hours, and maintains a plateau through 8 and 24 hours and decreases to baseline values after 2 days. The half-life of PCT is around 20–24 hours. Usually in normal healthy individuals, PCT is detectable in very low concentrations. Low or negligible rise in PCT levels may be seen in localized infections. However, it can increase 1000-fold during active infection and sepsis. Interferon-gamma released during viral infections suppresses PCT; hence high levels are not observed in viral sepsis. Gram-negative bacteremia causes higher elevation of PCT than that caused by gram- positive pathogens. The release of PCT is determined only in systemic infection. Therefore, local bacterial colonizations, encapsulated abscesses and localized and limited infections do not cause PCT release. In addition to bacterial infections, plasma PCT concentration has been shown to increase in acute forms of malaria and fungal infections.5
Procalcitonin may also be elevated in absence of bacterial infections in neonates <48 hours age, first days after major surgery, trauma, burns, pancreatitis, treatment with OKT3 antibodies, interleukins, TNF-α, invasive fungal infections, acute falciparum malaria, severe cardiogenic shock, malignancies, e.g., medullary C-cell carcinoma of thyroid, small cell Ca lung, bronchial carcinoid.5
TABLE 2   Interpretation of procalcitonin levels.
Procalcitonin values (ng/mL)
Localized infection possible. Retest after 6–24 hours
Systemic bacterial infection possible. Retest after 6–24 hours
Systemic bacterial infection highly likely. High risk for severe sepsis
Severe bacterial sepsis
Procalcitonin levels may be falsely low in presence of bacterial infection in early course of infection, localized infections and subacute bacterial endocarditis. Table 2 summarizes the significance of PCT values in various conditions.
Utility of Procalcitonin
Diagnosis of Bacterial Infection and Sepsis
Procalcitonin has been evaluated as a biomarker for infection and sepsis. Assicot et al. in 1993 first described that PCT values may be considerably increased in patients with sepsis and infections.6 Muller et al. studied whether biomarkers increased diagnostic and prognostic accuracy in community acquired pneumonia and found that procalcitonin indeed increased the accuracy and was useful in severity assessment.7 A prospective controlled trial concluded that procalcitonin is a reliable diagnostic and prognostic marker in patients with septic shock compared to nonseptic shock.8 In another study, PCT, CRP, IL-6 and lactate were evaluated for diagnosis of sepsis and PCT was found to be the most reliable marker for the diagnosis of sepsis, with 89% sensitivity and 94% specificity.9 However few studies found that PCT could not accurately differentiate infection from inflammation.10,11A systematic review and meta-analysis on PCT as a diagnostic marker of sepsis found sensitivity of 0.77 (95% CI 0.72–0.81) and specificity of 0.79 (95% CI 0.74–0.84) with area under receiver operating curve to be 0.85 (95% CI 0.81–0.88). The authors concluded that PCT is helpful for early diagnosis of sepsis in critically ill patients. However, they also warned that the results of the test must be interpreted carefully in the context of medical history, physical examination, and microbiological assessment.12
Differentiation of Bacterial and Viral Infections
Procalcitonin is produced in response to endotoxin or few inflammatory mediators released by human body through humoral or cell-mediated immune response such as ILs, TNF. This sort of a response is classically seen in bacterial infections. On the other hand, in viral infections there is release of interferon (IF), a cytokine which attenuates PCT production. Hence, PCT 6levels rarely increase in response to viral infections, indicating that PCT may be useful for discrimination between bacterial and viral infections.13,14
De-escalation of Antibiotics
Due to rampant usage of antibiotics in past few decades, there is emergence of antibiotic resistance and development of multidrug resistance in pathogens. The concept of antibiotic stewardship for optimal usage of antibiotics and early de-escalation of antibiotics is accepted and encouraged. This helps prevent unnecessary usage of antibiotics and development of drug resistance. Due to favorable kinetics of PCT (in the presence of systemic bacterial infections, levels start rising by 2 hours after stimulus, peak at around 6 hours, and maintain a plateau through 8 and 24 hours and decrease to their baseline values after 2 days), PCT has been evaluated for discontinuation of antibiotics. Several studies have studied PCT as an aid for de-escalation of antibiotics after clinical stabilization. Initial single center studies found significant reduction of usage of antibiotics by using PCT based algorithms where antibiotics were stopped when PCT decreased 90% from the initial value.15 Few studies considered cut-off value of PCT <1 µg/L or reduction by 25–35% of initial values over 3 days.16,17 A large multicenter RCT—the PROcalcitonin to Reduce Antibiotic Treatments in Acutely ill patients (PRORATA) trial randomized 621 adult patients with suspected bacterial infection and utilized an algorithm in which initial procalcitonin was used to assess whether to start antibiotics. Subsequent daily procalcitonin levels were used to help decide when to stop antibiotics. Antibiotics were discontinued when PCT levels were <0.5 µg/L or decreased from peak value by ≥80%. They found that the PCT group had significantly fewer days on antibiotics and mortality was noninferior to control group with no significant complications.18 ProGUARD, an RCT done in 11 Australian ICUs used an algorithm in which antibiotics were stopped if PCT levels were <0.1 µg/L or levels decreased by >90% from baseline. They enrolled 400 patients with suspected sepsis and did not find significant reduction in antibiotic use in PCT group. Probably the cut-off was too low and the study was under-powered which led to negative results.19 Subsequently, a multicenter randomized trial—Stop Antibiotics on Procalcitonin guidance Study (SAPS) was done in Netherlands. The algorithm used was similar to PRORATA where antibiotics was stopped when PCT decreased to ≥80% of peak value, or ≤0.5 µg/L and they found significant reduction in antibiotic requirement with no increased rates of complications or mortality. However, there was mild increase in reinfection rates in PCT arm. The study provides a strong evidence for use of PCT based algorithms in sepsis.20 Hence, the current evidence on PCT suggests utilization of PCT values as trends and de-escalation of antibiotics when there is significant reduction of PCT from baseline. Guidelines from the Infectious Diseases Society of America (IDSA) and the Surviving Sepsis Campaign (SSC) suggest utilization of PCT for cessation of antibiotics.7
Procalcitonin in the Postoperative Period
The body's response to surgery consists of a complex inflammatory response to promote healing. Following cell disruption, hemorrhage or ischemia-reperfusion injury there occurs activation of the innate proinflammatory response as well as adaptive anti-inflammatory response. The proinflammatory response helps in destruction of harmful molecules whereas the anti-inflammatory response promotes healing by restricting inflammatory process. Apart from usual mediators which are released following tissue injury such as oxygen reactive species, cytokines and nitric oxide, molecules such as high-mobility group B1 (HMGB1), mitochondrial DNA, glycosaminoglycans, heat shock protein (HSP), adenosine triphosphate (ATP), protein S100 and uric acid collectively called damage associated molecular patterns (DAMPs) are also released. The activation of innate immunity leads to release of cytokines such as IL-6, IL-1b, IL-8, TNF, etc. IL-6 stimulates production of PCT. Depending on the degree of tissue injury during surgery, levels of PCT rise in the postoperative period based on inflammatory response. Normally levels rise up to 9 ng/mL in the postoperative period.21 Usually in postoperative period PCT levels start rising few hours after surgery, peak around 24 hours and start declining to normal levels. However, persistently high levels should raise suspicion of postoperative infection.22 Any PCT more than 10 ng/mL in the postoperative non-transplant patient is considered to be abnormal. Site of surgery influences levels of PCT. Typically, PCT elevations are greatest with abdominal and retroperitoneal surgery. Other sites such as thoracotomies lead to minor elevations in PCT.23 PCT has been used for detection of postoperative complications and has been found to be more useful than CRP, white cell count, and IL6 in detecting infections.24 Some studies have utilized PCT kinetics for detection of postoperative infection and sepsis. Trásy et al. used delta-PCT (PCT level from preceding day subtracted from PCT level on day of suspected infection) and found that patients with an infection exhibited a significantly higher delta PCT than those without an infection.25 Tsangaris et al. in their study concluded that a twofold increase in PCT within a 24-hour period together with fever was useful to detect infections in an intensive care unit (ICU) population.26 Few studies have looked at PCT kinetics for appropriateness of initial antibiotic therapy as well as adequacy of source control after abdominal surgery; however more studies and RCTs are required to reach conclusions.27
Guide Antibiotic Therapy in Respiratory Infections
Several studies have been done looking at PCT as a guide for initiation and discontinuation of antibiotics in respiratory infections. An initial study PROCAP trial done in a single hospital in Switzerland first demonstrated that in patients who presented to the emergency department with suspected lower respiratory 8tract infections, use of procalcitonin to determine whether not to initiate antibiotics, a cut-off threshold of 0.25 µg/L had a 47% reduced rate of antibiotic exposure in the procalcitonin group with no difference in laboratory or clinical outcomes.28 Subsequent RCTs on respiratory tract infections have explored PCT levels for initiation and discontinuation of antibiotics. Prominent among them is the PROHOSP study which was a multicenter RCT which explored whether PCT based algorithm could reduce antibiotic exposure in patients with lower respiratory tract infections. Patients were randomized into either PCT based algorithm group—antibiotics were strongly discouraged if procalcitonin was <0.1, discouraged if 0.1–0.25, encouraged if 0.25–0.5, strongly encouraged if >0.5. They found that antibiotic exposure and antibiotic associated adverse events were significantly decreased in the PCT group while adverse outcomes were similar in both groups.29 Hence in patients with suspected respiratory tract infections, procalcitonin can help differentiating between infectious and noninfectious causes as well as differentiating bacterial from viral causes. However, if patients present with features of lower respiratory tract infections, clinical picture and radiology is suggestive of bacterial infections, antibiotics are initiated without procalcitonin levels, as delay in initiation has been found to increase mortality. In these cases, procalcitonin is used primarily after initiation and trends of procalcitonin are used for discontinuation of antibiotics.
Several studies have looked at levels of PCT as well as PCT clearance as prognostic markers and found varying results. A systematic review and meta-analysis which evaluated prognostic value of procalcitonin in adult patients with sepsis found that an elevated PCT was associated with higher risk of death, initial PCT value had limited prognostic value and PCT nonclearance was significant prognostic factor for mortality. However, the optimal cut-offs and definition of procalcitonin clearance is not yet defined.30
Procalcitonin in Renal Failure
In patients with renal dysfunction and on renal replacement therapy, basal PCT may be raised as half-life increases, however kinetics is not altered and hence PCT decline rates may be unaltered.31,32
Several other biomarkers are investigated for sepsis. Some of them are triggering receptor expressed on myeloid cells-1 (TREM-1), interleukin 27 (IL-27), presepsin, cell free DNA, miRNA. Biomarkers related to the symptoms of sepsis rather than the mechanisms of inflammation have also been tested, such as CT-pro-AVP (C-terminal segment of pro-arginine 9vasopressin), which aids in regulation of blood pressure; however, these biomarkers have not proven effective in diagnostic testing.33 TREM 1, an immunoglobulin induces inflammatory process by activation of production of chemokines, cytokines and reactive oxygen species. Levels of its soluble form sTREM-1 can be detected by enzyme linked immunosorbent assay (ELISA). A recent review and meta-analysis by Jiyong et al. showed that elevated sTREM-1, sampled and measured from the location of infection, is highly predictive of bacterial infection. However further studies are required for validation and to be used clinically.34
Interleukin 27 is a cytokine produced upon exposure to microbial products and inflammatory stimuli which has found to have both pro- and anti-inflammatory effects. Initial studies done in pediatric population was found to have good specificity and positive predictive value however similar results through subsequent studies in adults could not be reproduced. Combination of IL-27 along with PCT is being explored but yet not validated.35 CD64 is an immunoglobulin which when activated by proinflammatory cytokines leads to phagocytosis of bacteria. Studies have found that CD64 is specific to bacterial infection hence used as a biomarker in sepsis. A systematic review and meta-analysis by Cid et al., found sensitivity and specificity of CD64 to be 79% and 91% respectively, however authors concluded that methodological quality of studies to be poor.36 Hence, further studies are required to confirm its validity.
Presepsin is a soluble form of CD14 which is expressed on monocytes and macrophages leading to activation of toll-like receptors and TNF alpha. A multicenter study was done to evaluate utilization of presepsin in SIRS without infection, sepsis, severe sepsis and septic shock. It was noted that presepsin was consistently elevated with higher degrees of sepsis and was significantly lower in noninfected patients and concluded to be a good diagnostic biomarker.37 A recent systematic review and meta-analysis which compared diagnostic accuracy of presepsin and procalcitonin for sepsis in critically ill adults concluded that both were useful for early detection of sepsis and lead to reduction of mortality in critically ill patients.38 Cell-free plasma DNA (cfDNA) are fragments of DNA that are released because of cell necrosis or apoptosis. This is being explored as a prognostic biomarker of sepsis and is usually associated with cell death. Observational studies found that nonsurvivors of sepsis and septic shock had higher levels of cfDNA compared to survivors. Hence, it is being explored as a prognostic biomarker35 miRNAs are a newly identified class of biomarkers that may serve as diagnostic or prognostic role in various human pathologic conditions, including sepsis. miRNAs are short sequences of endogenous RNAs that are involved in translational gene regulation.
The combination of three sentinel biomarkers, IL-6, PCT, and sTREM-1, is uncommon, but pairs within the three have been attempted before to predict and/or prognosticate sepsis: sTREM-1 and PCT or sTREM-1 and IL-6.39 10Finally, it is being increasingly recognized that while sepsis is often thought of as an exaggerated proinflammatory state, there may be a significant anti-inflammatory and immunosuppressive component, especially in late sepsis or sepsis occurring in elderly patients. New biomarkers to estimate the degree of immunosuppression include circulating blood monocyte expression of HLA-DR, monocyte expression of programmed cell-death ligand-1 (PD-L1), and low absolute lymphocyte counts. These could help identify patients who might require immunostimulating or immunomodulating therapy rather than anti-inflammatory therapies in the immunosuppressed stages.40 However, this is still experimental.
Biomarkers are naturally occurring molecules, genes, or other characteristics by particular physiologic or pathologic processes can be identified. Several biomarkers such as WBC count, ESR, lactate, CRP and procalcitonin have been investigated. CRP has been found to have high sensitivity but poor specificity for infection. It has been found to be a better indicator of inflammation than infection. Procalcitonin (PCT), a precursor of calcitonin which is usually undetectable has been found to be increased several fold in sepsis. PCT is used in diagnosis of sepsis, de-escalation of antibiotics, and differentiation of bacterial and viral infections. In postsurgical patients, PCT levels raise on first postoperative day depending on degree of injury. PCT levels start rising few hours after surgery, peak around 24 hours and start declining to normal levels by 48 hours. Persistent elevations of PCT especially >10 ng/L in nontransplant postsurgery patients should raise suspicion of postoperative infection. PCT is recommended for de-escalation of antibiotics when PCT reduces significantly from baseline. Newer biomarkers such as triggering receptor expressed on myeloid cells-1 (sTREM-1), interleukin 27 (IL-27), presepsin, cell free DNA, miRNA are being evaluated for sepsis but are not yet validated.
  1. Gül F, Arslantaş MK, Cinel İ, Kumar A. Changing definitions of sepsis. Turkish J Anesthesiol. 2017;45:129–38.
  1. van Engelen TSR, Wiersinga WJ, Scicluna BP, Poll TVD. Biomarkers in sepsis. Crit Care Clin. 2018;34:139–52.
  1. Barati M, Alinejad F, Bahar MA, Tabrisi MS, Shamshiri AR, Bodouhi NO, et al. Comparison of WBC, ESR, CRP and PCT serum levels in septic and non-septic burn cases. Burns. 2008;34:770–4.
  1. Faix JD. Biomarkers of sepsis. Crit Rev Clin Lab Sci. 2013;50:23-36.
  1. Iskandar A, Susianti H, Anshory M, Di Somma S. Biomarkers utility for sepsis patients management. London: Intechopen;  2018.
  1. Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet. 1993;341:515–8.

  1. 11 Müller B, Harbarth S, Stolz D, Bingisser R, Mueller C, Leuppi J, et al. Diagnostic and prognostic accuracy of clinical and laboratory parameters in community-acquired pneumonia. BMC Infect Dis. 2007;7:10.
  1. Clec'h C, Ferriere F, Karoubi P, Fosse JP, Cupa M, Hoang P, et al. Diagnostic and prognostic value of procalcitonin in patients with septic shock. Crit Care Med. 2004;32:1166–9.
  1. Müller B, Becker KL, Schächinger H, Rickenbacher PR, Huber PR, Zimmerli W, et al. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med. 2000;28:977–83.
  1. Ugarte H, Silva E, Mercan D, De Mendonça A, Vincent JL. Procalcitonin used as a marker of infection in the intensive care unit. Crit Care Med. 1999;27:498–504.
  1. Ruokonen E, Ilkka L, Niskanen M, Takala J. Procalcitonin and neopterin as indicators of infection in critically ill patients. Acta Anaesthesiol Scand. 2002;46:398–404.
  1. Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis. 2013;13:426–35.
  1. Delèvaux I, André M, Colombier M, Albuisson E, Meylheuc F, Bègue RJ, et al. Can procalcitonin measurement help in differentiating between bacterial infection and other kinds of inflammatory processes? Ann Rheum Dis. 2003;62:337–40.
  1. Lee H. Procalcitonin as a biomarker of infectious diseases. Korean J Intern Med. 2013;28:285–91.
  1. Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med. 2008;177:498–505.
  1. Hochreiter M, Köhler T, Schweiger AM, Keck FS, Bein B, von Spiegel T, et al. Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial. Crit Care. 2009;13:R83.
  1. Schroeder S, Hochreiter M, Koehler T, Schweiger AM, Bein B, Keck FS, et al. Procalcitonin (PCT)-guided algorithm reduces length of antibiotic treatment in surgical intensive care patients with severe sepsis: results of a prospective randomized study. Arch Surg. 2009;394:221–6.
  1. Bouadma L, Luyt CE, Tubach F, Cracco C, Alvarez A, Schwebel C, et al. Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet. 2010;375:463–74.
  1. Shehabi Y, Sterba M, Garrett PM, Rachakonda KS, Stephens D, Harrigan P, et al. Procalcitonin algorithm in critically ill adults with undifferentiated infection or suspected sepsis. A randomized controlled trial. Am J Respir Crit Care Med. 2014;190:1102–10.
  1. Jong EA, Lange DW, Van Oers JA, Nijsten MW, Twisk JW, Beishuizen A. Stop Antibiotics on guidance of procalcitonin Study (SAPS): A randomised prospective multicenter investigator-initiated trial to analyse whether daily measurements of procalcitonin versus a standard-of-care approach can safely shorten antibiotic duration in intensive care unit patients. BMC Infect Dis. 2013;13:178.
  1. Paruk F, Chausse JM. Monitoring the postsurgery inflammatory host response. J Emerg Crit Care Med. 2019;3:47.
  1. Lindberg M, Hole A, Johnsen H, Asberg A, Rydning A, Myrvold HE, et al. Reference intervals for procalcitonin and C-reactive protein after major abdominal surgery. Scand J Clin Lab Invest. 2002;62:189–94.
  1. Meisner M, Tschaikowsky K, Hutzler A, Schick C, Schüttler J. Postoperative plasma concentrations of procalcitonin after different types of surgery. Intensive Care Med. 1998;24:680–4.
  1. Domínguez-Comesaña E, Estevez-Fernández SM, López-Gómez V, Ballinas-Miranda J, Domínguez-Fernández R. Procalcitonin and C-reactive protein as early markers of postoperative intra-abdominal infection in patients operated on colorectal cancer. Int J Colorectal Dis. 2017;32:1771–4.

  1. 12 Trásy D, Tánczos K, Németh M, Hankovszky P, Lovas A, Mikor A, et al. Delta procalcitonin is a better indicator of infection than absolute procalcitonin values in critically ill patients: a prospective observational study. J Immunol Res. 2016;2016:3530752.
  1. Tsangaris I, Plachouras D, Kavatha D, Gourgoulis GM, Tsantes A, Kopterides P, et al. Diagnostic and prognostic value of procalcitonin among febrile critically ill patients with prolonged ICU stay. BMC Infect Dis. 2009;9:213.
  1. Novotny AR, Emmanuel K, Hueser N, Knebel C, Kriner M, Ulm K, et al. Procalcitonin ratio indicates successful surgical treatment of abdominal sepsis. Surgery. 2009;145:20–6.
  1. Christ-Crain M, Jaccard-Stolz D, Bingisser R, Gencay MM, Huber PR, Tamm M, et al. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet. 2004;363:600–7.
  1. Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA. 2009;302:1059–66.
  1. Liu D, Su L, Han G, Yan P, Xie L. Prognostic value of procalcitonin in adult patients with sepsis: a systematic review and meta-analysis. PLoS One. 2015;10(6):e0129450.
  1. Meisner M, Lohs T, Huettemann E, Schmidt J, Hueller M, Reinhart K. The plasma elimination rate and urinary secretion of procalcitonin in patients with normal and impaired renal function. Eur J Anaesthesiol. 2001;18:79–87.
  1. Grace E, Turner RM. Use of procalcitonin in patients with various degrees of chronic kidney disease including renal replacement therapy. Clin Infect Dis. 2014;59:1761–7.
  1. Laribi S, Lienart D, Castanares-Zapatero D, Collienne C, Wittebole X, Laterre P. CT-proAVP is not a good predictor of vasopressor need in septic shock. Shock. 2015;44(4):330–5.
  1. Jiyong J, Tiancha H, Wei C, Huahao S. Diagnostic value of the soluble triggering receptor expressed on myeloid cells-1 in bacterial infection: a meta-analysis. Intensive Care Med. 2009;35:587–95.
  1. Sandquist M, Wong HR. Biomarkers of sepsis and their potential value in diagnosis, prognosis and treatment. Expert Rev Clin Immunol. 2014;10:1349–56.
  1. Cid J, Aguinaco R, Sanchez R, García-Pardo G, Llorente A. Neutrophil CD64 expression as marker of bacterial infection: a systematic review and meta-analysis. J Infect. 2010;60:313–9.
  1. Ulla M, Pizzolato E, Lucchiari M, Loiacono M, Soardo F, Forno D, et al. Diagnostic and prognostic value of presepsin in the management of sepsis in the emergency department: a multicenter prospective study. Crit Care. 2013;17(4):R168.
  1. Kondo Y, Umemura Y, Hayashida K, Hara Y, Aihara M, Yamakawa K. Diagnostic value of procalcitonin and presepsin for sepsis in critically ill adult patients: a systematic review and meta-analysis. J Intensive Care. 2019;7:22.
  1. Gibot S, Béné MC, Noel R, Massin F, Guy J, Cravoisy A, et al. Combination biomarkers to diagnose sepsis in the critically ill patient. Am J Resp and Crit Care Med. 2012;186(1):65–71.
  1. Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013;13:260–8.