Boston University

OpenBU http://open.bu.edu

Theses & Dissertations Boston University Theses & Dissertations

2016

Necrotizing fasciitis: a cumulative

review and new techniques in

emergency room diagnosis

Khoshab, Nima

http://hdl.handle.net/2144/16995

Boston University

BOSTON UNIVERSITY

SCHOOL OF MEDICINE

Thesis

NECROTIZING FASCIITIS:

A CUMULATIVE REVIEW AND NEW TECHNIQUES

IN EMERGENCY ROOM DIAGNOSIS

by

NIMA KHOSHAB

B.S., University of California, Irvine, 2013

Submitted in partial fulfillment of the

requirements for the degree of

Master of Science

2016

     

© 2016 by NIMA KHOSHAB All rights reserved

     

Approved by

First Reader Vickery Trinkaus-Randall, Ph.D. Professor of Biochemistry and Ophthalmology

Second Reader Michael Neeki, D.O. Emergency Department Physician

 

  iv

DEDICATION

I would like to dedicate this work to future patients diagnosed with necrotizing fasciitis in

the thought that my effort will help in their successful diagnosis and treatment.

 

  v

ACKNOWLEDGMENTS

I would like to thank my friends, family, and advisors for their ongoing support

throughout the writing process. Specifically, my advisors, Dr. Michael Neeki and Dr.

Vickery Trinkaus-Randall who made the writing of this thesis possible through their

persistent mentorship.

 

  vi

NECROTIZING FASCIITIS: A CUMMULATIVE REVIEW

AND NEW TECHNIQUES IN EMERGENCY ROOM DIAGNOSIS

NIMA KHOSHAB

ABSTRACT

Necrotizing fasciitis (NF) is a rare and life threating soft-tissue infection specific

to the skin’s fascia layer. It is most often encountered in the peripheries, abdominal wall,

and perineum and has numerous etiologies and associated pathogens. Early diagnosis and

rapid surgical debridement are essential in treating NF as the infection progresses rapidly

and mortality rate increases significantly with time. The current difficulty in initial

diagnosis is due to the lack of obvious skin findings early on in the infection. Laboratory

tests, including the laboratory risk indicator for necrotizing fasciitis (LRINEC) score, gas

on imaging tests, and physical exam findings are the current clues to an early diagnosis

but official diagnosis can only be confirmed by surgical exploration and discovery of a

lack of resistance to dissection in the fascia layer. The LRINEC score analyzes one

variable, specifically C-reactive protein (CRP), which is often not included in routine

laboratory tests skin infections at the emergency department (ED). Furthermore, no

specific set of physical exam findings has been distinctly associated with diagnosis of NF

over other soft-tissue infections and the most specific imaging tests are too expensive for

routine use. A new and modified LRINEC score based only on routine ED laboratory

tests as well as an additional objective scoring system for physical exam findings are the

next steps toward rapid diagnosis. This approach requires large-scale retrospective

 

  vii

statistical analyses of NF cases across the country for identification of the most prevalent

physical exam findings and abnormal laboratory values.

 

  viii

TABLE OF CONTENTS

TITLE……………………………………………………………………………………...i

COPYRIGHT PAGE……………………………………………………………………...ii

READER APPROVAL PAGE…………………………………………………………..iii

DEDICATION ................................................................................................................... iv  

ACKNOWLEDGMENTS .................................................................................................. v  

ABSTRACT ....................................................................................................................... vi  

TABLE OF CONTENTS ................................................................................................. viii  

LIST OF TABLES .............................................................................................................. x  

LIST OF FIGURES ........................................................................................................... xi  

LIST OF ABBREVIATIONS ........................................................................................... xii  

INTRODUCTION .............................................................................................................. 1  

Etiology ............................................................................................................................... 5  

Microbiology ....................................................................................................................... 7  

Pathophysiology ................................................................................................................ 14  

Comorbidities / Risk Factors ............................................................................................ 19  

Diagnosis ........................................................................................................................... 22  

Treatment .......................................................................................................................... 28  

 

  ix

PUBLISHED STUDIES ................................................................................................... 37  

RESULTS ......................................................................................................................... 43  

DISCUSSION ................................................................................................................... 46  

LIST OF JOURNAL ABBREVIATIONS ........................................................................ 53  

REFERENCES ................................................................................................................. 55  

CURRICULUM VITAE ................................................................................................... 62  

 

 

  x

LIST OF TABLES

Table Title Page

1 Etiologies of Necrotizing Fasciitis 18

2 Pathogens of Necrotizing Fasciitis 21

3 Prevalence of Pathogens in Necrotizing Fasciitis Cases 22

4 Prevalence of Pathogens in Necrotizing Fasciitis Cases (2) 23

5 Four Types of Necrotizing Fasciitis 25

6

7

8

9

10

11

Common Risk Factors for Necrotizing Fasciitis Infections

Predisposing Conditions to NF (by Ethnicity)

LRINEC Score Breakdown

First-line Antimicrobial Treatments

LRINEC Score Analysis

Prevalent Physical Exam Findings

32

33

39

47

50

52

 

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LIST OF FIGURES

Figure Title Page

1 Anatomy of Soft-tissue Infections 14

2 Presentation of Lower Extremity Necrotizing Fasciitis 28

3 Presentation of Lower Extremity Necrotizing Fasciitis (2) 29

4 “Dishwasher Pus” 30

5 Change in Cumulative Survival Rate by Time 35

6

7

8

9

10

11

12

13

Change in Cumulative Survival Rate by Time (2)

Surgical Incision for Initial Debridement

Upper Extremity Debridement

Lower Extremity Debridement

Vacuum-assisted Wound Closure Therapy

LRINEC Score Accuracy of Diagnosis

Categorical Severity by LRINEC Score

Successful Treatment of Necrotizing Fasciitis Infection

41

43

44

45

48

56

57

63

 

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LIST OF ABBREVIATIONS

ARMC ........................................................................ Arrowhead Regional Medical Center

BC .................................................................................................................... Before Christ

BMP .................................................................................................. Basic Metabolic Panel

CBC .................................................................................................. Complete Blood Count

CI ............................................................................................................ Confidence Interval

CMP .................................................................................. Comprehensive Metabolic Panel

CRP .......................................................................................................... C-reactive Protein

CT ............................................................................................. Computerized Tomography

ED ................................................................................................... Emergency Department

HBO ....................................................................................................... Hyperbaric Oxygen

LRINEC ............................................... Laboratory Risk Indicator for Necrotizing Fasciitis

MRI ........................................................................................ Magnetic Resonance Imaging

NF ........................................................................................................ Necrotizing Fasciitis

NSAID .................................................................. Non-steroidal Anti-inflammatory Drugs

IV ........................................................................................................................ Intravenous

ROC ............................................................................................ Receiver Operating Curve

SAP ............................................................................................... Systolic Arterial Pressure

VAC .............................................................................................. Vacuum-assisted Closure

WBC ......................................................................................................... White Blood Cell

 

  1

INTRODUCTION

  Necrotizing Fasciitis (NF) describes a variety of rare necrotizing soft-

tissue infections (NSTI) characterized by tissue necrosis specific to the fascia layer of

skin. It is imperative to distinguish NF diagnosis from other skin and soft tissue

infections due to a high rate of mortality and the immediate demand for surgical

debridement when NF diagnosis is indicated. As opposed to other soft-tissue infections

NF is rapidly fatal unless quickly diagnosed and aggressively treated.46

Specifically, NF primarily damages the subcutaneous fat layer (containing nerves

and vascular structures) as well as the superficial and deep fascia layers. The anatomical

differentiation between a variety of skin and soft tissue infections including erysipelas,

impetigo, folliculitis, ecythyma, furunculosis, carbuncolosis, cellulitis, myonecrosis, and

NF are included in Figure 1 below (Figure1).28

 

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Figure 1: Anatomy of Soft-tissue Infections. Anatomical classification of skin and soft tissue infections by anatomical location within skin layers helps in the development of prognoses and treatment plan. Necrotizing fasciitis infections extend from the deep fascia to the superficial fascia and include all subcutaneous tissue including fat, nerves, arteries and veins. 28

 Hippocrates was the first to describe NF, in 500 BC as a complication of

“erysipelas,” an acute and often recurring bacterial infection. Specifically he said “…the

erysipelas would quickly spread widely in all directions. Flesh, sinews and bones fell

away in large quantities…Fever was sometimes present and sometimes absent…There

were many deaths. The course of the disease was the same to whatever part of the body it

spread.” 19

 

  3

In the early 1800s NF was described by a variety of different names including

gangrenous ulcer, putrid ulcer, malignant ulcer, hospital gangrene, phagedena (“eating

away”), phagedenic ulcer, and phagedena gangraenosa but by the mid-1800s two names

predominated, phagedena and hospital gangrene.41 In England, between 1780 and 1850,

two naval physicians, Sir Gilbert Blane and Thomas Trotter, along with a naval surgeon,

Leonard Gillespie, delivered the first detailed description of NF in the English language.

As described, amongst army and navy personnel, the disease was one of the most

dreadful to appear, although “hospital gangrene,” as it was called, was rarely present

amongst civilians at the time.41 Later in 1871, Confederate Army surgeon, Joseph Jones,

the first to describe NF in the United States, again called it “hospital gangrene” and

reported a total of 2,642 cases treated during the American Civil War.34

By the early 1900s it appeared as if hospital gangrene was a disease of the past;

Park, 1908, “Hospital gangrene so-called…is now practically never seen.”3 The current

name, necrotizing fasciitis, first used by Wilson in 1952, describes the most consistent

and significant aspect of the disease, necrosis of the fascia.71 Since the 1980s, a renewed

interest in the pathology of NF has arisen. After a study by Stevens et al. reported 20

patients with streptococcal shock, 11 of which were finally diagnosed with NF, the name

“flesh-eating bacteria syndrome” became popularized in the media.62

There has been some confusion in current literature regarding the exact definition

of NF.64 There are a variety of terms, past and present, which refer to NF (including

suppurative fasciitis, acute dermal gangrene, hemolytic streptococcal gangrene,

progressive synergistic bacterial gangrene, necrotizing erysipelas, and Fournier’s

 

  4

gangrene). The abundance of terms has added to the complexity of specifically defining

NF and has exacerbated the challenge of accumulating accurate epidemiological statistics

regarding diagnosis. (Fournier’s gangrene is a type of NF infection specific to the

perineum and particular to males.)46

In 1997, the incidence of NF was estimated to be 500-1000 cases per year and the

global prevalence was 0.4 cases per every 100,000 people. There seems to also be an

exponential increase in this rate recently, possibly due to a rise in the prevalence of

concomitant risk factors.36 The ratio of men to women diagnosed with NF is 3:1,

although the increased incidence in males is correlated with an increased incidence of

Fournier’s gangrene, which is NF of the perineum specific to males. NF affects all ages

but the highest rate of incidence has been reported in middle-aged and elderly patients

(over 50 years of age). 40

Most commonly, NF occurs in diabetics, alcoholics, IV drug users,

immunosuppressed patients, and patients with peripheral vascular disease 16, 66 but also

often presents in young, healthy individuals 13, 62 Approximately 50% of the patients

diagnosed with NF have a history of skin injury leading up to the infection while 25%

have experienced blunt trauma, and 70% have a minimum of one chronic illness.57

The infection most often develops in the extremities, the perineum and genital

area, or the abdominal wall.65 The extremities are the most common; 50% of total cases

occur in a single lower limb and 33% occur in a single upper limb.57

The average mortality of NF is controversial and the literature reports a variety of

numbers in regard to morbidity. In one review of literature a median mortality ratio of

 

  5

21.5 % was calculated 27 but median mortality ratios throughout the literature range all

the way from 8.7% to 76%.28 When the infection presents in the extremities, the

mortality rate is slightly lower than when the infection develops in the abdominal wall or

perineum.56 Generally, without treatment the mortality rate of NF approaches 100%.46

Etiology

It is often unknown what inciting event leads to an NF infection and idiopathic

causes have been recorded in anywhere from 13 to 31% of all patients. 45, 68 When the

cause is identifiable it is most often due to trauma, either minor or major trauma. In this

case, trauma includes both external injuries and surgical wounds, such as perforated

diverticulitis, necrotic cholecystitis, obstructive colon cancer with perforation, infection

following the repair of an incarcerated hernia, appendicitis with perforation, small bowel

perforation, or gastroduodenal perforation, as some of the most common.46 Furthermore,

the pathogens causing NF can be introduced into subcutaneous spaces through any

number of ways that involve a disruption of the overlying layers of skin. Other reported

etiologies include cutaneous infections or ulcers,54 illicit IV drug injections,63 perirectal

abscesses,63 animal or insect bites,63 incarcerated hernias,63 subcutaneous insulin

injections,23 colocutaneous fistula,23 and renal calculi.68 There have also been reports of

NF spreading hematatogenously from a distant site of infection throughout the body.44

Table 1 is included for a more complete list of NF etiologies by location of subcutaneous

infection site (Table 1).28

 

  6

 

Table 1: Etiologies of Necrotizing Fasciitis. The table includes a comprehensive list of most common etiologies of NF infections organized by the specific site of infection. Most common sites of infection include extremities, abdominal wall, and perineum but other locations have been recorded as indicated in the table. Idiopathic etiology is also included for completeness as this is often the case in NF infections.28

 

  7

Microbiology

The majority of recorded NF cases are synergistic polymicrobial infections

although there are cases of monomicrobial infections as well. One group reported that

from 182 cases of NF studied, upon culture, 154 patients had polymicrobial infections

while the remaining 28 patients developed NF from one single pathogen. The 154 cases

of polymicrobial infections consisted of 4.4 organisms found on average upon wound

culturing.20 A wide variety of pathogens can make up polymicrobial and monomicrobial

NF infections. In the study above by Myers et. al, with 182 cases of NF, monomicrobial

NF infections were most commonly caused by streptococcal species such as β-hemolytic

streptococci (particularly group A streptococci or Streptococcus pyogenes).12, 20

Interestingly, from all patients with NF described by McHenry et al., half the

monomicrobial infections were caused solely by the S. pyogenes species, whereas only of

2 of the 45 patients with polymicrobial infections had the S. pyogenes species isolated in

their cultures.45 S. pyogenes is therefore often closely associated with monomicrobial

infections.

Polymicrobial infections in this case were most commonly caused by

combinations of staphylococci species (particularly Staphylococcus epidermidis with β-

hemolytic streptococci), enterococci, Enterobacteriaceae species (commonly

Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, and Pseudomonas

aeruginosa), streptococci, Bacteroides/Prevotella species, anaerobic gram-positive cocci,

and Clostridium species.12, 20 Another study found that 69% of NF infections were

polymicrobial, 29% were monomicrobial, and no organisms grew in the remaining 2% of

 

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cultures.45 The exact proportion of monomicrobial to polymicrobial NF infections

slightly fluctuates throughout the literature but in general, polymicrobial cases including

aerobic and anaerobic species are more common.30 This is an important consideration in

the approach to antibiotic treatment of NF cases within the emergency department (ED).

Due to the variability of bacterial species associated with NF infections in the literature, it

is imperative that a broad range of antibiotics is given upon initial presentation until

cultures and gram stain are determined. Guiliano et al. isolated up to 11 different bacterial

species from an individual patient,26 further emphasizing the importance of initial broad

range antibiotic treatment. The following table indicates a comprehensive list of

pathogenic species that have been associated with NF infections to date (Table 2).28

 

  9

 

Table 2: Pathogens of Necrotizing Fasciitis. The table above includes a comprehensive list of pathogens that have been recorded in NF infections including all bacterial species and even the rare fungal species. The wide variety of possible bacterial species includes gram-positive aerobes, gram-negative aerobes, anaerobes, and marine Vibrio species.28

 The prevalence of individual pathogens in a number of NF cases is reported in the

following two tables (Table 3 and Table 4),1, 18 each from different patient populations,

both indicating that most cases are polymicrobial and furthermore, that specific

 

  10

pathogens consistently predominate. Beyond administering broad range antibiotics, it

should be ensured that antibiotics targeting the most common NF species be administered

in the ED upon initial presentation (See “Treatment” section).

 

Table 3: Prevalence of Pathogens in Necrotizing Fasciitis Cases. 73 patients with NF were studied and the species implicated in their infections were cultured. The prevalence of a variety of bacterial and fungal organisms recovered from these individuals is indicated in the table above. A total of 162 organisms were recovered from 73 patients and the majority of infections were polymicrobial. The Streptococcus species was most common amongst this group and included Streptococcus pyogenes, group B and G Streptococcus, and Streptococcus milleri.1

 

  11

 

Table 4: Prevalence of Pathogens in Necrotizing Fasciitis Cases (2). Cultures representing 238 patients with NF. Microorganisms implicated in their infections were isolated. Streptococcus pyogenes was the most common species isolated, both independently and in combination with other species.18

 

  12

NF is currently classified into four different types, each with different

microbiological findings. 49 Type I is the most common of the four, also known as the

polymicrobial type, in which a minimum of two pathogens are implicated and the

infection is most often found in the perineum and trunk.46 Type II on the other hand, is

known as the monomicrobial type, and is most often an infection of beta-hemolytic

Streptococcus A (Streptococcus pyogenes), common in the extremities and often

occurring in young, healthy individuals.70 Type II infections are also often associated

with methicillin resistant, Staphylococcus aureus (S. aureus), which inflicts tissue

necrosis through toxin release and leukocyte destruction. These specific Type II

infections are usually localized to the limbs, and often occur in patients without

significant co-morbidities, after small skin incisions. Type II infections have been highly

correlated with the use of non-steroidal anti-inflammatory drugs (NSAIDs).59 In this

manner, patient history upon ED presentation can provide significant insight for

diagnosis; i.e. if a type II infection is suspected a specific treatment plan can be employed

immediately. One study with 149 patients included 24 cases that led to mortality and 125

patients that survived NF infections. Of the 24 persons that deceased, 14 individuals

(58%) had monomicrobial infections. Of the 125 survivors, 50 (40%) had monomicrobial

infections. Researchers concluded that monomicrobial infections, although less common

than polymicrobial, presented with higher rates of mortality (P value of 0.09) than

polymicrobial infections.19

Monomicrobial NF infections that involve gram-negative rods, such as Vibrio

spp., or Clostridium species comprise Type III NF infections. Vibrio vulnificus is an

 

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aquatic bacterium found in Asia and is believed to be the most virulent Vibrio species

indicated in NF. The species includes Vibrio parahemolyticus, Vibrio damsela, and

Vibrio alginolyticus.27, 77 The Clostridium species on the other hand is a gram-positive

bacteria that is often introduced following external injuries that cause devascularization,

or surgical wounds, usually obstetric or intestinal. Clostridium infections are also more

common among drug addicts.37

Lastly, fungal NF infections, specifically Candida spp. and Zygomycetes make up

Type IV infections, most commonly found in immune-compromised individuals.46 The

following table categorizes the four types of NF infections by pathogen type, site of

infection, and the co-morbidities that are most commonly associated with each type of

infection (Table 5).46

 

Table 5: Four Types of Necrotizing Fasciitis. Classification of the four types of NF infections based on microbiological findings is indicated in the table. The commonly associated pathogenic species, site of infection, and co-morbidities are included.46

 If clinical signs of NF are indicated in the ED culture should be obtained as soon

as possible. In contrast to cellulitis, where the leading edge of the lesion is aspirated to

obtain culture material for gram stain from a wound, in NF, the necrotic center of the

 

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lesion is the preferred site of collection.26 In 75% of all NF cases, diagnosis is obtained

through microbiological cultures.25 In confirmed cases of NF, cultures obtained from

sites of surgical debridement indicate a positive result in 80% of cases whereas blood

cultures only indicate a positive result 25% of the time.6 Therefore, when NF is clinically

indicated in the ED, it is imperative that culture be obtained as quickly as possible and

that the necrotic center of the lesion be aspirated as opposed to collecting samples from

blood or other locations within the wound.

Pathophysiology

NF infections begin in deeper layers of skin, which include the hypodermis and

superficial fascia, initially causing very little outward change on superficial layers such as

the dermis and epidermis.33 This fact makes early stage NF infections difficult to

diagnose, as there are often little or no outward clinical changes. Usually, within 7 days

of the provoking event, certain characteristic skin changes can be seen, although not all

signs are clearly indicative of an NF infection.51 It is important for clinicians to

understand this difficulty of diagnosis and maintain a high clinical suspicion.

The most common histopathological changes found in NF include necrosis of the

superficial fascia, thrombosis of blood vessels and suppuration. Other consistent changes

include severe subcutaneous fat necrosis, severe inflammation of the dermis and

subcutaneous fat, vasculitis, sometimes with endarteritis, and local hemorrhage. 7 Again,

as reported by Umbert et al., the epidermis in most cases of NF initially shows no major

changes.7

 

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Fibrous attachments between subcutaneous tissue and fascia help limit the spread

of infection but the lack of these attachments in the trunk and extremities allow for

widespread infection in these regions.31 This leads to a slight variation in the time course

of NF infections depending on initial location. Infections can progress for days to weeks

but usually, the more significant life threating or limb-threating NF infections progress

very rapidly within the first few hours post-infection.31 The spread of necrosis and

infection is due to the synergistic actions of the variety of microbial agents involved as

well as the enzymes and toxins produced by these pathogens.49 The earliest presentation

of NF is usually in the form of a warm area of cellulitis displaying erythema, tenderness,

and swelling with severe local pain.63 Erythema then spreads diffusely and the skin is

reported to become shiny, smooth, and tensely swollen in the surrounding regions of the

site of infection.71 Clinical signs of NF infections are evident in the following images

(Figure 2 and Figure 3).30, 57

 

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Figure 2: Presentation of Lower Extremity Necrotizing Fasciitis. In this case, the left lower extremity of a female diabetic patient with NF is demonstrated. She presents with painful swelling, erythema, and local heat as well as a bullae on her dorsum (indicated with black arrow). Her third phalanx indicates chronic gangrene (due to diabetes). Upon culture from the site of infection, Staphylococccus aureus (methicillin-sensitive) was isolated. Similar signs and symptoms are usually only present later in the timeline of the infection and should ideally be managed well before this point.57

 

  17

Figure 3: Presentation of Lower Extremity Necrotizing Fasciitis (2). This 59-year-old female patient presents with erythema and edema in her right lower extremity from the medial malleolus to the tibia. Late stage infections often present with more rigorous signs including the bullae that are observed in two places along her leg.30

 The exact margins of the infection are often absent or difficult to discern and the

infected area gradually changes to normal appearing skin. Within a few days, blisters and

bullae, initially filled with serous fluid and later becoming hemorrhagic, develop on the

infected skin and lead to a patchy, darker blue appearance.9, 69 When these changes are

observed, it can be determined that the infection is well established within the

subcutaneous region and necrosis of the superficial fascia and hypodermis is under way.

This necrosis produces a foul-smelling, watery, and thin fluid called “dishwater pus” 71,

evident in the following figure (Figure 4).27

 

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Figure 4: "Dishwasher Pus". One of the commonly discovered positive macroscopic findings indicative of NF infections is called “dishwasher pus.” This is described as a bad-smelling, thin and watery fluid often found in the fascial layer at a wound site. The small black arrow indicates a cutaneous vein that has been thrombosed due to NF pathology.27

 Liquefactive necrosis, leading to “dishwasher pus”, is caused by bacterial

enzymes such as lipases and hyaluronidases that degrade superficial fascia and fat

(respectively).71 The process leads to the destruction of nerves and vascular structures of

the subcutaneous layers causing the skin to become hypesthetic or even anesthetic.14 Four

to five days after initial infection, usually following the presentation of “dishwasher pus”,

the skin becomes seriously gangrenous.69 Patients begin to develop signs of sepsis

 

  19

syndrome as bacterial organisms and toxins enter into their blood stream. Extensive

tissue damage and systemic toxicity can take place, due both to bacterial toxins and

endogenous cytokines.61, 78 The spread of bacteria, producing endo and exotoxins,

throughout the subcutaneous tissue causes vascular thrombosis, tissue ischemia, and

liquefactive necrosis terminating in multisystem organ dysfunction and eventually death,

if not treated.60

Comorbidities / Risk Factors

There are several reported risk factors for NF including diabetes mellitus, over 50

years of age, malnutrition, peripheral vascular disease, intravenous drug abuse, chronic

alcoholism, atherosclerosis, obesity, and hypoalbuminemia.30 The following figure

provides a comprehensive list of the most common risk factors leading to NF infections

(Table 6).30

 

  20

 

Table 6: Common Risk Factors for Necrotizing Fasciitis Infections. A comprehensive list of the most common risk factors leading to NF infections is indicated. These risk factors are indicative of an immune-compromised state in the patient, which may be one of the overarching lead factors in contracting an NF infection.30

 The most prevalent co-morbidity in NF patients is diabetes mellitus, present in

approximately 40-60% of cases.27, 55 Some other common co-morbidities include liver

cirrhosis, chronic heart failure, immunodeficiency, Addison’s disease, systemic lupus

erythematosus, and pre-existing hypertension43, 77 The following table (Table 7) indicates

the ethnic distribution of certain predisposing conditions to NF found in a New Zealand

study. The data supports the fact that diabetes mellitus is the most common comorbidity

among patients with NF, in this case, followed next by obesity.18

 

 

  21

 

Table 7: Predisposing Conditions to NF (by ethnicity). Although significant differences between ethnicities were found with certain factors, such as diabetes mellitus, it was not established what this difference could be due to. The table demonstrates the most common pre-disposing conditions in cases of NF and presents similar findings to previous literature in which diabetes-mellitus is the most prevalent pre-disposing condition.18

 There are also certain factors that lead to a higher rate of mortality among patients

diagnosed with NF. For example, a septic condition or hypotension at the time of hospital

admission as well as chronic renal failure, elevated serum creatinine, and elevated blood

urea all increase the risk of mortality.46 Risk factors and co-morbidities must be taken

into serious consideration among hospital admission. A higher risk patient should be

provided with more severe care. This understanding provides clinicians a separate avenue

of analysis to apply when diagnosing a patient’s risk for NF. A patient with diabetes

mellitus demands in depth consideration due to the severity and prevalence of their pre-

disposing condition.

 

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Diagnosis

Diagnosis of NF requires the evaluation of physical signs, laboratory tests, and

imaging results along with a heightened sense of clinical suspicion. It is critical that NF

be differentiated from other skin infections due to its rapid progression and high risk of

mortality. In the ED, diagnosing NF is extremely time sensitive. The time between onset

of symptoms and initial operation significantly increases mortality rate. It is crucial to

minimize this time and promote rapid diagnosis in the ED. The following figure indicates

the time between the onset of symptoms and initial operation and how this time effected

the resulting survival rate in a cohort of patients with NF (Figure 5).74

 

  23

 

Figure 5: Change in Cumulative Survival Rate by Time. As the time between initial onset of symptoms and first surgical debridement increases (in days), the cumulative survival rate in patients drops. Each individual point estimate along with four confidence intervals (95%) are calculated at 2, 4, 6, and 8 days after symptom onset in the above Kaplan-Meier curve.74

The changes in overlying skin are initially difficult to detect. Therefore, a

necessary tool for early diagnosis of NF is a high clinical index of suspicion. Beyond a

high clinical index of suspicion there are several clues that allow differentiation of NF

from other skin infections. Some of the most prevalent signs include local pain, fever,

and indications of systemic toxicity while patient history and physical examination may

 

  24

be relatively nonspecific. One systematic review of literature found that the most

common diagnostic features include severe local pain, paucity of skin findings, fever,

signs and symptoms of systemic toxicity, nonspecific results on physical exam, and

uncommon soft-tissue gas.28 This lack of specificity demands further studies into clinical

signs and symptoms with more clear indication of NF diagnosis.

Other changes are often evident, although not all are specific to NF infections. In

one study it was reported that sites of infection display erythema (80% of cases),

induration (66%), tenderness (54%), fluctuance (35%), skin necrosis (23%), and bullae

(11%).24 Another study compared NF infections to soft tissue infections to determine

differentiating signs and symptoms and these yielded a number of indicators; increased

tense edema (23% vs. 3%, p<0.0002), purplish skin discoloration (10% vs. 1%, p=0.02),

and sensory or motor deficit (13% vs. 3%, p=0.03).67 In the case of an uncertain

diagnosis, tense edema, purple skin discoloration, and sensory/motor deficit can be used

as possible clues to an NF diagnosis although more specificity and more clues are

required. Ecchymotic and erythematous skin lesions are common initial physical findings

of NF. These symptoms may rapidly progress into hemorrhagic bullae, due to blood

vessel occlusion in the fascia or muscle compartments. In this way, the presence of bullae

is another important diagnostic feature of NF.57

Fever and tachycardia (>100 beats/min) followed by hypotension (SAP <100mm

Hg) and tachypnea (>20/min) are the most common vital sign abnormalities in patients

with NF. The combination of these vital sign abnormalities and previously described skin

 

  25

changes including pain and erythema, are currently the most useful signs for initial rapid

suspicion of NF diagnosis over other soft tissue infections.57

The official diagnosis for NF can only be made after surgical exploration and

determination that the normally adherent fascia displays a lack of resistance to blunt

dissection.27 Usually such surgical exploration is prompted after certain clinical signs are

in place although some advocate immediate surgical exploration for biopsy and frozen

section examination whenever there is a suspected diagnosis, even with lack of

significant clinical findings.45

Beyond physical examination, diagnosis may be suggested with the help of

laboratory and imaging tests. Radiologic studies aid in diagnosing NF by detecting

accumulated gas in soft tissue regions infected by anaerobic bacteria; this includes X-

rays, CT, ultrasound, and MRI.8, 22, 35, 76 These imaging techniques are more accurate for

detecting soft-tissue gas than using physical examination.45 CT scanning in particular is

more sensitive than plain radiographs and can even be helpful in identifying the spread of

infection.29, 76 One group used MRI techniques to identify NF infections that require

immediate surgical intervention and were able to accurately distinguish such infections

from non-necrotizing cellulitis, avoiding the need for unnecessary surgical debridement.53

Unfortunately this group was unable to go on and address whether the use of MRI

imaging positively impacted mortality rates of the NF patients. Although these imaging

techniques can prove to be useful in diagnosis, due to their cost effectiveness it is

recommended that their use be reserved for very specific cases where diagnosis is highly

uncertain and a definite diagnosis is needed to shape the immediate treatment plan.

 

  26

Lastly, many laboratory tests are used to lead to a diagnosis of NF. Low et al.

conducted a retrospective observational cohort study of 89 patients with confirmed

diagnosis of NF using a control group of 225 patients admitted to the hospital for

abscesses or severe cellulitis during the same time frame.73 Investigators studied the

values recorded from laboratory tests in each patient’s chart to determine if certain

variables provide significant insight into diagnosis of NF over other soft-tissue infections

(i.e. cellulitis/abscess). Variables included age and gender as well as sodium,

hemoglobin, creatinine, glucose, urea, potassium chloride and more. From these data

certain variables were consistently and significantly varied in the cohort diagnosed with

NF compared to control patients. These variables included C-reactive protein (CRP), total

white blood cell (WBC) count, hemoglobin, sodium, creatinine, and glucose. The novel

insight led investigators to develop a LRINEC (Laboratory Risk Indicator for Necrotizing

Fasciitis) score based on laboratory results and the indicated suspicion of NF diagnosis. 73

The following table (Table 8) indicates the cutoffs that were statistically indicated in the

LRINEC study and the accumulation of points that are meant to provide various degrees

of suspicion to clinicians on a diagnosis of NF.1

 

  27

 

Table 8: LRINEC Score Breakdown. Six variables and their significant threshold as well as contributing scores formulate the laboratory risk indicator for necrotizing fasciitis (LRINEC) score used to help differentiate necrotizing from non-necrotizing soft-tissue infections. A maximum score of 13 is possible if each variable is measured beyond threshold. Variables include C-reactive protein, white-blood-cell count, hemoglobin, sodium, creatinine, and glucose. It is worth noting that C-reactive protein is the most impactful variable on the LRINEC score.1

 Based on these six measurements, each providing additional points to the overall

LRINEC score, and statistical analyses, investigators found that an overall LRINEC score

 

  28

greater than or equal to six (out of a maximum 13) should raise physician suspicion for

NF. Furthermore, an overall LRINEC score greater than or equal to eight is strongly

indicative of an NF diagnosis.73

Treatment

Treatment for severe NF requires multiple modalities, most importantly, rapid

surgical debridement. Following surgical debridement, current approaches include

antibiotics, supportive care, hyperbaric oxygen therapy, as well as vacuum assisted

closure devices. 46 It is imperative that surgical debridement be performed as soon as

possible, ideally within 12 hours of onset for full form NF, otherwise the increasing

possibility of mortality and life-threating illness become more and more significant.46

Surgical debridement should also be repeated within a 24-hour period depending on

patient condition following the initial operation; this requires the monitoring of patient

vital signs and the spread of infection.46 The risk of mortality increases by 7.5 times if

only one surgical debridement procedure is performed. Furthermore, primary

debridement after more than 24 hours of symptom onset increases relative risk of

mortality by 9 times.48, 55 Rapid primary debridement, quickly followed by further

necessary surgical explorations, is one of the most important actions in reducing the

mortality of NF cases. The following figure indicates how survival rate decreases as the

time between hospital admission and first surgical debridement increases (Figure 6).74

 

  29

 

Figure 6: Change in Cumulative Survival Rate by Time (2) The effect of increasing time between hospital admission and first surgical debridement on patient survival rate is demonstrated above. Cumulative survival rate was measured at 93.2% (95% CI; 99.8-86.6) when surgery was undergone before the 24-hour point of hospital admission but drops to 75.2% (95% CI; 88.4-62.0) at 48 hours post-admission. Kaplan-Meier curve indicates the cumulative survival rate and an estimate of the 95% confidence interval at 24, 48, 72, and 96 hours.74

Most operations involve surgical debridement, fasciotomy, and necrosectomy and

the average NF patient can require up to 40 additional operations depending on several

variables including time and adequacy of initial debridement as well as symptoms of

patient stability and co-morbidities.46, 55 Although surgical debridement removes tissue,

 

  30

the current techniques decreases tissue loss in the long term by limiting the spread of

infection throughout the fascia and therefore reducing the need for amputation.75 The

following images show the extent and approach to tissue debridement currently used in

NF treatment (Figure 7).46 (The figure also shows that incisions are made along Langer’s

lines, allowing for less surgical scarring and improvement in wound healing. The extent

of tissue excision is ideally extended until healthy tissue is visualized and limited to this

edge. Healthy tissue that is salvageable should be kept but it is simultaneously important

to ensure all infected tissue is removed, especially during the primary debridement). 46

 

  31

Figure 7: Surgical Incision for Initial Debridement. This specific excision extends until healthy tissue is reached while non-infected skin is shown unattached. It is important to carefully remove as much necrotic tissue as possible and prevent the reappearance of infection within the fascial plane.46

 The next series of images depict pictures of NF infections of both the upper and

lower extremities prior to any surgical intervention and after the first debridement

operation. Large amounts of necrotic tissue and adjacent fascial planes have been

removed indicating the degree of aggressive tissue removal that is necessary to prevent

further infection (Figure 8 and Figure 9).27

 

  32

 

Figure   8:   Upper   Extremity   Debridement.   (a) NF of upper extremity before debridement demonstrating gangrene, erythema, edema, and ruptured bullae. (b) After the first surgical debridement, fascia layers extending up the upper extremity are removed and underlying tendons and muscle layers are exposed.27  

 

 

 

  33

 

Figure 9: Lower Extremity Debridement. (a) Late stage NF of the left foot with severe skin discoloration and necrosis. (b) After complete surgical debridement the same foot is visualized demonstrating the depth reached upon removal and the extent of tissue removed from the site of infection. Tendons and muscle layers are exposed.27

 

34

Beyond surgical debridement a combination of antibiotic therapy and supportive

care should be provided. Supportive care is similar to that required for other critical

patients and includes intensive fluid resuscitation, sufficient nutrition, and analgesics.68

Antibiotic treatment on its own is not sufficient for treating NF infections due to

ischemia of tissue, which does not allow for sufficient delivery of antibiotics to the site of

infection. Tissue ischemia also limits polymorphonuclear-cell destruction by oxidation of

bacteria and their toxins and therefore surgical debridement is required beyond antibiotic

therapy on its own.32 With only antibiotic treatment and supportive care it has historically

been demonstrated that mortality in NF infections is close to 100%.30 This is not to say

that antibiotic therapy is not important, but that it should only be used in conjunction with

rapid surgical debridement. Due to the variety of bacterial organisms often responsible

for NF infections, a broad-spectrum range of antibiotics should initially be used until

results for gram stain and culture are completed.57 The following table (Table 9) indicates

a first-line approach in antimicrobial treatment against NF infections.57

 

35

 

Table 9: First-line Antimicrobial Treatments. The combination of antibiotic treatments demanded in mixed infections, Streptococcus infections, S. aureus infections, and Clostridium infections are indicated in the table above (organized by infection type).57

 Beyond surgical treatment, antibiotics, and supportive care, new supplemental

treatments include hyperbaric oxygen and the use of a vacuum-assisted closure (VAC)

device. Vacuum-assisted wound closure is now used by many surgeons and is thought to

increase the efficiency and the time frame for wound closure.58 The vacuum-assisted

wound closure device consists of a sponge attached to a vacuum pump, through tubing,

that allows the passage of negative pressure, improving wound healing through

microstrain.46 Specifically, the negative pressure that is regularly applied to the site of the

wound throughout the healing process is meant to optimize oxygenation of tissue by

increasing local blood flow.47 Accelerated formation of granulation tissue, fibroblast

 

36

growth, removal of wound fluids and a decrease in local edema at the site of the wound

are other common benefits of VAC therapy.47 Before vacuum-assisted wound closure

techniques, gauze therapy was a more common approach to wound closure but several

studies have indicated that wound management and wound surface area are significantly

improved with vacuum assisted therapy.50 Example of vacuum-assisted wound closure

used to close a surgical wound (Figure 10)46:

 

Figure 10: Vacuum-assisted Wound Closure Therapy. Above is a sterile open-cell sponge at the site of a wound covered with adhesive tapes creating an air-tight environment. A vacuum pump is attached using tubing and continuous negative pressure is applied through the tube, ideally removing exudates, decreasing local edema and bringing wound edges closer together through microstrain.46

 

37

Hyperbaric oxygen is another supplemental treatment modality that still remains

controversial in its specific efficacy toward treating NF wounds. Use of this modality

requires placing the patient into a high oxygen environment under specific atmospheric

pressures for variable durations of time.39 Hyperbaric oxygen theoretically increases the

efficiency of leukocyte function, destroys anaerobic bacterial species, decreases edema,

and stimulates the growth of fibroblasts and formation of collagen structures throughout

the exposed tissue.15, 38 There have been several studies indicating that HBO treatment

increases survival rates among patients requiring wound repair and treatment, but specific

to necrotizing wounds none are completely conclusive. In treating necrotizing wounds

specifically, no specific protocol for optimum treatment has yet been determined.

PUBLISHED STUDIES

  Diagnosis of NF in the ED requires several challenges for physicians. Certain

distinguishing factors must be incorporated into their clinical suspicion in order to avoid

misdiagnosis of a less severe soft-tissue infection and to maintain awareness of the rapid

treatment that must be employed if NF is suspected. The study published by Low et al.

introducing the LRINEC score provides a critical tool for the diagnosis of NF in an

emergency room setting. Through the analysis of various results indicated in the

following table the most significant variables contributing to the NF diagnosis were

identified (Table 10).73

 

38

 

Table 10: LRINEC Score Analysis. Univariate and multivariate logistic regression analysis was applied to all variables tested including laboratory tests, age, and gender. From the thirteen variables, seven were excluded; they did not reach statistical significance at the level of p<0.05. The other six including CRP, hemoglobin, sodium, glucose, creatinine, and white blood cell count were determined as candidate diagnostic variables.73

 

39

The LRINEC score calculation requires the measurement of CRP, glucose,

hemoglobin, creatinine, total WBC count, and sodium values. The most recent data

collected by Neeki et al. at the Arrowhead Regional Medical Center ED in California

retrospectively studying 139 adult cases of confirmed NF found the fraction of vital sign

abnormalities, physical exam symptoms, imaging results, and abnormal lab values among

the cohort to inform physicians and raise their sense of clinical suspicion on clues to

diagnosis. The most prevalent signs and symptoms observed in this cohort study include

local pain, erythema, edema, tachycardia, tachypnea, and fever.5 These signs and

symptoms have been consistently observed as the most common across several other

studies as well.28, 56, 66 Furthermore, Wong et. al also composed a study analyzing

physical findings of NF patients upon hospital admission and found tenderness,

erythema, warmth to palpation, tachycardia, and fever as the most common symptoms.74

The following signs and symptoms as well as their prevalence among the individual

patient population studied are indicated in the following table (Table 11).74

 

40

 

Table 11: Prevalent Physical Exam Findings. A total of 89 patients with necrotizing fasciitis and the prevalence of their signs and symptoms upon hospital admission are presented above. In this case, swelling (edema) is not included in the table but was observed in 82 of the 89 patients (92.1%). Erythema, tenderness, and warm skin to palpation were the most common physical findings in this cohort.74

 Early diagnosis is critical in patients with NF and the time until first surgical

debridement is a significant indicator of patient mortality. Primary debridement delayed

more than 24 hours after symptom onset increases relative risk of mortality by 9 times.55

Diagnosis in an emergency setting is the focus here and although the LRINEC score and

the signs and symptoms can provide dramatic insight to a physician, it is essential to also

 

41

maintain a high clinical suspicion for NF. Once diagnosis has been confirmed and a

broad spectrum of antibiotics has been administered, the next immediate step is surgical

debridement in the operating room.

Techniques in surgical debridement have been normalized in most cases of NF

and involve incision at the site of maximum fluctuance followed by cuts extending

parallel to the skin’s Langer lines to minimize future scaring and maximize rapid wound

healing. This approach is also thought to decrease the need for future amputation by

limiting the course of infection throughout the fascial plane and therefore minimizing the

loss of tissue.42 The most important aspect of surgical debridement is that it be done early

and that it also be followed up within the next 24 hours and in the future with further

debridement and tissue exploration as needed.55 The extent of tissue that should be

initially removed remains controversial due to reports of microscopic pathologies

discovered in normal appearing skin around the site of infection.3 For this reason, many

groups have encouraged adequate and aggressive excision of tissue, especially upon the

first operation.10 In one case, up to 45% of a patients surface area was excised with

recorded recovery and survival.10

The majority of treatment for NF is otherwise standardized as described by Roje

et al. and begins with general resuscitation if the patient is in shock, followed by a broad

range of antibiotics covering anaerobic and aerobic pathogens. Next, the patient should

receive surgical debridement in the operating room; at this time cryosections, gram stain,

and culture should be obtained from the wound for biopsy and specified diagnosis.

Repeated surgical debridement should be continued regularly and an adjusted regiment of

 

42

antibiotics (based on cultures) should be administered until the patient’s infection is

under control. Follow-up debridement and skin grafts should be continued as needed. 55

In one study, the median number of follow up surgical debridement operations was four

but if debridement as well as skin grafting procedures are considered, the average rises to

33 follow up procedures.21, 55 Lastly, it is recommended that antibiotic therapy be

continued up for 3-5 days following the termination of all signs and symptoms of soft

tissue infection.55

In regards to VAC therapy, the current evidence is not completely conclusive on

its benefits. The lack of negative effects recorded across all studies as well as the minor

improvements in patient comfort as a result of the therapy have increased the use of VAC

therapy in NF treatment and for general wound care.47 The alternative to VAC therapy

consists of covering the surgical wound site with saline wet-to-dry dressings that are

regularly changed for cleanliness and optimal healing. A previous study that compared

this conventional therapy to the use of VAC therapy found that there was no significant

difference in wound healing as a result of either treatment. On the other hand, VAC

therapy significantly lessened patient pain throughout the process, increased patient

mobility, and decreased the number of dressing changes that were required.52 Another

case study found that VAC therapy among NF patients significantly reduced hospital

admission time and general patient discomfort and proved effective in not only cleaning

open wounds but also disrupting the process of fasciitis specific to NF infections.17 Other

groups have studied the effectiveness of VAC therapy in treating acute and chronic

wounds distinct from NF infections. Generally, VAC therapy, with respect to wound

 

43

care, has demonstrated a faster rate of wound healing when compared to conventional

treatments and a reduction in the hospital stay period and costs of patient care.4 VAC

therapy is promising in its ability to decrease patient discomfort and improve patient

satisfaction throughout the recovery process.4

RESULTS

The LRINEC score is an important tool for clinicians and has demonstrated

significant success in the prediction of NF diagnosis. Wong et al. were able to separate

patients in their retrospective observational cohort study into three different risk level

categories depending on calculated LRINEC score. LRINEC score less than or equal to 5

indicates low risk and corresponds to a probability of less than 50% for developing an NF

infection. LRINEC score of 6-7 indicates moderate risk and corresponds to a probability

of 50-75% for developing NF. Lastly, a LRINEC score greater than or equal to 8 is

indicative of the high-risk category and corresponds to a greater than 75% probability of

developing NF.73 The maximum LRINEC score obtainable is 13 and an official cutoff for

probable diagnosis is made at 6. Using this model they calculated a positive predictive

value of 92% (with a 95% confidence interval, 84.3-96.0) and a negative predictive value

of 96% (95% confidence interval, 92.6-97.9) for the LRINEC score cutoff.73

A validation cohort was also used to externally confirm the LRINEC score model.

In this case, 56 patients with confirmed NF diagnosis and 84 control patients again with

cellulitis, from a different hospital, were evaluated. The model was confirmed through

 

44

external validation and demonstrated an area of 0.976 (95% confidence interval, 0.955-

0.997) under the receiver operating characteristic curve. (If a predictive model functions

with perfect accuracy the area is 1.0).73 The receiver operating characteristic curve

demonstrating the accuracy of LRINEC score diagnosis is indicated in the following

figure (Figure 11).73

 

Figure 11: LRINEC Score Accuracy of Diagnosis. To validate the LRINEC model an external cohort from a separate hospital of 56 patients diagnosed with NF and 84 control patients with abscesses or severe cellulitis were compared. In this “validation” cohort, CRP values were only available for 87.9% of the 140 patients but the model was otherwise found to be reliable with an area under the receiver operating characteristic curve (ROC) of 0.976 with 95% CI between 0.955 to 0.997.73

 

45

In the developmental cohort and external validation cohort, 89.9% and 92.9%

respectively, of patients with NF had a LRINEC score greater than or equal to 6.

Likewise, only 3.1% and 8.4% respectively, of control patients in the two groups had a

LRINEC score greater than or equal to 6.73 The following figure (Figure 12) 73 combines

both the developmental cohort and the validation cohort to stratify patients into low,

moderate, and high-risk categories based on LRINEC score.

 

Figure 12: Categorical Severity by LRINEC Score. Patients were stratified into three groups (low, moderate, and high risk for NF diagnosis) based on LRINEC score values. Each level risk group correlates to a certain probability of developing an NF infection. Low risk group (LRINEC ≤ 5); moderate risk group (LRINEC 6-7); high risk group (LRINEC ≥ 8).73

 

46

Beyond the LRINEC score, clinicians should maintain an elevated level of

suspicion for NF and also look to physical exam signs and symptoms. When Neeki et al.

retrospectively studied 139 patients with a confirmed diagnosis of NF over a seven-year

period at Arrowhead Regional Medical Center (ARMC), the following signs and

symptoms prevailed: local pain (85.9%) was the most common physical exam symptom

in NF patients followed by erythema (67.4%), edema (58.5%), and tenderness to

palpation (35.0%). In regards to vital signs, the most common abnormality was

tachycardia (heart rate > 98 beats per minute) (75.6%), followed by tachypnea

(respiratory rate > 19 breaths per minute) (53.3%), and fever (temperature > 100.4

degrees Fahrenheit) (47.4%). Imaging exams indicated gas on CT in 62.5% of cases and

gas on X-ray in 22.2% of cases. Lab values indicated values of D-dimer > 250 in 97.0%

of patients, glucose > 110 in 74.1% of patients, bandemia > 9 in 71.9% of patients and

lactate > 2.1 in 56.4% of patients.5

DISCUSSION

Current literature proposes several signs and symptoms indicative of NF

infections for clinicians to consider when diagnosis is suspected. Furthermore, the

LRINEC score has demonstrated considerable accuracy in diagnosing NF infections over

other soft-tissue infections. Still, the scarcity of skin findings, the rare instance of these

infections, and a lack of proper clinical suspicion causes cases of NF to often go missed

or misdiagnosed. In the developmental cohort of 89 patients with NF from the

retrospective study that was used to develop the LRINEC score model, only 14.6% (13)

 

47

were initially admitted for necrotizing fasciitis. In the remaining 76 (85.4%) patients,

there was no suspicion or diagnosis of NF until after hospital admission, essentially

delaying surgical debridement and increasing the possibility of mortality.73 If the

LRINEC score was applied in these cases, there could have been a significant

improvement in time to initial surgical debridement and therefore in mortality rate. From

the 89 patients, 80 of them (89.9%) had a LRINEC score retrospectively calculated to be

greater than or equal to 6 (the minimum cutoff for increased clinical suspicion).

The LRINEC score has minor complications of its own that may require revision.

Unfortunately, the most impactful variable required to calculate the score is a CRP value.

This lab result, if greater than the indicated threshold, adds 4 points to the LRINEC score.

All other variables, if significant, can add a maximum of 2 points to the LRINEC score.

In this case, the CRP value is heavily weighted in a LRINEC score calculation.

Unfortunately, the CRP value is not always measured in an emergency room setting and

was often not collected in the study that initially developed the LRINEC mode. This

laboratory test requires a specific order from clinicians and is not included on the basic

laboratory tests that are routine for skin infections, including the Complete Metabolic

Panel (CMP) or Basic Metabolic Panel (BMP), and Complete Blood Count (CBC) blood

tests. For this reason, it is critical to develop a new model of the LRINEC score, namely a

modified LRINEC score. Future studies need to be initiated to retrospectively study a

larger number of NF cases throughout the nation to statistically develop a modified

LRINEC score based solely on laboratory results indicated in basic ED lab tests. This

 

48

advancement would ensure that less NF diagnoses are missed in the ED and rapid

evaluation will decrease the time to first surgical debridement.

Furthermore, it is important to analyze the signs of NF beyond only laboratory

tests. A retrospective observational study with a very large number of NF cases is

required in order to determine immediate clues to NF diagnosis through physical

examination. Although the pathogens may vary greatly, it is evident both through the

most recent analyses by Neeki et al and past literature that certain physical exam signs

are consistent among patients with NF. The consistencies and distinctiveness in clinical

signs have not yet been statistically analyzed to the point of developing a scoring system

similar to the LRINEC score. The analysis and determination of the most prominent

clinical signs such as tachycardia, fever, local pain, and others can lead to an objective

scoring system further assisting clinicians in their diagnosis of NF. Using the most

prominent signs of NF, a diagnostic measure must be made that is meant to increase

clinical suspicion depending on the number of signs that are, or are not present.

A modified LRINEC score along with a scoring system set up for distinguishing

clinical signs of NF will greatly decrease the chances of missing a diagnosis. By properly

educating clinicians on the implications of this serious infection and the signs and

symptoms that come along with it, it is possible to lessen the rate of mortality in NF cases

across the country. Statistical analyses of routine laboratory results and clinical signs

from past and present cases of NF are an imperative next step. Through this in depth,

large-scale analysis, a confident method of NF diagnosis for emergency departments

across the country will arise.

 

49

Once a confident method of diagnosis has been established, routine treatment,

which is based primary on surgical debridement, should proceed as current methods

suggest. There is no current method allowing specification of the required antibiotics

based on initial lab tests and clinical signs and therefore a broad spectrum is necessarily

administered until cultures have been resulted. Hyperbaric oxygen therapy remains

controversial and it is uncertain whether it is beneficial in most cases. Previous studies

have not applied proper controls and remain open to criticism. To determine the potential

benefits of hyperbaric oxygen therapy, similar NF infections in matched patients must be

compared. The challenge lies in the variability of NF infections. Depending on

comorbidities, demographics, location of infection, and several other factors, it is difficult

to match individual patients into treatment and control groups for hyperbaric oxygen

therapy. The possible benefits that may arise from successful HBO therapy warrant the

need for future studies. Before the use of HBO therapy is widely suggested in all cases of

NF wound healing, it is important that large-scale studies with proper controls be set in

place to determine the effectiveness of the treatment.

On the other hand, vacuum-assisted closure therapy has recently demonstrated

more promising results for wound healing after surgical debridement. One of the most

recent case reports employing VAC for wound healing, by Mizuguchi et al. demonstrated

successful treatment of a potentially lethal case of NF, of a 58 year-old male, reaching

from the lower leg to the perineum. Following surgical debridement, VAC therapy was

applied before skin grafting procedures and notably expedited wound healing as

compared to conventional therapy. The therapy also greatly improved comfort levels

 

50

during the process of healing, for both the patient involved and the medical staff

managing his wounds.47 The case can be used as a model for treatment of severe NF. The

successful transformation and wound healing process are demonstrated in the images

below (Figure 13).47

 

51

a) b)

c) d)

Figure 13: Successful Treatment of Necrotizing Fasciitis Infection. (a) Status-post second surgical debridement (b) VAC therapy applied to site of wound after debridement (c) Status-post sixth surgical debridement and VAC therapy; healthy granulation tissue present throughout (post-operative day 21) (d) Site of infection healed using mesh-graft skin procedure to cover wound.47

 

52

Beyond this individual case, VAC therapy has provided promising results in cases

of NF wound management as well as the management of a variety of other acute and

chronic wounds.47 Although its application in managing cases of NF infections may only

alleviate and improve minor factors in wound care and patient satisfaction, the lack of

noted negative effects warrants its application in future cases. The improvements in cost,

decreased hospital stay, and patient comfort indicate that the treatment should be widely

applied in addition to other current conventional NF treatment. VAC therapy has not been

indicated to decrease patient mortality but its application will be a successful step toward

better patient management.

The greatest improvement in patient mortality can be made through early

diagnosis in emergency departments leading to rapid surgical treatment and minimization

of worsening symptoms and the spread of infection. Future studies are necessary to

develop a modified LRINEC score from basic ED laboratory tests as well as an objective

scoring system for the clinical signs and symptoms that most commonly accompany NF

infections. Through the development of these two models and an advancement of clinical

suspicion through physician education, the diagnosis of NF can become standardized and

conventional.

 

53

LIST OF JOURNAL ABBREVIATIONS

 Am  J  Med                                American  Journal  of  Medicine  

Am  J  Surg                                      American  Journal  of  Surgery  

Ann  Fr  Anesth  Reanim                          Annales  Francaises  Anesthesie  Reanimation  

Ann  Otol  Rhinol  Laryngol                      Annals  of  Otology,  Rhinology,  &  Laryngology    

Ann  Plast  Surg                        Annals  of  Plastic  Surgery  

Ann  Surg                                                      Annals  of  Surgery  

Ann  Thorac  Surg                                  Archives  of  Thoracic  Surgery  

Arch  Dermatol                        Archives  of  Dermatology    

Arch  Intern  Med                                Archives  of  Internal  Medicine  

Arch  Surg                    Archives  of  Surgery  

BMJ                                        BMJ:  British  Medical  Journal  

Br  J  Surg                        British  Journal  of  Surgery  

Can  J  Surg               Canadian  Journal  of  Surgery  

Cleve  Clin  J  Med                                Cleveland  Clinic  Journal  of  Medicine  

Clin  Dermatol                 Clinical  Dermatology  

Clin  Exp  Dermatol           Clinical  Experimental  Dermatology  

Clin  Infect  Dis                  Clinical  Infectious  Diseases  

Clin  Orthop  Related  Res            Clinical  Orthopedics  &  Related  Research  

Crit  Care  Med                                    Critical  Care  Medicine  

Dermatol  Surg                            Dermatological  Surgery  

 

54

Hong  Kong  Med               Hong  Kong  Medicine  

Infect  Dis  Clin  North  Am                            Infectious  Disease  Clinics  of  North  America  

Intern  Med                            Internal  Medicine  

J  Am  Coll  Surg                Journal  of  American  College  of  Surgeons  

J  Clin  Pathol                                      Journal  of  Clinical  Pathology  

J  Emerg  Med                          Journal  of  Emergency  Medicine  

J  Hand  Surg                            Journal  of  Hand  Surgery  

J  Hosp  Infect                                  Journal  of  Hospital  Infections  

J  Trauma                          Journal  of  Trauma  

N  Engl  J  Med                  New  England  Journal  of  Medicine  

Nephrol  Dial  Transplant                Nephrology  Dialysis  Transplants  

Plast  Reconstr  Surg                          Plastic  Reconstructive  Surgery  

Rev  Urol                      Reviews  of  Urology  

Rheum  Dis  Clin  North  Am                  Rheumatoid  Disease  Clinics  of  North  America  

Urol  Int                                      Urology  International  

World  J  Emerg  Surg                            World  Journal  of  Emergency  Surgery    

 

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18. Das, D., Baker, M. and Venugopal, K. Risk factors, microbiological findings and outcomes of necrotizing fasciitis in New Zealand: a retrospective chart review. BMC Infectious Diseases 2012; 12:348 19. Descamps V, Aitken J, Lee MG. Hippocrates on necrotising fasciitis [letter]. Lancet 1994; 344:556 20. Elliott D, Kufera JA, Myers RA. The microbiology of necrotizing soft tissue infections. Am J Surg 2000;179:361-6 21. File TM Jr, Tan JS, DiPersio JR. Group A streptococcal necrotizing fasciitis. Diagnosing and treating the “flesh-eating bacteria syndrome”. Cleve Clin J Med 1998; 65: 241-249 22. Fischer JR, Conway MJ, Takeshita RT. Necrotizing fasciitis: importance of roentgenographic studies for soft-tissue gas. JAMA 1979; 241:803-06 23. Francis KR, Lamaute HR, Davis JM. Implications of risk factors in necrotizing fasciitis. Am Surg 1993; 59:304-08 24. Frazee BW, Fee C, Lynn J, et al. Community-acquired necrotizing soft tissue infections: a review of 122 cases presenting to a single emergency department over 12 years. J Emerg Med 2008; 34: 139-146

 

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76. Yamaoka M, Furusawa K, Uematsu T. Early evaluation of necrotizing fasciitis with use of CT. J Cranioma Nillofac Surg 1994; 22:268-71 77. Yeung YK, Ho ST, Y en CH, Ho PC, Tse WL, Lau YK, et al. Wong factors affecting mortality in Hong Kong patients with upper limb necrotising fasciitis. Hong Kong Med J 2011; 17:96–104 78. Yong JM. Necrotising fasciitis [letter]. Lancet 1994; 343:1427

 

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CURRICULUM VITAE

NIMA KHOSHAB

February 16, 1991 23 Bayberry Way, Irvine, CA 92612

(949) 735-2350 nkhoshab2@gmail.com

EDUCATION Boston University – (4.00) (August 2014 – May 2016) Master of Science – Medical Science University of California, Irvine – (3.46) (September 2009 - June 2013) Bachelor of Science – Neurobiology RESEARCH & PROFESSIONAL EXPERIENCE University of California, Irvine (October 2015 – Present) Department of Neurology Principal Investigator: Steven Cramer, M.D. Junior Specialist

• Study the mechanisms of neural plasticity in relation to sensory and motor rehabilitation • Use EEG cap to collect EEG data from emergency room patients at UCI Medical Center • Apply both Cognionics and MATLAB software to examine and interpret EEG data • Process MRI files using Linux and MRIcron software in collaboration with other

laboratories Arrowhead Regional Medical Center (October 2015 – Present) Emergency Department (ED) Supervisor: Michael Neeki, D.O. Clinical Researcher

• Directly assist in writing and data interpretation for several ongoing studies in the ED including literature reviews on necrotizing fasciitis and tranexamic acid

Scribe America (October 2015 – Present) Emergency Department—Hoag Hospital Supervisor: Nadja Pearlman, Chief Scribe Emergency Room Scribe

• Work with emergency physicians to document and manage patient charting information National Institute of Mental Health (August 2013-July 2014) Section on Molecular Neurobiology Principal Investigator: Barry Kaplan, Ph.D. Post-baccalaureate Research Fellow

• Investigate the role of microRNAs in local protein synthesis in axons • Isolate and culture rat primary superior cervical ganglia (SCG) using Campenot

 

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compartmentalized chambers • RNA isolation and qRT-PCR from axonal mRNAs from primary neuronal cultures • Transgenic mouse breeding and genotyping • Behavioral phenotyping of transgenic mice

University of California, Irvine (June 2011 – June 2013) Department of Anatomy & Neurobiology Principal Investigator: Daniele Piomelli, Ph.D. Research Assistant

• Pursue independent project investigating the role of endocannabinoids in Alzheimer’s disease

• Generate and examine primary neuron cultures from over 300 rat embryos • Conduct literature search to develop hypothesis and design project • Analyze data and interpret results to build on the field of endocannabinoid research • Present findings from project in the form of multiple talks, a poster, and manuscript • Independently enhance lab protocols to increase yield of primary neuron cultures • Teach lab techniques to incoming undergraduates and graduate students

Radboud University, Netherlands (August 2012 –September 2012) Department of Neuroinformatics Principal Investigator: Armaz Aschrafi, Ph.D. Research Assistant

• Contribute to review article discussing long non-coding RNAs in neurodevelopmental disorders

• Gain exposure to unique tissue culture approach using chamber slides to study function of microRNAs

• Acquire skills working with neuron tracing software, Neurolucida • Perform previously mastered cell/molecular techniques in a foreign environment

HONORS & AWARDS Excellence in Research (May 2013) Excellence in Research Award at UC Irvine

• Completed a year-long independent project on undergraduate research interest • Wrote a manuscript to communicate results to the scientific community • Presented findings in a talk within the Department of Anatomy & Neurobiology at UC

Irvine • Assembled and displayed a poster outlining the conclusions of project at research

symposium UROP Research Grant (January 2013) Undergraduate Research Opportunity Program at UC Irvine

• Wrote grant proposal for independent project: “Oligomeric Amyloid-ß42 Increases Endocannabinoid Signaling in Cultured Cortical Neurons”

• Awarded $500.00 research grant to partially cover costs of the project • Presented findings and application of money at end of the year undergraduate symposium

 

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PUBLICATIONS Publication (December 2013)

• Van De Vondervoort II, Gordebeke PM, Khoshab N, Tiesinga PH, Buitelaar JK, Kozicz T, Glennon JC, Aschrafi A. (2013). Long non-coding RNAs in neurodevelopmental disorders. Frontiers in Molecular Neuroscience, doi: 10.3389/fnmol.2013.00053

VOLUNTEER EXPERIENCE The Tiyya Foundation (October 2015 – Present) Refugee Services Supervisor: Meymuna Hussein-Cattan, Director Workshop Coordinator & Tutor

• Lead weekly workshops for refugees searching for employment • Tutored refugee children in academic coursework including English, math, and sciences

National Institutes of Health (December 2013- July 2014) NIH Clinical Center Operating Room Supervisor: Courtney Duncan, Volunteer Coordinator Operating Room Patient Ambassador

• Assisted in patient preparation and transportation from in-patient centers to the operating room

Big Brother Mouse (July 2013) Youth Literacy; Luang Prabang, Laos Volunteer English Tutor

• Tutored Lao high school students in conversational English and English vocabulary Global Visions International (June 2010 – August 2010) Jatun Satcha Foundation; San Cristobal, Galapagos Islands Volunteer

• Preserved endemic species and helped develop self-sustaining food systems for island inhabitants

SPECIAL INTERESTS & SKILLS

• Fluent in spoken Persian; fluent in written and spoken Spanish • Excellent written and verbal skills; extremely organized and diligent • Self-sufficient and very quick to learn • Interests: traveling, cooking, chess, hiking, photography, reading, yoga, soccer, and

basketball