Content uploaded by Damian Mingle
Author content
All content in this area was uploaded by Damian Mingle on Jan 23, 2017
Content may be subject to copyright.
International Clinical Pathology Journal
| http://medcraveonline.com
Volume 2 Issue 6 - 2016
2
3
4
Damian Mingle, Chief Data
Scientist at WPC Healthcare 1802 Williamson Court,
Brentwood, Tennessee, USA,
Email:
September 20, 2016 | October 19,
2016
Review Article
Int Clin Pathol J 2016, 2(6): 00063
Abstract
Sepsis affects millions of people worldwide each year. It occurs when a normal
human immune response to a bacterial, viral or fungal infection becomes
dysfunctional and triggers widespread inflammation that results in severe tissue
damage that leads to organ failure, shock, and death. Sepsis requires immediate
treatment and has a high readmission rate for survivors. It is also one of the most
expensive conditions to treat. In 2013, there were more than 1.6 million cases of
sepsis in the United States with a financial cost of more than $23 billion. Sepsis
was first described in antiquity, and given its current name, by the ancient Greek
physician Hippocrates. Despite its long medical history, severity, and financial
burden, the causes of sepsis are not well understood, and there is no standard
approach to diagnosis and treatment. The definition of sepsis, the characterization
of its clinical stages, and sepsis monitoring tools have changed three times in the
past 25 years, most recently in March 2016. The universal adoption of this latest
definition, sepsis-3, and a screening tool, qSOFA, are currently under debate in
the medical community. A means to rapidly identify and treat sepsis could reduce
the five million deaths due to sepsis each year worldwide. This paper reviews the
evolution of the definition of sepsis and the controversy surrounding the sepsis-3
definition and the sepsis screening tool, qSOFA.
Keywords: Sepsis; Septic shock; Severe sepsis; SIRS; Critical care; Electronic
healthcare records; Sepsis-3; qSOFA
Abbreviations: APACHE: Acute Physiology and Chronic Health
Evaluation; EWS: Early Warning Score; HUCP: The Healthcare
Cost and Utilization Project; ICU: Intensive Care Unit; MEDS:
Early Warning System; MIMIC: Medical Information Mart for
Intensive Care; PIRO: Predisposition, Infection, Response to the
infectious challenge, and Organ dysfunction; qSOFA: quick Sepsis-
Response Syndrome; SOFA: the Sepsis-related Organ Failure
Introduction
Sepsis is one of the oldest, costliest, and most devastating
in ancient Egypt almost 5,000 years ago and given its current
name by the Greek physician Hippocrates about 2,400 years ago
States was more than $23 billion. Despite its long history and its
current impact on society, sepsis as a medical condition is not
there is no gold standard diagnostic test for sepsis, nor is there
a universally adopted treatment [6]. Along with revising the
identify sepsis. A medical task force utilized the recent availability
of large datasets of patients to compare and validate several
screening tools for sepsis. These tools were used to explore more
than one million patient electronic healthcare records (EHR) with
a known number of patients with sepsis [7]. The use of a data
science approach to validating a screening tool for sepsis is a
promising area of research. In this paper we describe the severity
e Severity of Sepsis
rates. Worldwide, an estimated 31.5 million people are treated
each year for sepsis of which 5.3 million end up dying from sepsis
[8]. In the United States, there are about 1.6 million cases of sepsis
each year with more than 258,000 deaths, which averages to one
of treating sepsis is staggering. The 2015 Healthcare Cost and
Utilization Project (HUCP) Statistical Brief places sepsis as the
most expensive condition treated in US hospitals at $23.7 billion
[10]. Sepsis accounts for 40 percent of all ICU costs in the United
States, and the average cost for treatment of ICU patients with
sepsis is six times greater than that for ICU patients that do not
have sepsis. Additionally, patients discharged after a serious
bout of sepsis have a 62 percent readmission rate [11,12]. This
information on the severity of sepsis is summarized in Table 1.
Notable facts about sepsis.
High cost to treat Most expensive condition treated in the
United States: $23.7B
High ICU costs 40% of all ICU costs
High mortality rate 60% for septic shock
High readmission rate 62%
Rapid decline Move to septic shock within 36 hours of
Challenging No standard diagnostic test, often appears
with co morbid conditions
2/6
Copyright:
©2016 Gary et al.
10.15406/icpjl.2016.02.00063
Research has shown early detection of sepsis is essential in
saving lives and reducing costs [6,13,14]. The Sepsis Alliance
estimates that 80percent of deaths due to sepsis could be
prevented with rapid diagnosis and treatment [9].
e Evolving Denition and Monitoring of Sepsis
was thought to be an internal rotting or decaying. This was due
word for decay-, meaning decay or to rot-to this
medical condition. The development of medical hygiene and
the germ theory in the late 1800s by Louis Pasteur, Joseph
Lister, and Robert Kock helped change the viewpoint of sepsis
from internal decay to originating from a harmful
microorganism. In 1914,
sepsis when he wrote, “Sepsis is
present if a focus has developed from which pathogenic bacteria,
constantly or periodically, invade the blood stream in such a
way that this causes subjective and objective symptoms” [16].
As sepsis became more common in ICUs, the role of the patient’s
immune response became a greater focal point [17]. In 1992, a
conference was held by the Society of Critical Care Medicine and
the American College of Chest Physicians to address the lack of
this created in studies and treatment. This conference and its
outcomes are now referred to as sepsis-1. This was followed by
sepsis-2 in 2002 and sepsis-3 in 2016.
A. Key outcomes from thesepsis-1 conference (Bone et al. [17]):
a)
response syndrome” (SIRS) was considered a clinical stage
of sepsis.
b)
c)
to diagnose sepsis.
d) The terms “severe sepsis” and “septic shock” were
introduced to differentiate degrees of severity.
B.
a)
response syndrome (SIRS) to infection.
b) Severe sepsis is sepsis associated with organ dysfunction,
hypo per fusion, or hypotension.
c) Septic shock is sepsis-induced hypotension persisting
The sepsis-1 conference also established four clinical stages or
by the presence of at least two of the following four indicators:
(1) a body temperature above 38.0 °C or below 36.0 °C; (2) a
heart rate above 90 beats/minute; (3) a respiratory rate above
20 breaths per minute; (4) a white blood cell count higher than
12,000 or lower than 4,000 cells per micro liter.
changes from SIRS to sepsis. As sepsis progresses from one stage
to another, there is a corresponding increase in the mortality
rate with septic shock having the highest. Table 2 lists the 30-
day mortality rates published for SIRS and sepsis [18] and those
published for severe sepsis and septic shock [19].
Each of the four stages listed in Table 2 have been used at
untreated the smell of rotting became apparent. This would be
focused on the infection in stage 2 until this shifted to stage 1,
beginning of organ failure in stage 3, severe sepsis.
Mortality rates within 30 days of diagnosis.
7% 16% 40% > 50%
Flu-like symptoms SIRS + infection Sepsis + signs of organ
failure Persistent severe sepsis
6
Sepsis-1 &-2
Pre-Sepsis-1
Sepsis-3
5
Hippocrates
be due to a
wide variety of other medical
conditions.
Time:
It could take days
to verify source of
infection.
Treatment:
Limited treatment
options when organs
begin to fail.
High mortality rate:
Often too late for
successful treatment.
3/6
Copyright:
©2016 Gary et al.
10.15406/icpjl.2016.02.00063
A.
sponsored by the Society of Critical Care Medicine, European
Society of Intensive Care Medicine, and American College of
Clinical Pharmacy, American Thoracic Society, and the Surgical
Infection Society. The consensus task force was formed to
review the clinical progress made in treating sepsis and sepsis-1
a)
limitations;
b) Expanding the list of diagnostic criteria for sepsis; and
c) Recognizing the separate characteristics or stages of sepsis
designated by the acronym PIRO: redisposition, infection,
response to the infectious challenge, and organ dysfunction
[20].
The expanded list of diagnostic criteria of sepsis included
21 bedside or laboratory tests designed to indicate either
Since the introduction of sepsis-2, there has been an increase
in the use of organ failure or mortality scoring systems also
known as early warning scores (EWS) systems. These EWS
systems are used in most ICUs as a method to triage the severity
of critically ill patients. They are bedside evaluations designed
to provide a likely mortality rate within 28 to 30 days. Several of
these EWS systems were developed in line with the sepsis-1 and
to monitor sepsis include:
a. APACHE II (the Acute Physiology and Chronic Health
Evaluation II) Score, introduced in 1985,
b.
[21].
c. MEDS (see Table 3 & 4), and
d. SOFA (the Sepsis-related Organ Failure Assessment) [22].
The MEDS EWS checklist.
MEDS’ score and corresponding mortality rate.
4/6
Copyright:
©2016 Gary et al.
10.15406/icpjl.2016.02.00063
To illustrate an EWS, the scores used to determine a
patient’s mortality rate using MEDS is shown below. Table 3 is
the checklist used to determine the score and Table 4 shows
the predicted mortality rate based on the score.
These EWS systems have helped identify the progress of
sepsis in patients and allowed ICUs to determine where to
deploy their
of sepsis, especially in the ICUs where up to 40
percent of the cost can be due to treating patients with sepsis.
Along with these early warning systems, sepsis awareness
Care Medicine and the European Society of Intensive Care Medicine
provide direction for the Surviving Sepsis Campaign, which, in
2009, helped achieve a 25 percent reduction in sepsis mortality
through awareness and education about sepsis, especially among
healthcare providers [23]. The Sepsis Alliance, a voluntary health
organization founded in 2004, is raising awareness of sepsis
among healthcare providers and the general public. This included
launching sepsis awareness month, September, helping launch
the global sepsis alliance, the heroes of sepsis celebration, and
designating September 13 as world sepsis day. The hero of sepsis
celebration focuses on recognizing organizations and individuals
that have contributed to advancing sepsis research and education.
This event brings together survivors with healthcare providers.
the 2016 hero of sepsis.
C.
In 2014, the European Society of Intensive Care Medicine
(ESICM) and the Society of Critical Care Medicine (SCCM)
convened a task force of 19 critical care, infectious disease,
surgical, and pulmonary specialists with the aim to update the
The sepsis-3 task force recognized sepsis as more complex
threatening organ dysfunction due to a dysregulated host
response resulting in organ failure from an infection is stressed
has been removed. The task force included advances made in
understanding the pathology, management, and epidemiology
of sepsis as well as an analysis of over one million patients. The
results published in the February 2016 issue of JAMA, the Journal
of the American Medical Association, reduced the clinical stages
in sepsis from the four described in Table 2 to the last two stages
[6]. The previous of clinical stage known as severe sepsis is now
organ dysfunction caused by a dysregulated host response to
in Table 5 below.
To determine which early warning signal to recommend, the
sepsis-3 task force compared a variety of EWS systems used to
monitor sepsis. The results showed that the qSOFA EWS
systems was similar to the accuracy in most EWS systems, but is
easier to use and more accurate in locations outside of or prior
to admissions into
suggests a high risk of poor outcome
and an indication that these patients have sepsis and should have
their lactate levels tested for evidence of organ dysfunction.
Key Feature
1. Severe sepsis
2. Septic shock
Introduces a
new diagnostic
tool, quick
SOFA, or qSOFA
is a life-threatening organ dysfunction
caused by a deregulated host response to
infection.
is a subset of sepsis in which
particularly profound circulatory, cellular, and
metabolic abnormalities are associated with
a greater risk of mortality than with sepsis
alone.
qSOFA scoring.
Criteria Point Value
Altered mental status +1
Respiratory rate > or = 22 +1
Systolic blood pressure < or = 100 +1
To validate qSOFA as a screening and monitoring tool for sepsis,
scores were applied to a large set of electronic health
record data that contained known patients with sepsis. The
dataset used contained the electronic health record data of 1.3
million encounters from January 1, 2010, to December 31,
2012, at 12 community and academic hospitals within the
University of Pittsburgh Medical Center health system in
southwestern Pennsylvania were used for this comparison.
The predictive validity of qSOFA and other EWS tools were
compared by plotting the area under the receiver operating
characteristic curve (AUROC). The recent availability of a large
set of electronic health record data made this study possible.
D.
and qSOFA has not been universally adopted. Several papers and
letters to the JAMA editor have raised concerns [5,24,25] A few
of
a) A focus on adult patients without including newborn and
pediatric patients.
b) Research generated from patients in the United States and
Europe but not from economically poorer countries.
c) A task force without
d) The change in the clinical stages of sepsis, making
past 25-year body of sepsis research focused on four clinical
clinical stages.
e) Too much reliance on qSOFA to diagnose sepsis.
5/6
Copyright:
©2016 Gary et al.
10.15406/icpjl.2016.02.00063
f) A lack of endorsement by all societies including the
Latin American Sepsis Institute, American College of
Chest Physicians, and
.
Area of Promising Research in Sepsis
of sepsis, key advances in research continue. One of the areas
of promise is using data science approaches to mine insights
and knowledge from large databases of electronic healthcare
records. This was done to verify and test qSOFA and other EWS.
Several hospitals are now utilizing computational means to
monitor patients within the ICU. The availability of large sets of
digital healthcare records that can be analyzed with data science
approaches is able to provide a new approach to the rapid
MIMIC (edical Information art for Intensive Care) is a
large database freely available to researchers. It contains heath
data from over 40,000 ICU patients who stayed at Beth Israel
Deaconess Medical Center between 2001 and 2012. This database
contains lab results, electronic documentation, and bedside
monitor trends and waveforms. Several research teams have
explored the MIMIC database to better understand sepsis [26,30].
patient suffering will decrease.
Summary
software and other coding updates, the task force recommends
and 2001 iterations being recognized as Sepsis-1 and Sepsis-2,
respectively, to emphasize the need for future iterations [6].
again and this time the focus was on the patient’s systemic
was updated a fourth time to focus on organ dysfunction. The
sepsis-3 task force.
factors contributing to the medical condition known as sepsis.
These include (1) the pathogen that triggers sepsis; (2) the
patient’s immune response to the pathogen; and (3) the patient’s
medical history and condition at the time of sepsis. It is the
interplay between these factors that make each case of sepsis to
be somewhat unique to the individual and their current medical
condition.
healthcare providers to diagnosis and treat. These challenges
include:
a)
b) Symptoms of other disorders mask that of sepsis (see
appendix A for list).
c) A low percentage of patients have sepsis (~2% of emergency
room patients have sepsis).
d) The rapidly progression of sepsis to a fatal outcome
e) A high mortality rate
Sepsis is often not suspected by heath care providers. The
clinical symptoms used in diagnosing sepsis (raised temperature,
increased breathing rate, and mental alertness) do not rule out
other common disorders. In fact, a number of disorders appear
as sepsis (see appendix A). Most of these disorders are seen in
a higher percentage of patients entering emergency rooms than
sepsis. As a result of these challenges, sepsis is often diagnosed
too late to save the patient, although awareness campaigns and
spite of these challenges, several investigators consider sepsis
reversible and preventable [28,29]. If sepsis can be rapidly
decrease. More exploration of large electronic patient databases
involving patients with sepsis, such as MIMIC, using data science
approaches is needed. Data science approaches, such as machine
learning, predictive analytics, and data mining, are beginning
of which should lead to insights into the best ways to identify,
monitor and treat for patients with sepsis.
Acknowledgment
The author would like to acknowledge MTSU, the WPC
Healthcare’s Visiting Scholar in Data Science program, the Sepsis
Alliance for providing insights, Sandra Wendel, Jeffry Porter
and Sarah Grotelueschen for their critical review of the paper.
References
1. Botero JSH, Pérez MCF (2012) The History of Sepsis from
Ancient Egypt to the XIX Century. INTECH.
2. Shankar-Hari M, Phillips GS, Levy ML, Seymour C, Liu V5, et al.
(2016)
Sepsis and Septic Shock (sepsis-3). JAMA 315(8):
775-787.
3. Simpson SQ (2016) New Sepsis Criteria: A Change We Should
Not Make. Chest 149(5): 1117-1118.
4. Cortés-Puch I, Hartog CS (2016) Change Is Not Necessarily
Progress:
Insights. Am J Respir Crit Care Med 194(1): 16-18.
5.
Continuing Evolution but with Much Still to Be Done.
JAMA 315(8):757-759.
6. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D,
et
and Septic Shock (sepsis-3). JAMA 315(8): 801-810.
6/6
Copyright:
©2016 Gary et al.
7. Seymour CW, Lui VX Iwashyna TJ, Brunkhorst, FM, Rea TD, et al.
(2016) Assessment of Clinical Criteria for Sepsis: for the Third
International
315(8): 762-774.
8. Fleischman C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, et
al. (2016) Assessment of Global Incidence and Mortality of
Hospital-treated Sepsis. Current Estimates and Limitations. Am
J Respir Crit Care Med 193(3): 259-272.
9. Sepsis Alliance. (2016) Sepsis 2016 fact sheet.
http://www.sepsisalliance.org/downloads/2016_sepsis_facts_media. pdf
10. Torio CM, Andrews RM (2015) National Inpatient Hospital Costs: The
Most Expensive Conditions in Payer: HCUP Stateistical Brief#160.
Healthcare Cost and Utilization Project (HCUP) Statistical Briefs
[Internet]. Rockville (MD): Agency for Healthcare Research and Quality.
11. Sutton J Friedman B (2013) Trends in Septicemia Hospitalizations and
Readmissions in Selected HCUP States, 2005 and 2010. Healthcare Cost
and Utilization Project (HCUP) Statistical Briefs.
12. Sepsis Alliance. (2014) Sepsis 2014 fact sheet. http://
www.sepsisalliance.org/downloads/2014_sepsis_facts_media. pdf
13. Shorr AF, Micek ST, Jackson WL Jr, Kollef MH (2007) Economic
Implications of an Evidence-based Sepsis Protocol: Can we
Improve Outcomes and Lower Costs? Crit Care Med 35(5):
1257-1262.
14. Jones SL, Ashton CM, Kiehne L, Gigliotti E, Bell- Gordon C, et al.
(2015) Reductions in Sepsis Mortality and Costs After Design and
Implementation of a Nurse- Based Early Recognition and Response
Program. Jt Comm J Qual Patient Saf 41(11): 483-491.
15. Funk DJ, Parrillo JE, Kumar A (2009) Sepsis and Septic Shock: Ha istory.
Crit Care Clin 25(1): 83-101.
16. Rittirsch D, Flierl MA, Ward PA (2008) Harmful Molecular
Mechanisms in Sepsis. Nat Rev Immunol 8(10): 776-787.
17. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, et al. (1992)
Definitions for Sepsis and Organ Failure and Guidelines for the Use of
Innovative Therapies in Sepsis. Chest 101(6):1644-1655.
18. Rangel-Frausto MS1, Pittet D, Costigan M, Hwang T, Davis CS, et al.
(1995) The natural history of the Systemic Inflammatory Response
Syndrome (SIRS). JAMA 273(2): 117-123.
19. Schoenberg MH, Weiss M, Radermacher P (1998) Outcome of Patients
with Sepsis and Septic Shock after ICU Treatment. Langenbecks Arch
Surg 383(1): 44-48.
20. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, et al. (2003)
International Sepsis Definitions Conference. Crit Care Med 31(4):
1250-1256.
21. Morgan RJM, Williams F, Wright MM (1997) An Early Warning
Scoring System for Detecting Developing Critical Illness. Clinical
Intensive Care 8: 100.
22. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, et al.
(1996) The SOFA (Sepsis-related Organ Failure Assessment) Score to
Describe Organ Dysfunction/failure. Intensive Care Med 22(7):
707-710.
23. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, et al. (2008)
Surviving Sepsis Campaign: International Guidelines for Management
of Severe Sepsis and Septic Shock: 2008. Intensive Care Med 34(1):
17-60.
24. Sprung CL, Reinhart K (2016) Definitions for Sepsis and Septic Shock.
JAMA 316(4):456-457.
25.
Implications for Critical Care Practitioners. Am J Crit Care 25(5):
457-464.
26. Calvert JS, Price DA, Chettipally UK, Barton CW, Feldman
MD, et al. (2016) A Computational Approach to Early Sepsis
Detection. Comput Biol Med 74: 69-73.
27. Henry KE, Hager DN, Pronovost PJ, Saria S (2015) A Targeted Real-
time Early Warning Score (TREWScore) for Septic Shock. Sci
Transl Med 7(299): 299ra122.
28. Levy MM, Pronovost PJ, Dellinger RP, Townsend S, Resar
RK, et al. (2004) Sepsis Change Bundles: Converting Guidelines
into Meaningful Change in Behavior and Clinical
Outcome. Crit Care Med 32(11): S595-S597.
29. Marshal JC (2015) Understanding the Global Burden
of Pediatric Sepsis. Am J Respir Crit Care Med 191(10): 1096-1098.
30. Holzinger A, Jurisica I (2014) Knowledge discovery and data
mining in biomedical informatics: The future is in
integrative, interactive machine learning solutions. In Interactive
knowledge discovery and data mining in biomedical informatics, p.
1-18.
31. Chennamsetty H, Chalasani S, Riley D (2105)
Predictive analytics on Electronic Health Records (EHRs) using
Hadoop and Hive. IEEE International Conference, p. 1-5. IEEE.
32. Sutton JP Friedman B (2013) Trends in Septicemia
Hospitalizations and Readmissions in Selected HCUP states, 2005 and
2010. Healthcare Cost and Utilization Project (HCUP) Statistical
Briefs.
33. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, et al. (2001)
Early Goal-Directed Therapy in the Treatment of Severe Sepsis
and Septic Shock. New England Journal of Medicine 345(19):
1368-1377.
34. Rodr
Sepsis and Septic Shock: What Does It Give Us?
Medicina Intensiva S0210-5691.
35. Remick DG (2007) Pathophysiology of Sepsis. Am J Pathol
170(5): 1435-1444.
36. Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE
II:
829.
37. Iwashyna TJ, Odden A, Rohde J, Bonham C, Kuhn L,
et al. (2014) Identifying Patients with Severe Sepsis
Using Administrative Claims: Patient-Level Validation of the
Angus Implementation of the
Care 52(6): 9-43.
38. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, et al.
(2008) Surviving Sepsis Campaign: International Guidelines for
Management of Severe Sepsis and Septic Shock: 2008.
Intensive Care Med 34(1):
17-60.
39. Gomez H (2014) The Sepsis Syndrome and the “One
Size Fits All” Construct: The Emperor Has No
Clothes!! Doctoral dissertation, University of Pittsburgh, USA, pp.
1-80.
40. Iwashyna TJ, Odden A, Rohde J, Bonham C, Kuhn L,
et al. (2014) Identifying Patients with Severe Sepsis
Using Administrative Claims: Patient-Level Validation of the
Angus Implementation of the
Care 52(6): 9-43.
10.15406/icpjl.2016.02.00063
Appendix(A:((
List(of(disorder(often(diagnosed(instead(of(sepsis*(
Meningitis!!
Intracranial/intraspinal!abscess!
Pericarditis!!
Acute!and!subacute!endocarditis!
Phlebitis!and!thrombophlebitis!Acute!
sinusitis!
Acute!pharyngitis!
Acute!tonsillitis!
Acute!laryngitis!and!tracheitis!Acute!
upper!respiratory!infections!!
Pneumococcal!pneumonia!
Other!bacterial!pneumonia!
Bronchopneumonia!
Pneumonia!
Bronchiectasis!
Empyema!
Abscess!of!lung!and!mediastinum!
Appendicitis!
Abscess!of!anal!and!rectal!regions!
Peritonitis!!
Infections!of!kidney!
Urethritis!!
Acute!salpingitis!and!oophoritis!
Inflammatory!diseases!of!prostate!
Inflammatory!diseases!of!uterus!!
Inflammatory!disease!of!cervix!
Inflammatory!disease!of!vagina!
Inflammatory!disease!of!vulva!
Cellulitis!and!abscess!of!finger!Acute!
lymphadenitis,!unspecified!
Osteomyelitis!periostitis!!
Other!functional!bladder!disorders!
Abscess!of!liver!
Portal!pyemia!
Acute!cholecystitis!
Urinary!tract!infection!
Pyogenic!arthritis!
Bacteremia!
Postoperative!infection!!Bronchitis!!
Diverticulitis!!
Perforation!of!intestine
Cholera!!
Typhoid!fever!
Salmonella!gastroenteritis!
Shigella!dysenteriae!
Staphylococcal!food!poisoning!
Escherichia!coli!infections!
Colitis!
Enteritis!and!gastroenteritis!
Tuberculosis!!
Bubonic!plague!
Cutaneous!anthrax!
Brucellosis!
Glanders!
Melioidosis!
Listeriosis!
Leprosy!
Pulmonary!mycobacteria!diseases!
Faucial!diphtheria!
Whooping!cough!!
Streptococcal!sore!throat!
Erysipelas!
Meningococcal!infection!
Tetanus!
Erythrasma!
Gas!gangrene!
Streptococcus!infection!!
Syphilis!
Gonococcal!infections!
Leptospirosis!icterohemorrhagica!
Vincent's!angina!
Yaws!
Primary!lesions!of!pinta!
Other!spirochetal!infection!
Tinea!barbae!and!tinea!capitis!Dermatomycosis!
Candidal!
Coccidioidomycosis!
Histoplasmosis!
Blastomycosis!
Other!mycoses!
Opportunistic!mycoses!
Bacterial!meningitis!
*This!list!is!adapted!from!Iwashyna!et!al.,!2014 [40].
10.15406/icpjl.2016.02.00063
