Download Case 4 – PATH 417A Signs and Symptoms: There are several signs

Case 4 – PATH 417A
Signs and Symptoms:
There are several signs and symptoms present in Ronnie’s medical history that could reveal the
nature of the bacteria infecting him. The signs include the low grade fever, the results of the stool
sample and the bloodwork. The symptoms Ronnie experiences include the abdominal cramps,
bloody diarrhea, fever, and peri-umbilical tenderness.
Although many of the symptoms and signs listed above are non-specific, in combination, they
hint towards two individual bacterial species. The first of which is the enteric illness causing
Campylobacter. Jejuni. C. jejuni, infection usually manifests within 2-5 days after consumption
of undercooked meat contaminated with animal feces, primarily poultry. Illness is associated
with bloody diarrhea, fever, abdominal cramps and peri-umbilical pain1 fitting well with
Ronnie’s case. The second putative cause of the patient’s symptoms could be E. coli O157:H7.
This strain of E.coli causes gastritis 3-4 days after exposure to undercooked meat/beef hence it is
commonly called the “hamburger disease”. Infection commonly presents with bloody diarrhea,
low grade or no fever, and abdominal cramps2.
Anatomy and Function of Affected Areas
The primary site of infection for both C. jejuni and E. coli O157:H7 is the gastrointestinal tract.
The specific cell type infected by the bacterium is the epithelial cell layer or gut enterocytes3.
The bacteria are both ingested via the mouth and pass through the esophagus and stomach to the
small intestine. Here the bacteria can attach to epithelial cells, invade, and initiate various
apoptotic and inflammatory effects leading to the symptoms of gastroenteritis.
The Anatomy of the GI Tract4
Component
Mouth
Pharynx and
Esophagus
Function + Anatomy
The mouth serves as the external opening to the GI tract. The
smell/taste/thought of food triggers salivary glands inside it to secrete
saliva. The mouth possesses teeth which aid in the mechanical
digestion of food. The bacteria present on the hamburger enters the
body in this way.
The pharynx/throat receives food from the mouth and branches off to
the esophagus. Food enters the pharynx and via movement of a flap
called the epiglottis during the process of swallowing. Depression of
the epiglottis prevents food from entering the trachea and the lungs.
During swallowing the tongue and soft palate (roof of mouth) push
food into the pharynx and cause closure of the epiglottis. The food and
bacteria now enter the esophagus. Muscular contractions called
peristalsis pushes the food through the esophagus. Near the end of the
esophagus, the lower esophageal sphincter controls food entry into the
stomach. The LES prevents stomach acid from entering the esophagus
and causing heartburn.
Stomach
Small and Large
Intestine
Rectum/anus
The stomach is a muscular sac that serves to mix and grind food
mechanically and to break down food products chemically through the
secretion of several enzymes as well as hydrochloric acid. The
stomach wall like the entire GI tract is covered with mucous and
protective factors to prevent auto-digestion (ulcers).
The small intestine is made up of 3 segments the duodenum, jejunum,
and ileum. The duodenum secretes several digestive enzymes as well
as accepting enzymes released from the gall bladder to further
chemical breakdown of food. The small intestine serves as the primary
site of nutrient/water absorption and the large intestine acts to reabsorb
any remaining water. Food moves through the small intestine both via
peristalsis and segmentation and through the large intestine via mass
movements as well.
The rectum is a short chamber that connects the LI to the anus and
stores fecal matter before defecation. The anus serves as the exit site
for food ingested through the mouth and completes the GI tract.
Impaired Physiology of the GI Tract
C. jejuni
Intestinal epithelial cells or gut enterocytes are normally covered in a thick mucous layer that
prevents entry of intestinal bacteria into underlying cells. The flagellum of C. jejuni is able to
corkscrew through this layer and adhere to or invade enterocytes5. The entry is mediated by the
stimulation of normal host protein kinases by bacterial effectors. C. jejuni secretes both
hemolysins and a cytolethal distending toxin which causes certain cell types to become distended
resulting in cell death. CDT also disturbs the survival and maturation of crypt cells into
functional villus cells and, as a result, impairs the absorptive functions of the small intestine5.
CDT is also thought to cause immunosuppression therefore preventing the body from effectively
dealing with intestinal bacteria7. The bacterium also expresses several iron-acquisition systems
that impair the normal sequestration and storage of iron in enterocytes and bound to proteins in
blood. The release of iron can result in the proliferation of gut bacteria that were previously
limited by iron scarcity. The bacteria are also able to convert ROS like superoxides into peroxide
and as such circumvent the normal defense strategies of the gut cells. The bacterium also induces
changes in the conformation of polarized epithelial cells leading to impaired barrier function and
increased permeability. This can cause water leakage back into the gut lumen and subsequent
diarrhea6. Dehydration results as the reabsorption of water in the gut is impaired. The many
mechanisms by which C. jejuni induces cell death including toxins, induction of cytotoxic Tcells, and inflammatory mediators, causes destruction of the intestinal wall. This leads to a loss
of the structural integrity of the gut barrier allowing entry of commensals into the blood and
intestinal cells which can initiate their own infection. Additionally, loss of villi again reduces the
absorptive capacity of the intestine.
E. coli O157:H7
One of the major E. coli virulence factors is the cytotoxic Shiga toxin which induces cell death
by inhibition of protein synthesis9. The toxin directly damages mucosal cells and vascular
endothelial cells in the gut wall8. The bacteria also cause effacement of the intestinal microvilli
causing decreased surface area for absorption. This is done via a bacterial Stx2 holotoxin which
causes miss-targeting of important brush border proteins such as villin. Additionally, E. coli
decreases ion reabsorption via secretion of effectors through a T3SS. This can cause increased
osmolality in the gut lumen leading to diarrhea. The build up of water in the intestinal lumen also
results in villus cell death leading to reduced nutrient reabsorption10.
Secondary Sites of Infection
C. jejuni
Infection of C. jejuni typically resolves within a week, however Guillain-Barre syndrome is a
common following infection. This is due to the fact that C. jejuni causes autoimmune disease
through molecular micmicry. Campylobacter contains ganglioside like epitopes that cause
formation of autoantibodies that react with peripheral nerves leading to acute flaccid paralysis
due to demyelination11. Another autoimmune syndrome linked to spread of C.jejuni to joints is
reactive arthritis which can in time lead to chronic arthritis. In immunocompromised patients,
infection may spread to other parts of the body including the heart, bloodstream, appendix, gall
bladder, central nervous system, colon, urinary tract, and abdominal cavity12. Spread of the
bacteria to the blood (bacteremia) can cause hemolytic anemia or hemolytic uremic syndrome in
response to bacterial hemotoxins, endotoxins, and the effect of the immunocomplex on the
vascular endothelium13,14. Carditis, encephalopathy, osteromyelitis, and uveitis are also postinfectious extra-intestinal complications that are possible. The bacteria are able to spread to these
sites via apoptotic effects on the intestinal and vascular epithelium. The bacterium first adheres
to intestinal enterocytes, invades, causes cell lysis and moves into the underlying tissue and
blood vessels. The bacteria migrate to other body sites via the blood network and via expression
of endotoxins that cause lysis of vascular cell walls. In this way C. jejuni enters distant tissues
and establishes secondary infection. In most cases, C. jejuni only causes a localized infection in
the gut and does not spread systemically, however highly virulent C. jejuni strains may be able to
penetrate the epithelial barrier and spread to extraintestinal sites, such as the liver, gallbladder,
pancreas, uterus, and fetal tissues20. The spread is heavily dependent on flagellar motility as well
as chemotaxic ability mediated by agglutination, attachment, and biofilm formation. Bacteremia
is highly uncommon in the case of C. jejuni infection but has been known to occur in
immunocompromised individuals and has increased prevalence in those > 6519. Years of age.
Systemic infection with the bacteria such as those described above does not occur with most
diarrheal strains and requires specific variants possessing persistence genes and mechanisms that
allow survival in the bloodstream18.
E. coli O157:H7
After infection with E.coli the bacteria rapidly multiply in the intestine and secrete Shiga toxin.
Bacteria stimulate macropinocytosis of the toxin via actin remodeling. After absorption of the
toxin into the intestinal capillaries, transcytosis occurs to the basolateral environment21. Once
Shiga toxin has escaped into systemic circulation via intestinal capillaries, it binds weakly to
receptors on white blood cells. On the WBC’s the bacteria travel to the kidneys where they are
transferred via strong binding to Gb3 receptors. These receptors are also present on other organs
such as the brain or pancreas and site of secondary infection depends primarily on the density of
receptor expression in each tissue type. The toxin enters glomerular endothelial cells, podocytes,
and tubular epithelia cells in the kidney, causing kidney damage9. The toxin shuts down protein
synthesis causing cell death and injury. The injury activates blood platelets causing a coagulation
cascade that leads to formation of clots in the kidney and subsequent kidney failure and
hemolytic uremic syndrome15. E. coli can also travel through the small intestine to the colon
where they invade and destroy colonic epithelial cells or cholangiocytes. The bacteria utilize host
actin to navigate the host cell, spread to adjacent cells, and multiple in the cytoplasm. The
resultant epithelial cell destruction can lead to colonic ulceration22.
Routine Bloodwork
Routine bloodwork for suspected gastroenteritis includes a complete blood count (CBC),
electrolyte counts, renal function tests, and blood urea nitrogen tests among others16. The CBC
tests for RBC’s, WBC’s, hemoglobin, hematocrit, and platelets. C. jejuni infection could result in
a high WBC and platelet count as well as a low hemoglobin, hematocrit, and RBC count17. Renal
function and blood urea nitrogen tests will be abnormal if the E. coli infection has caused kidney
or liver damage.
Works Cited:
1) "Pediatric Campylobacter Infections Clinical Presentation." Pediatric Campylobacter
Infections Clinical Presentation: History, Physical, Causes. Web. 20 Mar. 2016.
2) "Department of Health." E. Coli 0157:H7 Infection. Web. 20 Mar. 2016.
3) "Campylobacter Jejuni - MicrobeWiki - Kenyon College." Web. 20 Mar. 2016.
4) "The Digestive System Diagram, Organs, Function, and More." WebMD. WebMD. Web. 20
Mar. 2016.
5) Vliet, A.h.m. Van, and J.m. Ketley. "Pathogenesis of Enteric Campylobacter Infection." J
Appl Microbiol Journal of Applied Microbiology 90.S6 (2001). Web.
6) Wine, Eytan, Voon L. Chan, and Philip M. Sherman. "Campylobacter Jejuni Mediated
Disruption of Polarized Epithelial Monolayers Is Cell-Type Specific, Time Dependent, and
Correlates With Bacterial Invasion." Pediatr Res Pediatric Research 64.6 (2008): 599-604.
Web.
7) "Campylobacter Jejuni - MicrobeWiki - Kenyon College." Web. 20 Mar. 2016.
8) "Escherichia Coli Infections." Merck Manuals Professional Edition. Web. 20 Mar. 2016.
9) "Enterohaemorrhagic Escherichia Coli (EHEC)." World Health Organization. Web. 20 Mar.
2016.
10) Hodges, Kim, and Ravinder Gill. “Infectious Diarrhea: Cellular and Molecular Mechanisms.”
Gut Microbes 1.1 (2010): 4–21. PMC. Web. 20 Mar. 2016.
11) Nachamkin, Irving, Ban Mishu Allos, and Tony Ho. “Campylobacter Species and GuillainBarré Syndrome.” Clinical Microbiology Reviews 11.3 (1998): 555–567. Print.
12) "Campylobacter Jejuni." Government of Canada, Health Canada and the Public Health
Agency of Canada. Web. 20 Mar. 2016.
13) Smith, Malcolm A., Narayan R. Shah, Jeffrey S. Lobel, and Wade Hamilton.
"Methemoglobinemia and Hemolytic Anemia Associated with Campylobacter Jejuni
Enteritis." Journal of Pediatric Hematology/Oncology 10.1 (1988): 35-38. Web.
14) "Hemolytic Uremic Syndrome After Campylobacter-Induced Diarrhea in an Adult." JAMA
Network. Web. 20 Mar. 2016.
15) "Hemolytic Uremic Syndrome (HUS)." Hemolytic Uremic Syndrome (HUS). Web. 20 Mar.
2016.
16) "Emergent Treatment of Gastroenteritis Workup." Emergent Treatment of Gastroenteritis
Workup: Laboratory Studies, Imaging Studies, Procedures. Web. 20 Mar. 2016.
17) "Campylobacter Jejuni Gastroenteritis Complicated by Pancytopenia." Campylobacter Jejuni
Gastroenteritis Complicated by Pancytopenia. Web. 20 Mar. 2016.
18) Blaser, M. J., G. P. Perez, P. F. Smith, C. Patton, F. C. Tenover, A. J. Lastovica, and W. I.
Wang. 1986. Extraintestinal Campylobacter jejuni and Campylobacter coli infections: host
factors and strain characteristics. J. Infect. Dis. 153:552-559.
19) Skirrow, M. B., D. M. Jones, E. Sutcliffe, and J. Benjamin. 1993. Campylobacter
bacteraemia in England and Wales, 1981-91. Epidemiol. Infect. 110:567-573.
20) Smith, J. L. 2002. Campylobacter jejuni infection during pregnancy: Long-term
consequences of associated bacteremia, Guillain-Barre syndrome, and reactive arthritist. J.
Food Prot. 65:696-708.
21) Lukyanenko, Valeriy et al. “Enterohemorrhagic Escherichia Coli Infection Stimulates Shiga
Toxin 1 Macropinocytosis and Transcytosis across Intestinal Epithelial Cells.” American
Journal of Physiology - Cell Physiology 301.5 (2011): C1140–C1149. PMC. Web. 20 Mar.
2016.
22) "Infections of the Large Intestine." Infections of the Large Intestine. Web. 20 Mar. 2016.