Crohn disease is one of the intestinal inflammatory diseases that does not have a permanent cure. Here a brief explanation of the history, epidemiology, etiology, pathology, microscopic features, pathogenesis, clinical features and management have been discussed.. reference: latest edition of Love & Bailey, Sabiston, Schwartz

1. CROHN DISEASE
BY- DR DEBASHIS NANDA
PG 1ST YR RESIDENT
DEPT. OF GENERAL SURGERY
HI-TECH MEDICAL COLLEGE & HOSPITAL, BHUBANESWAR

2. Brief History
Although many different (and sometimes misleading) terms have been
used to describe this disease process, Crohn disease has been
universally accepted as its name.
However, it is the landmark paper by Crohn, Ginzburg and
Oppenheimer in 1932 that provided, in eloquent detail, the pathologic
and clinical findings of this inflammatory disease in young adults.
In 1913, the Scottish surgeon Dalziel described nine cases of intestinal
inflammatory disease.
The first documented case of Crohn disease was described by Morgagni
in 1761.

3. Introduction & General Trivia
Crohn disease is a chronic, transmural inflammatory disease of the gastrointestinal tract for
which the definitive cause is unknown, although a combination of genetic and environmental
factors has been implicated.
Crohn disease can involve any part of the alimentary tract from the mouth to the anus but most
commonly affects the small intestine and colon.
The most common clinical manifestations are abdominal pain, diarrhoea, and weight loss.
Crohn disease can be complicated by intestinal obstruction or localized perforation with fistula
formation.
Crohn disease is the most common primary surgical disease of the small bowel.

4. Crohn disease primarily attacks young adults in the second and third decades of
life.
However, a bimodal distribution is apparent, with a second smaller peak
occurring in the sixth decade of life.
Crohn disease is more common in urban dwellers.
Although earlier reports suggested a somewhat higher female predominance, the
two genders are affected equally.
The risk for development of Crohn disease is about twice as high in smokers as in
non-smokers.
Several studies indicate an increased incidence of Crohn disease in women using
oral contraceptives; however, more recent studies have shown no differences.

5. Worldwide, Crohn disease is relatively uncommon in African
Americans; however, in the United States, the rates of Crohn
disease in African Americans is similar to that seen in
Caucasians.
Individuals born during the spring months (e.g., April to June)
are more likely to develop Crohn disease.
Within one generation, migrants moving from a low-risk region
to a high-risk region develop Crohn disease at similar rates to
those in the high-risk region.
There is a strong familial association, with the risk for
development of Crohn disease increased about 30-fold in
siblings and 14- to 15-fold for all first-degree relatives.

6. Etiology
Infectious
agents
Immunologic
factors
Genetic
factors
Environmental
factors

7. Infectious agents
Although a number of infectious agents have been proposed as potential causes of Crohn disease, the few that
have received the most attention are mycobacterial infections, particularly Mycobacterium paratuberculosis,
chlamydia, Listeria monocytogenes, Pseudomonas species, reovirus and enteroadherent E. coli.
Transplantation of tissue from patients with Crohn disease has resulted in ileitis, but antimicrobial therapy
directed against mycobacteria has not been effective in ameliorating the established disease process.
Strains of enteroadherent E. coli are in higher abundance in patients with Crohn disease compared with the
general population based on PCR analysis
More recent studies have used fluorescent in situ hybridization to demonstrate increased numbers of E. coli in
the lamina propria of patients with active Crohn disease compared with those with inactive disease.
Furthermore, an increased number of E. coli has been associated with a shorter time before relapse of the
disease.

8. Immunologic factors
Humoral and cell-mediated immune reactions directed against intestinal cells
in Crohn disease suggest an autoimmune phenomenon.
Attention has focused on the role of cytokines, such as interleukin IL-1, IL-2,
IL-8, and TNF-α, as contributing factors in the intestinal inflammatory
response.
The role of the immune response remains controversial in Crohn disease and
may represent an effect of the disease process rather than an actual cause.

9. Genetic factors
Genetic factors play an important role in the pathogenesis of Crohn disease because the single
strongest risk factor for development of disease is having a first-degree relative with Crohn disease
The genes with the strongest and most frequently replicated associations with Crohn disease are
NOD2, MHC, and MST1 3p21 .
The most important gene in Crohn disease development is NOD2.
The presence of a locus on chromosome 16 (the so-called IBD1 locus) has been linked to Crohn’s
disease. The IBD1 locus has been identified as the NOD2 gene.
The NOD2 gene is associated with a decreased expression of antimicrobial peptides by Paneth cells.
Heterozygosity of one NOD2 variant confers a 2- to 4-fold increase in risk of Crohn disease, while
homo- zygosity confers a 17- to 40-fold increase in risk.
In addition, NOD2 has been identified as a genetic predictor of ileal disease, ileal stenosis, fistula,
and Crohn-related surgery.

10. CARD15 is also helpful in distinguishing Crohn disease from ulcerative
colitis as it is more strongly associated with Crohn disease, especially in
patients of northern European descent.
The FHIT gene located on 3p14.2 has been identified as a tumor suppressor
gene and is suggested to play a role in the pathogenesis of Crohn disease
as well as in the development and progression of Crohn disease–related
cancers.
it is unlikely that somatic mutations have a substantial impact on the
development of the disease, and simple Mendelian inheritance cannot
account for the pattern of occurrence. Therefore, it is likely that multiple
causes (e.g., environmental factors) contribute to the cause and
pathogenesis of this dis- ease.

12. Environmental factors
Low-risk countries in Asia that have adopted a more Western lifestyle have noted a significant
rise in the incidence of Crohn disease.
Smoking is the single largest environment factor, with a two-three fold increase in risk of Crohn
disease.
Single nucleotide polymorphisms associated with smoking increase the risk of Crohn disease in
smokers, identifying a genetic disposition for an environmental risk factor.
In addition, other factors that increase the risk of Crohn disease include medications (oral
contraceptives, aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs]), decreased dietary
fiber, and increased fat intake.
In addition, dysbiosis with a decrease in intraluminal Bacteroides and Firmicutes and an
increase in Gammaproteobacteria and Actinobacteria are associated with higher risk.
Specifically, an increase of mucosal—adherent—invasive E. coli survive within macrophages and
induce higher TNF-α production.

13. Pathogenesi
s
In both CD and UC increased gut mucosal permeability
appears to develop at a relatively early stage and may lead
to increased passage of luminal antigens that induce a cell-
mediated inflammatory response.
Proinfammatory cytokines, such as interleukin-2 and tumour
necrosis factor, are then released.
It has been suggested that CD is associated with a defect in
suppressor T cells. It is unclear whether the proposed
increase in intestinal permeability is a cause or
consequence of the disease process.
Studies of healthy and apparently unaffected first- degree
relatives of patients with CD suggest that gut permeability
is increased
which in turn suggests that a genetically determined
increase in gut permeability

14. Pathology
The most common sites of Crohn disease are the small intestine and colon.
The involvement of the large and small intestine has been noted in about 55% of patients.
Thirty percent of patients present with small bowel disease alone, and in 15%, the disease
appears limited to the large intestine
The disease process is discontinuous and segmental.
In patients with colonic disease, rectal sparing is characteristic of Crohn disease and helps
distinguish it from ulcerative colitis.
Perirectal and perianal involvement occurs in about one third of patients with Crohn
disease, particularly those with colonic involvement.
Crohn disease can also involve the mouth, oesophagus, stomach, duodenum, and appendix.
Involvement of these sites can accompany disease in the small or large intestine, but in
only rare cases have these locations been the only apparent sites of involvement.

15. Gross pathologic features.
At exploration, thickened grey- pink or dull purple-red loops of bowel are noted, with areas of thick gray-white
exudate or fibrosis of the serosa.
Areas of diseased bowel separated by areas of grossly appearing normal bowel, called skip areas, are commonly
encountered.
A striking finding of Crohn disease is the
presence of extensive fat wrapping caused by the
circumferential growth of the mesenteric fat
around the bowel wall, also known as creeping
fat.
As the disease progresses, the bowel wall
becomes increasingly thickened, firm, rubbery,
and almost incompressible
The uninvolved proximal bowel may be dilated
secondary to obstruction of the diseased segment
and deep mucosal ulcerations with linear or
serpiginous (snake-like) patterns in the strictured
area itself.

18.  Involved segments often are adherent to
adjacent intestinal loops or other viscera,
with internal fistulas common in these
areas.
 The mesentery of the involved segment
is usually thickened, with enlarged lymph
nodes often noted.
■ On opening of the bowel, the earliest
gross pathologic lesion is a superficial
aphthous ulcer noted in the mucosa.
■ With increasing disease progression,
the ulceration becomes pronounced,
and complete transmural inflammation
results.
■ The ulcers are characteristically linear
and may coalesce to produce
transverse sinuses with islands of
normal mucosa in between, thus giving
the characteristic cobblestone

21. Microscopic features
Granulomas appear later in the course and are found in the
wall of the bowel or in regional lymph nodes in 60% to 70% of
patients.
Characteristic histologic lesions of Crohn disease are non-
caseating granulomas with Langerhans giant cells.
This inflammatory reaction is characterized by extensive
oedema, hyperaemia, lymphangiectasia, intense infiltration
of mononuclear cells, and lymphoid hyperplasia.
A chronic inflammatory infiltrate appears in the mucosa and
submucosa and extends transmurally.
Mucosal and submucosal oedema may be noted
microscopically before any gross changes.

22. Clinical Manifestations
Crohn disease can occur at any age, but the typical patient is a young adult in the second or third
decade of life.
The onset of disease is often insidious, with a slow and protracted course.
Characteristically, there are symptomatic periods of abdominal pain and diarrhea interspersed
with asymptomatic periods of varying lengths.
With time, the symptomatic periods gradually become more frequent, more severe, and longer
lasting.
The most common symptom of Crohn disease is chronic diarrhoea, followed by intermittent and
colicky abdominal pain, most commonly noted in the lower abdomen.
Children developing the illness before puberty may have retarded growth and sexual development.

23. ■ The pain, however, may be more severe and localized in the right lower quadrant and may
mimic the signs and symptoms of acute appendicitis.
■ In contrast to ulcerative colitis, patients with Crohn disease typically have fewer bowel
movements, and the stools rarely contain mucus, pus, or blood.
■ Systemic nonspecific symptoms include a low-grade fever present in about one third of the
patients, weight loss, loss of strength, and malaise.
 The main intestinal complications of Crohn disease include obstruction and perforation.
 Obstruction can occur as a manifestation of an acute exacerbation of active disease or as the
result of chronic fibrosing lesions, which eventually narrow the lumen of the bowel, producing
partial or near-complete obstruction.

24. This classification was developed to provide a reproducible
staging of the disease, to help predict remission and relapse,
and to direct therapy.
 Free perforations into the peritoneal
cavity leading to a generalized peritonitis
can occur in patients with Crohn disease,
but this presentation is rare.
 More commonly, fistulas occur between
the sites of perforation and adjacent
organs, such as loops of small and large
intestine, urinary bladder, vagina,
stomach, and sometimes the skin,
usually at the site of a previous
laparotomy.
 Localized abscesses can occur near the
sites of perforation.

25. Patients with Crohn colitis may develop toxic megacolon and present with a marked
colonic dilation, abdominal tenderness, fever, and leukocytosis.
Bleeding is typically indolent and chronic, but massive gastrointestinal bleeding can
occasionally occur, particularly in duodenal Crohn disease associated with chronic
ulcer formation.
Long-standing Crohn disease predisposes to cancer of the small intestine and colon.
These carcinomas typically arise at sites of chronic disease and more commonly occur
in the ileum as a result of the chronic inflammation of the mucosa. Most are not
detected until in advanced stages, and the prognosis is poor.
Dysplasia is the putative precursor lesion for Crohn disease–associated cancer.
Patients with long-standing Crohn disease should have an equally aggressive
colonoscopic surveillance regimen as patients with extensive ulcerative colitis

26. Extraintestinal cancer, such as squamous cell carcinoma of the vulva and anal
canal and Hodgkin and non-Hodgkin lymphomas, may be more frequent in
patients with Crohn disease, especially those treated with immunomodulators.
Perianal disease (fissure, fistula, stricture, or abscess) is common and occurs in
25% of patients with Crohn disease limited to the small intestine, 41% of patients
with ileocolitis, and 48% of patients with colonic involvement alone.
Crohn disease should be suspected in any patient with multiple, chronic perianal
fistulas.
Extraintestinal manifestations of Crohn disease may be present in 30% of
patients.
The most common symptoms are skin lesions which include erythema nodosum
and pyoderma gangrenosum, arthritis and arthralgias, uveitis and iritis,
hepatitis, pericholangitis, and aphthous stomatitis.

30. Diagnosis
The diagnosis should be considered in
those presenting with acute or chronic
abdominal pain, especially when
localized to the right lower quadrant,
chronic diarrhoea, evidence of intestinal
inflammation on radiography or
endoscopy, the discovery of a bowel
stricture or fistula arising from the
bowel, and evidence of inflammation or
granulomas on intestinal histology.
However, there is not a single diagnostic
test for Crohn disease; a multimodal
approach of laboratory testing,
endoscopy, radiology, and pathology is
required.
•Laboratory
•Radiology
•Endoscopy

31. Laboratory
Serologic markers may be useful in the diagnosis of Crohn disease.
In particular, perinuclear antineutrophil cytoplasmic antibody , anti–
Saccharomyces cerevisiae antibody (ASCA), outer membrane porin of
flagellin (anti-CBir1), and outer membrane porin of E. coli (OmpC-IgG)
can predict the development of inflammatory bowel disease even in
patients thought to be at low risk for development of disease.
Stool lactoferrin, an iron-binding protein in the secretory granules of
neutrophils, and fecal calprotectin, a protein with antimicrobial
properties released by squamous cells in response to inflammation, are
inflammatory markers specific to the intestine that have shown
promising results for the detection and surveillance of Crohn disease.

32. A prospective study showed that both calprotectin and lactoferrin
levels correlate well with CT Enterography (CTE) images of small bowel
inflammation.
Fecal calprotectin levels greater than 140 ng/mL, predicted small
bowel inflammation with a sensitivity of 69% and a specificity of 82%.
Similarly, fecal lactoferrin (>6 ng/ mL) predicted small bowel
inflammation with a sensitivity of 69% and a specificity of 79%.
Fecal calprotectin is associated with elevated C-reactive protein and
erythrocyte sedimentation rate levels, whereas fecal lactoferrin is only
associated with elevated C-reactive protein levels.
Together, these findings identify fecal calprotectin and lactoferrin as
helpful screening tools for detecting early small bowel Crohn disease.

33. A full blood count should be performed as anaemia is common, resulting
from iron defciency owing to blood loss, malabsorption or chronic disease.
Vitamin B12 and folate deficiency may occur as a consequence of terminal
ileal disease or resection.
Active inflammatory disease is usually associated with low serum albumin,
magnesium, zinc and selenium.
Acute-phase protein measurements (C-reactive protein) and erythrocyte
sedimentation rate may correlate with disease activity.

34. Radiology
CTE or magnetic resonance enterography (MRE) are
often used as the initial assessment of Crohn
disease to complement direct ileo-colonoscopy.
Previously, barium enema was commonly used to
identify features of Crohn disease.
CTE may be useful in demonstrating the marked
transmural thickening; it can also greatly aid in
diagnosing extramural complications of Crohn
disease, especially in the acute setting.
Both MRE and CTE are equally accurate in assessing
disease activity and bowel damage; however, MRE
may be superior to CTE in detecting intestinal
strictures and ileal wall enhancement.

38. Endoscopy
Ileocolonoscopy with biopsies of the terminal ileum are the gold standard for the diagnosis of
Crohn disease.
When the colon is involved, sigmoidoscopy or colonoscopy may reveal characteristic aphthous
ulcers with granularity and a normal-appearing surrounding mucosa.
The presence of discrete ulcers and cobblestoning as well as the discontinuous segments of
involved bowel favors a diagnosis of Crohn disease.
Endoscopic advances that allow better evaluation of the small intestine include single- balloon
enteroscopy, double-balloon enteroscopy, and spiral enteroscopy; the most well-established
technique is double- balloon enteroscopy, which allows increased enteral intubation (240–360 cm)
compared with push enteroscopy (90–150 cm) or ileocolonoscopy (50–80 cm).

39. ■ After the diagnosis is
confirmed, the Crohn
Disease Endoscopic
Index of Severity
(CDEIS) or the Simple
Endo- scopic Score for
Crohn Disease (SES-
CD) is used to define ex-
tent of disease and
severity.
■ Recently, capsule
endoscopy was
approved by the U.S.
Food and Drug
Administration (FDA) in
2001 and is helpful in
the diagnosis of
superficial mucosal
abnormalities.

41. Differential diagnosis
The differential diagnosis of Crohn disease includes specific and nonspecific causes of
intestinal inflammation.
Bacterial inflammation (such as that caused by Salmonella and Shigella), intestinal
tuberculosis, and protozoan infections (such as amebiasis) may manifest as an ileitis.
In the immunocompromised host, rare infections, particularly mycobacterial and
cytomegalovirus (CMV) infections, have become more common and may cause ileitis.
Acute distal ileitis may be a manifestation of early Crohn disease, but it also may be
unrelated, such as when it is caused by a bacteriologic agent (e.g., Campylobacter, Yersinia).
Patients usually present with a sudden onset of right lower quadrant pain, nausea, vomiting,
and fever.

43. Management
■ Medical therapy
■ Nutritional therapy
■ Smoking cessation
■ Surgical Treatment

44. Medical management
There is no cure for Crohn
disease. Therefore, medical
therapies are directed toward
inducing and maintaining
steroid-free remission as well
as preventing acute
exacerbations or
complications of the disease.
The primary target of medical
treatment is the reduction of
the Crohn Disease Activity
Index (CDAI), which uses eight
major clinical factors to
evaluate disease severity

45. Clinical remission is achieved when CDAI is below 150
Clinical response to therapy occurs with a drop of 100 points
A score between 150 and 220 is considered mild to moderate disease
a score between 220 and 450 is considered moderate to severe disease and occurs after failure to first
line therapy
A score greater than 450 is considered severe fulminant disease with failed medical therapy and
complications of obstruction, peritonitis, and abscess.
Other innovative therapies such as MadCAM-1 ([mucosal addressin cell adhesion molecule 1] inhibitor),
tofacitinib (JAK3 pathway inhibitor), mongersen (SMAD7 inhibitor), and ozanimod (S1P1 inhibitor) are
all currently under phase II/III clinical trials.

46. In these patients, along with those who do not respond to steroids at all (steroid resistant), use of immune modulators
should be considered.
Some patients are unable to undergo glucocorticoid tapering without suffering recurrence of symptoms. Such patients
are said to have steroid dependence.
Although glucocorticoids are effective in inducing remission, they are ineffective in preventing relapse, and their
adverse effect profile makes long-term use hazardous. Therefore, they should be tapered once remission is achieved.
Patients with severe active disease usually require intravenous administration of glucocorticoids.
Orally administered glucocorticoids are used to treat patients with mildly to moderately severe disease that does not
respond to aminosalicylates.

47. The recent increase in the use of immunomodulators and biologic agents has significantly reduced
surgery rates.
Drugs that have demonstrated efficacy in the induction or maintenance of remission in Crohn
disease include Aminosalicylates, such as sulfasalazine and mesalamine; corticosteroids; TNF
antagonists, such as infliximab, adalimumab, and certolizumab; immunosuppressive agents,
such as azathioprine (AZT), 6-mercaptopurine (6-MP), methotrexate (MTX), and tacrolimus (FK-
506); antiadhesion molecules such as vedolizumab, etrolizumab, and natalizumab; the
interleukin inhibitor ustekinumab; and antibiotics(Metronidazole and ciprofoxacin may be used,
particularly for periods of a few weeks at a time, especially in perianal disease).

49. Nutritional therapy
Nutritional therapy in patients with Crohn disease has been used with varying success.
Although the primary role of nutritional therapy is questionable in patients with inflammatory bowel
disease, there is definitely a secondary role for nutritional supplementation to replenish depleted
nutrient stores, allowing intestinal protein synthesis and healing, and to prepare patients for surgery.
The use of chemically defined elemental diets has been shown in some studies to reduce disease
activity, particularly in patients with disease localized to the small bowel, and they can reduce
corticosteroid-induced toxicities.
Liquid polymeric diets may be as effective as elemental feedings and are more acceptable to
patients.

50. Smoking cessation
Although the implication of tobacco abuse as a causative
factor in the development of Crohn disease has been difficult
to prove, smoking clearly affects the disease course.
Smoking is associated with the late bimodal onset of disease
and has been shown to increase the incidence of relapse and
failure of maintenance therapy.
It also appears to be associated with the severity of disease in
a linear dose-response relationship.

51. Surgical Treatment
Although medical management is indicated during acute exacerbations of
disease, most patients with chronic Crohn disease will require surgery at
some time during the course of their illness.
The goals are to preserve bowel length while minimizing postoperative
complications and disease recurrence.
Approximately 70% of patients will require surgical resection within 15
years after diagnosis.
Indications for surgery include failure of medical treatment, bowel
obstruction, fistula or abscess formation, steroid dependence, dysplasia or
malignancy.

53. Patients with intestinal perforation, peritonitis, excessive bleeding, or toxic
megacolon require urgent surgery. Children with Crohn disease and resulting systemic
symptoms, such as growth retardation, may benefit from resection.
The extraintestinal complications of Crohn disease, although not primary indications
for operation, often subside after resection of the involved bowel; exceptions are
that problems may continue with ankylosing spondylitis and hepatic complications.
The aim of surgery for Crohn disease has shifted from a radical operation to one that
achieves inflammation-free margins with minimal surgery, intended to remove just
grossly inflamed tissue or to increase the luminal diameter of the bowel.
Even if adjacent areas of bowel are clearly diseased, they should be ignored.
Fistulizing disease rarely requires operative intervention unless the fistula involves
the bladder, vagina or skin.

54. A bowel resection with fistulotomy may be needed.
Frozen sections to determine microscopic disease are unreliable and should be performed only when malignant
disease is suspected.
It must be emphasized that operative treatment of a complication must be limited to that segment of bowel
involved with the complication, and no attempt should be made to resect more bowel, even though grossly evident
disease may be apparent.
However, often after removal of a diseased segment, endoscopic recurrence can occur up to 70% to 90% within 1
year after surgery in patients with Crohn disease.
Laparoscopic surgery for patients with Crohn disease has been determined to be safe and feasible in appropriately
selected patients.
A large comparative study evaluating laparoscopic colectomy for Crohn colitis determined that the laparoscopic
group had a significantly shorter median operative time, earlier return of bowel function, and shorter hospital
stay.

55. The potential for earlier recovery after laparoscopic resection has stimulated interest in
extending the role of surgical resection to induce remission.
Another difficult surgical decision important in Crohn disease involves performing a primary
anastomosis versus initial ostomy formation with delayed reconstruction.
Patients with adequate nutrition and minimal intraabdominal sepsis can safely undergo primary
anastomosis at the initial operation, whereas malnourished and septic patients are best served
by diversion, if possible.
Regarding the anastomotic technique, several studies suggest that creating a wider anastomosis
with a stapled functional end- to-end anastomosis may decrease fecal stasis and subsequent
bacterial overgrowth, which are implicated in anastomotic recurrence in Crohn disease.

56.  However, a randomized controlled
trial comparing side-to-side
anastomosis versus end-to-end
anastomosis determined that there
was no difference in overall
complication rates, anastomotic
leak rates, or rates of symptomatic
recurrence, with only a slight
increase in endoscopic recurrence
seen in the end-to-end
anastomosis group.
 Additionally, a new antimesenteric
functional end-to-end hand-sewn
anastomosis (known as Kono-S
anastomosis) was created to
minimize anastomotic restenosis in

58. Complications
Acute ileitis (non-stricturing, nonpenetrating).
Stricturing disease.
Penetrating disease.
Perforation
Gastrointestinal bleeding
Urologic complications
Colorectal disease
Perianal disease
Duodenal disease

59. Prognosis
Crohn disease is a chronic inflammatory disorder that is not medically or surgically
curable; therefore, therapeutic approaches are re- quired to induce and to maintain
symptomatic control, to improve quality of life, and to minimize long-term
complications.
It is estimated that approximately 71% of patients will require surgery within 10 years
of diagnosis, and 50% require a second procedure within 20 years.
Symptomatic recurrence varies from 40% to 80%, and endoscopic recurrence is much
higher, with up to 90% of patients having visible lesions within 5 years.
The only clearly modifiable risk factor is smoking cessation.

60. Multiple studies have shown that patients report significant
improvement in quality of life scores after surgical intervention.
Standardized mortality rates in patients with Crohn disease show
an increase in those whose disease began before the age of 20
years and in those who have had disease for longer than 13
years.
Long-term survival studies suggest that patients with Crohn
disease have a death rate approximately two to three times
higher than that of the general population, which is most
commonly re- lated to chronic wound complications and sepsis.

62. Thank you all for your patient hearing.
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