Chăm Sóc Và Điều Trị Bỏng Toàn Diện (Total Burn Care – Tập 5)

42  •  Exfoliative Diseases of the Integument and Soft Tissue Necrotizing Infections
433
First described by Bryant and White in 1898 and later
investigated by Selye in 1962, it was not until 1976 that
the true clinical significance of the syndrome was formally
recognized by Gipstein et al. The clinical syndrome of cal­
ciphylaxis is characterized by:137,138 (1) painful purpuric
cutaneous lesions (Fig. 42.9), (2) histological evidence of
systemic medial calcifications of arteries (tunica media),
and (3) histological evidence of small-vessel mural calci­
fication with or without endovascular fibrosis leading to
vascular thrombosis and tissue necrosis.
As previously stated, the exact pathophysiology of calci­
phylaxis is unknown, although the best theory was offered
by Selye et al. in 1962. Utilizing a rat model, he suggested
that calciphylaxis was a condition of hypersensitivity
caused by exposure to “sensitizing agents” (nephrectomy/
parathyroid hormone) and “challengers” (egg albumin/
metallic salts) over a defined period of time. Simply stated,
calciphylaxis appears to be a clinical syndrome induced by
a series of events that predispose the patient to extraskeletal
calcifications. Most recently, Nigwekar et al. have suggested
that the matrix protein GLA(MPG) may serve as a bio­
marker.139 MPG is found in the walls of blood vessels and
cartilage and functions to prevent calcium buildup. It
requires activation by vitamin K to function well, and it is
hypothesized that normal activation is impaired in calci­
phylaxis. Further studies are required to solidify the role of
MPG in calciphylaxis, but the work appears promising.
Clinically, calciphylaxis affects approximately 1–4% of
the population with underlying end-stage renal disease.140
effects to antibiotic treatment.131 In summary, hyperbaric
oxygen therapy, if available, should not delay radical sur­
gical débridement and should be used as an adjunct to
radical surgery and antibiotic therapy.129,132
PURPURA FULMINANS
Purpura fulminans is a term that describes an acute syn­
drome of rapidly progressive hemorrhagic necrosis of the
skin due to dermal vascular thrombosis associated with
vascular collapse and disseminated intravascular coagula­
tion (DIC).133 It may occur in individuals with dysfunction
of the protein C anticoagulant system, with acute severe
infection, or idiopathically without any coagulation dys­
function or infection.
It has been associated with systemic infection by Menin­
gococcus, Gram-negative bacilli, Staphylococcus, Streptococ­
cus, and Rickettsia organisms. Skin necrosis begins in a
region of dermal discomfort, which rapidly progresses to
evanescent flush, followed by petechiae. Hemorrhagic
bullae progress to frank skin necrosis. The process generally
involves the skin and subcutaneous tissues, without involve­
ment of muscle. Skin involvement is frequently an early
manifestation of the disease process. Skin biopsy will there­
fore allow an earlier diagnosis. Mortality in the acute phase
is 18–40%.134
Management is directed at halting progression of the
underlying infectious disease, preventing secondary infec­
tions, and removing nonviable tissue. Early heparin admin­
istration and replacement of clotting factors have proved
useful to stop intravascular clotting.134 Shock from blood
extravasation and sepsis require extensive volume replace­
ment. Limb vascular and compartmental pressure should
be monitored closely to enable early escharotomy and/or
fasciotomy, when needed. Skin lesions resulting only in blis­
ters should be treated with topical antimicrobials (e.g.,
silver sulfadiazine) to prevent secondary infection. Nonvi­
able tissue should be removed as soon as the patient’s condi­
tion allows. Small areas can be covered with autografts but
because large areas are frequently involved, allograft or
xenograft skin coverage may be required. Limb amputa­
tions may be frequently required due to vascular compro­
mise, as well as revisions for progression of disease.135
Isolation of the affected patient, as well as monitoring and
prophylactic treatment of patients and staff, may be neces­
sary to prevent further spread and outbreaks of the disease,
especially in the case of meningococcal infection.
CALCIPHYLAXIS
Calciphylaxis is a rare condition that is characterized by the
development of extraskeletal calcifications resulting in
tissue necrosis. Although the exact etiology is unknown,
the condition appears to be most commonly associated with
disorders that alter calcium/phosphate homeostasis. Thus
the condition is usually diagnosed in individuals undergo­
ing renal replacement therapy or who have recently under­
gone renal transplantation. Despite the close association
with renal failure, Nigwekar et al. have identified a sub­
group of individuals with the same pathological condition
but without end-stage renal failure and coined the term
“nonuremic calciphylaxis” (Fig. 42.8, Box 42.1).136
Fig. 42.8  Early calciphylaxis lesion. (Courtesy of Dr. Shawn Fagan.)
Box 42.1  Conditions Associated With Non-
Uremic Calciphylaxis
■ Primary hyperparathyroidism
■ Breast cancer + chemotherapy
■ Liver cirrhosis
■ Cholangiocarcinoma
■ Crohn’s disease
■ Rheumatic arthritis
■ Systemic lupus erythematosus

42  •  Exfoliative Diseases of the Integument and Soft Tissue Necrotizing Infections
434
of systemic involvement. The overall mortality rate from
calciphylaxis appears to be closely related to the extent of
internal organ involvement and development of sepsis from
infected cutaneous lesions.
The diagnosis of calciphylaxis should be suspected in any
patient with painful cutaneous lesions and a history sup­
portive of the clinical syndrome. Although diagnostic lab
testing and imaging are not helpful, the diagnosis can be
formally established with a tissue biopsy.
Once the diagnosis is established, the treatment should
be initiated using a multidisciplinary approach. The treat­
ment should be based on improving the underlying condi­
tion, such as reformulation in hemodialysis or potentially
administering sodium thiosulfate, which acts as an antioxi­
dant and chelator of cations. Unfortunately, despite the best
medical efforts, treatment usually becomes supportive from
an analgesic and wound standpoint. Wound management
should be aggressive to avoid local wound infections. The
primary goal is to establish a healthy wound bed without
evidence of disease progression prior to definitive closure.
Conclusion
Inflammatory and infectious conditions of the skin and
underlying tissues represent a major diagnostic and thera­
peutic challenge. The team approach to their care is essen­
tial, and wound management is paramount. Burn centers
are ideally suited to deal with patients with these conditions
and should be considered as the appropriate site of referral
for these critically ill patients.
Complete references available online at

Further Reading
Becker DS. Toxic epidermal necrolysis. Lancet. 1998;351:1417-1420.
Cartotto R, Mayich M, Nickerson D, et al. SCORTEN accurately predicts
mortality among toxic epidermal necrolysis patients treated in a burn
center. J Burn Care Res. 2008;29(1):141-146.
Koh MJ, Tay YK. An update on Stevens–Johnson and toxic epidermal
necrolysis in children. Curr Opin Pediatr. 2009;21:505-510.
Weenig RH, Sewell LD, Davis MD, et al. Calciphylaxis: natural history, risk
factors, outcome. J Am Acad Dermatol. 2009;61(1):73-79.
Wilkins J, Morrison L, White CR. Oculocutaneous manifestations of the
erythema multiforme/Stevens–Johnson syndrome/toxic epidermal
necrolysis spectrum. Dermatol Clin. 1992;10:571-582.
The condition has been reported in age groups ranging
from 6 months to 83 years of age. The condition appears to
affect predominantly Caucasian women, with a female to
male ratio of 3:1. Unfortunately the mortality rate associ­
ated with calciphylaxis is as high as 60–80% and appears
to be related to the distribution of cutaneous lesions. Distal
lesions have a reported mortality rate of 42%, whereas
more proximal lesions (trunk, abdomen, buttocks, and
proximal extremities) have a reported mortality rate
approaching 72%. The association between mortality rates
and lesion distribution may in fact be related to the degree
Fig. 42.9  Proximal calciphylaxis. (Courtesy of Dr. Shawn Fagan.)

434.e1
42  •  Exfoliative Diseases of the Integument and Soft Tissue Necrotizing Infections
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73. Hertl M, Merk HF, Bohlen H. T-cell subsets in drug-induced toxic
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123. Steven DL. Invasive group A streptococcal infections. Clin Infect Dis.
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124. Francis KR, Lamaute HR, Davis JM, et al. Implications of risk factors
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127. Freischlag JA, Ajalat G, Busuttil RW. Treatment of necrotiz­
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128. Kaiser RE, Cerra FB. Progressive necrotizing surgical infections: a
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129. Green RJ, Dafoe DC, Raffin TA. Necrotizing fasciitis. Chest.
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131. Zamboni WA, Mazolewski PJ, Erdmann D, et al. Evaluation of peni­
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135. Genoff MC, Hoffer MM, Achauer B, et al. Extremity amputation in
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105. Prins C, 2003, Effect of high-dose intravenous immunoglobulin
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111. Fischer M, Fiedler E, Marsch WC, Wohlrab J. Antitumour necrosis
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113. Birchall N, Langdon R, Cuono C, et al. Toxic epidermal necrolysis: an
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1993;15:235-239.
118. Elias PM, Fritsch P, Epstein EH. Staphylococcal scalded skin syn­
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435
Burn Injuries of the Eye
KAREL D. CAPEK, DEREK M. CULNAN, KEVIN MERKLEY, TED T. HUANG, and
STEFAN TROCME
43 
and temporal branches of the facial nerve. Epidermal
appendages, including follicular sebaceous glands (of Zeiss),
modified apocrine sweat glands (of Moll), and eyelashes, are
located at the anterior margin of the mucocutaneous junc­
tion. Posteriorly, the fibrous tarsi harbor the Meibomian
glands (about 50 in the upper lid and 25 in the lower lid)
that secrete lipid-rich material into the tear film.
The tear film is a trilaminar structure; moving from the
ocular surface externally, there is mucus on the cornea and
conjunctiva, covered by an aqueous layer, with a lipid layer
most externally. A healthy tear film remains stable for at
least 10 s and maintains more than 300 µm of meniscus
height.7 The lacrimal gland, located laterally and superiorly
in the orbit, produces the aqueous phase of the tear film,
along with accessory lacrimal glands (of Krause and Wol­
fring) located in the superior and inferior fornices. The lipid
layer is secreted by the Meibomian glands, stabilizing the
tear film and reducing evaporative loss. A complex protein
mixture within the tear film confers antimicrobial, inflam­
matory, and antiinflammatory properties and regulates
corneal epithelial cell function.8
The conjunctiva covers the inner surface of the eyelids
and the anterior sclera, reflecting between the two at the
superior and inferior fornices. It is composed of stratified
nonkeratinized squamous and columnar cells interspersed
with goblet cells upon a continuous basement membrane
and lamina propria. Other tissues include accessory lacri­
mal glands and immune surveillance cells; the lymphatic
drainage of the conjunctiva is via the submandibular,
parotid, and preauricular nodes. The limbus is the border
between the conjunctiva and corneal epithelium. Circum­
scribing the limbus, the palisades of Vogt harbor the corneal
epithelial stem cell niche.9,10
The corneal epithelium is approximately 6–7 cell layers
(50 µm) tall and composed of stratified squamous epithe­
lium with minimal keratinization. The basal layer is mitoti­
cally active and replenishes the more external layers as they
are continuously sloughed. The corneal epithelial stem cell
niche, at the limbus within the palisades of Vogt, allows
reepithelialization when the entire basal layer is lost, as in
severe burn injuries or toxic epidermal necrolysis. This
mechanism requires cell proliferation and migration from
the limbus to the center of the cornea and can take weeks
to fully reepithelialize the cornea, compared with days
when the basal corneal epithelial layer remains intact. The
corneal epithelium produces and rests upon a basement
membrane.11 The layers deep to this basement membrane
comprise the corneal stroma. The first 8–12 µm of stroma
is called Bowman’s membrane and is composed of ran­
domly oriented collagen fibers. The stroma is approximately
500 µm (0.5 mm) thick. Precise arrangement of about 200
collagenous lamellae confers transmittance of visible
ὁ λύχνος τοῦ σώµατός ἐστιν ὁ ὀφθαλµός
ὅταν οὖν ὁ ὀφθαλµός σου ἁπλοῦς ᾖ, καὶ ὅλον τὸ
σῶµά σου φωτεινόν ἐστιν.
ἐπὰν δὲ πονηρὸς ᾖ, καὶ τὸ σῶµά σου σκοτεινόν
Introduction
Both immediate and delayed presentations exist for eye
problems in burned patients. Accordingly, in burns, the
structure and function of a normal eye can be disrupted by
concurrent blunt or penetrating injury, electrical current,
thermal energy, or chemical agents. After the initial insult,
foreign bodies, ongoing chemical injury, deterioration of
the facial burn wound, infection, and environmental expo­
sure can cause additional damage or progression of existing
pathology. Although many providers may view comprehen­
sive eye examination as an esoterica outside their skillset
and purview, the frequency and acuity of sight-threatening
complications necessitate the burn team learning the basics
of eye evaluation.1
Selected Anatomy
The organ of sight arises through reciprocal interac­
tion between the optic vesicle (neuroectoderm) and the
lens placode (facial ectoderm). The full-thickness neu­
roectoderm protrudes toward the surface, inducing the
primordial lens, and invaginating to form the optic cup.
The lens vesicle, separating from the surface ectoderm,
induces corneal development.2 The upper and lower eyelids
develop from primordial eyelid folds, fusing transversely
from 8 weeks to 5 months, protecting the nascent ocular
surface from initial environmental exposure as the fetal
urinary system begins to contribute to the amniotic fluid
composition.3,4
Eyelids are four-layered structures of skin, orbicularis
muscle, tarsus with fibrous septae, and palpebral conjunc­
tiva. The skin of the eyelids is thin and elastic in the normal
state. Upper eyelid skin folds are formed from terminal skin
attachments of underlying levator muscle, which functions
with Müller’s muscle to open the upper eyelid. The inferior
rectus muscle provides analogous function via the capsulo­
palpebral fascia and inferior tarsus, retracting the lower lid
with down-gaze.5,6 The orbicularis muscle can be divided
into pretarsal, preseptal, and orbital segments based on the
structure they overlay: tarsus, orbital septum, or orbital
rim. The pretarsal and preseptal parts are used in blinking
and voluntary winking, while the orbital segments are used
in forced closure. Motor innervation is via the zygomatic

43  •  Burn Injuries of the Eye
436
irrigated to remove any discharge or ointment. A normal
healthy cornea should appear clear and “glassy” with a
sharp light reflex. A hazy light reflex can usually be appre­
ciated in early-stage keratopathies. We generally apply dye
in a balanced salt solution to the lateral canthus/inferior
fornix and then have the patient blink a few times. Next
the eye is opened and examined for epithelial irregulari­
ties and negative staining. Excess dye is then rinsed away
with balanced salt solution. A normal healthy cornea will
be devoid of stain; dye retention signifies pathology.15–20
Areas of confluent, homogeneous stain signify epithe­
lial defect (Fig. 43.1C). “Lacey” staining patterns usually
signify epithelial keratopathy (Fig. 43.1B). Early-stage
epithelial lesions of exposure and herpetic keratopathies
are often difficult to appreciate without the assistance of
dye. Adjustable-intensity pocket LED flashlights often have
fairly cool light, which sufficiently highlights fluorescein;
otherwise, a cobalt-blue filter or near-ultraviolet hand-
held light can be used. Photographs of findings often allow
more comprehensive review while minimizing patient
discomfort.
Indirect ophthalmoscopy via adilated pupil is occasion­
ally useful and indicated in the burn unit. In cases of nonac­
cidental trauma, distinctive retinal lesions may be observed
and should be documented with fundus photography for
potential medicolegal review.21 In the first 48–96 hours fol­
lowing carbon monoxide intoxication, cerebral swelling and
herniation syndromes are frequently causes of death.22–24
Funduscopy may show papilledema, which can be graded
in severity.25 In cases where persistently positive blood
cultures raise clinical concern for hematogenous seeding,
infectious microemboli can occasionally be visualized on
thorough funduscopy.26–29 Similarly there is a spectrum of
retinal findings with disseminated candidiasis, defined as
Candida isolated from three or more sites (urine, sputum,
wound, blood, or eye).30–32 Because choroidal blood flow
is much higher than retinal blood flow,33 these hematog­
enous lesions more frequently occur within the choroid and
are initially observed underlying the retinal layers as gray-
white round lesions, rather than occlusive lesions within
the retinal vessels proper.34–37 These lesions, termed chorio­
retinitis, enlarge as the infection progresses and may erupt
into the vitreous.38-40 This distinction is important because
the stage/level of involvement determines treatment choices
(ranging from intravenous antimicrobial therapy, intravit­
real antimicrobial instillation, to vitrectomy for significant
vitreitis).39–47
Applied Pathology
Thermal injuries to the eye concurrent with the burning
event are, fortunately, rare. The typical presentation is
decreased vision, eye pain/foreign body sensation, perilim­
bal hyperemia, and epithelial defect with fluorescein stain­
ing. If detected early, a corneal epithelial lesion, analogous
to a blister, may be present and is usually translucent to
opaque. Upon sloughing, an underlying epithelial defect of
varying depth is apparent.48 In the setting of closed-space
(house) fires, it is difficult to determine whether a corneal
injury is thermal or (gaseous) chemical in nature, and
copious irrigation is recommended. In addition to tissue
light.12 Fibroblasts and immune surveillance cells populate
the stroma. A deep layer, Descemet’s membrane, about
10 µm in thickness, provides posterior structural integrity.
Upon this membrane rests the corneal endothelium, rich in
mitochondria and nonproliferative, which maintains
corneal dehydration (and transparency) via active trans­
port of solute into the aqueous. The cornea provides about
two-thirds of the refractive power of a normal eye, approxi­
mately +40 diopters.
Examination
Eye examination in a burn ICU requires several modifica­
tions from the standard clinic setting. Clinicians must adapt
to the overall patient condition and support machinery,
which may include multiple intravenous and enteral access
lines, ventilator and dialysis support, bulky wound dress­
ings, difficult patient positioning, and, frequently, severe
comorbid injuries and burns of the face. This is not the
“comfort zone” for the ophthalmologist, but the frequency
and acuity of comorbid eye involvement necessitate adapta­
tion and innovation.13 An assessment of visual function
can be made with a near vision card, finger counting, or, at
a minimum, light perception. Patients with endotracheal
tubes can generate various responses, head nod or hand
signal, to visual acuity testing under appropriate sedative/
analgesic conditions. There are a variety of portable slit
lamps that can be employed. Our preference is a handheld
lens (20 diopter or equivalent) and penlight. With practice,
the penlight may be axially directed through the lens or
shone indirectly upon the ocular surface to section through
the anterior segment, thereby providing fine detail of
stromal and corneal epithelial problems. Loupes provide
additive magnification when used with a handheld lens.
Topical ocular surface anesthesia is usually employed.
If the injury was associated with an explosion, with
flying debris or blunt/penetrating trauma to the eye and
periorbita, an open globe injury may result. In this situa­
tion, examination must be performed without pressure on
the globe until corneal or scleral perforation can be excluded.
Pressure applied to an open globe could cause (further) her­
niation of intraocular contents and detract from potential
recovery. If an open globe–suspect injury is identified, pupil­
lary light response and visual acuity should be grossly doc­
umented (at least light perception/hand motion/finger
counting), photographs obtained, and a shield placed over
the eye sufficient to transmit any applied pressure to the
osseous orbital rim rather than the orbital contents. Imme­
diate ophthalmological consultation is indicated to evaluate
a possible open globe.
Once an open globe injury is excluded, cotton swabs,
Desmarres retractors, or an eyelid speculum are useful and
often necessary due to facial burns and lid edema. “Swell­
ing” is never an excuse to defer examination of the ocular
surface because any delay in the recognition of significant
injuries subjects a patient’s visual recovery to avoidable
jeopardy. Superficial foreign bodies can usually be removed
by saline irrigation alone if identified quickly postburn.
Fluorescein dye (strips or equivalent) should be available in
the burn unit and used if there is any suspicion of corneal
or conjunctival pathology.14 The ocular surface should be

43  •  Burn Injuries of the Eye
437
A
A
A
A
A
A
A
A
A
B
C
D
E
F
G
H
Fig. 43.1  Spectrum of exposure-related ocular surface disease encountered in the burn unit. A, Lagophthalmos. B, Exposure keratopathy. C, Epithelial
defect. D, Herpetic keratitis. E, Corneal ulcer. F, Same, with hypopyon. G, Descemetocele. H, Corneal perforation.

43  •  Burn Injuries of the Eye
438
EXPOSURE KERATITIS AND EYELID BURNS
Eyelid burns and singed eyelashes identify a group of
patients at high risk for ocular surface problems, with likeli­
hood ratios (LR+), if present, for the development of corneal
ulceration of 12 and 6.9, respectively.105 Punctate epitheli­
opathy, or keratopathy, is usually the earliest stage of per se
corneal injury, and, if present, it confers an LR+ for the
development of corneal ulceration of 6.4. These subtle
irregularities on the normally glassy corneal surface can be
discerned with magnification and are accentuated by the
application of fluorescein dye (Fig. 43.1B). The severity of
epitheliopathy ranges from scattered, superficial submilli­
meter dots to a homogeneous area of abnormal epithelium,
confluent keratopathy. The latter is essentially an epithelial
defect prior to sloughing of the diseased epithelium. While
keratopathy may be caused by direct thermal or chemical
injury of the eye, it is much more frequently observed with
corneal exposure resulting from the contraction of eyelid
burn wounds/scars. It generally develops around 1 week
postburn, and careful observation of the sleeping patient
demonstrates incomplete resting eyelid closure, with scleral
or corneal show (Fig. 43.1A). Any patient with incomplete
lid closure, best observed while asleep, should undergo
detailed examination of the ocular surface. Bell’s phenom­
enon, up-gaze with lid closure, is absent in 25% of patients
and does not reliably protect the ocular surface when
present; however, an intact Bell’s phenomenon may some­
what mitigate the severity of exposure keratopathy.
EPITHELIAL DEFECTS
An epithelial defect is present when an area of the cornea
has lost epithelium (Fig. 43.1C). It is denoted by a subtle
ridge where epithelium remains and by a solid area of fluo­
rescein staining. This can be either full or partial thickness.
Partial-thickness epithelial defects can heal rapidly from
the remaining basal layers, whereas full-thickness inju­
ries must heal from the periphery. Typically the epithelial
defect seen from incomplete eyelid closure (exposure) is
transverse, linear, and centered over the inferior third of
the cornea. Careful daily examination of epithelial defects
is required in burn patients, as is correction of underly­
ing causes. If magnified examination reveals stromal
opacification (i.e., any finding other than clear cornea at
and around the epithelial defect), then a corneal ulcer is
present and there is a high risk of vision loss. All indicated
diagnostic and therapeutic maneuvers should be employed
without delay.
CORNEAL ULCER
We define a corneal ulcer as an epithelial defect with any
associated stromal infiltrate (Fig. 43.1E). Corneal transpar­
ency, or lack thereof, is an important finding with histo­
pathological correlates. Transparency is lost when the
stroma becomes hydrated. In burns, this is typically in
response to injury or infection. This occurs when the kera­
tinocyte basement membrane has been compromised, a
process that can develop independent of phagocytic cells via
production of active matrix metalloproteinase-9 (MMP-9)
and then MMP-2 by corneal cells.106 The active form of
destruction, eyelid burns compromise the skin barrier func­
tion and predispose to burn wound cellulitis and infection.
Development of a preseptal inflammatory process (eyelid
swelling, hyperemia, and pain) is frequent after eyelid burn
injury, and microbiological cultures help in determining
whether this process is sterile or infectious. If infected, it is
termed preseptal cellulitis.49–53 When observed, it is cru­
cially important to evaluate extraocular muscle mobility
and function. If the orbital septum is compromised, an
orbital cellulitis or abscess may develop, which is an eye-
threatening emergency.54–62 Typical presentation of orbital
cellulitis or abscess includes reduced extraocular move­
ments and pain on extraocular muscle testing. Ophthalmo­
logical consultation, systemic antimicrobial therapy, and
frequent reexamination are indicated. Surgical débride­
ment may be needed for orbital abscess.
Chemical eye injuries are a true ophthalmological
emergency.63–65 Frequent and copious eye irrigation is gen­
erally indicated. Solid chemical particles should be removed
by irrigation as rapidly as possible with upper and lower lid
eversion and examination. Alkali injuries may need pro­
longed irrigation, up to several hours. Wound pH can be
litmus tested, preferably 2–5 minutes after cessation of irri­
gation as early false-normal results may occur. Insertion of
an irrigation aid, such as Morgan lenses, can provide con­
tinuous irrigation for several hours; these can also be useful
for continuous antibiotic delivery in cases of refractory bac­
terial keratitis.66–68
Patients with Stevens–Johnson syndrome/toxic epider­
mal necrolysis (TEN) are treated in the burn unit, and eye
involvement is seen in more than 60% of these cases. At
worst, they present with complete corneal slough, membra­
nous conjunctivitis, and lash auto-epilation (Fig. 43.1C).
The natural history is scar formation at involved areas,
symblepharon, forniceal shortening, corneal opacification/
scarring, mucocutaneous junction loss/keratinization,
entropion, and chronic, severe, dry-eye symptoms. Mount­
ing evidence indicates that ocular surface recovery may be
hastened, with improvement in vision, by prompt coverage
of the ocular surface with amniotic membrane.69–77 Patients
with these conditions should receive definitive treatment at
burn units where amniotic membrane transplantation is
available and applied immediately when ocular surface
involvement is apparent.70,78
ELECTRICAL INJURY
As with the systemic response, there are a number of
unique ocular aspects of electrical burn injury. Cataract for­
mation following electrical injury has been recognized for
more than a half a century.79–96 While the mechanism is not
fully understood, within the lens (and other ocular tissues)
there is substantial intercellular electrical coupling.97–101
These reports note that electrical cataract tends to present
within 12 months of the electrical burn event and that
visual outcome following cataract extraction can be good
in the absence of other eye pathology. Other findings, such
as chorioretinal atrophy, are seen less frequently.102,103
For both patient care and medicolegal reasons, electrical
injury patients should be evaluated for cataract via dilated
exam at admission, discharge, and 6 and 12 months
postinjury.104

43  •  Burn Injuries of the Eye
439
severely burned patients.122 Bacterial keratitis typically
follows a more fulminant course than sterile corneal ulcers
caused by exposure (Fig. 43.1F).
FUNGAL KERATITIS
Burn patients are in jeopardy for developing secondary
infections of persistent exposure-related epithelial lesions.
Not infrequently, fungal organisms are isolated as coloniz­
ers or active pathogens from burn wounds of the face and
eyelids; thus facial wound microbiology determines the risk
of secondary infection at ocular surface lesions. We have
seen secondary Candida keratitis (ulcer) arising in this
manner. Fungal keratitis is typically more indolent and is
unresponsive to antibacterial treatment. With magnifica­
tion, satellite lesions may be observed around the primary
lesion. Diagnosis can be made through scraping, potassium
hydroxide prep, and fungal culture. Rarely a corneal biopsy
is necessary to establish the diagnosis if a high clinical sus­
picion for fungal keratitis exists while cultures remain nega­
tive. In refractory cases, débridement and corneal transplant
may be necessary.123
VIRAL (HERPETIC) KERATITIS
The systemic response to burn injury entails profound
alterations in host immunity, including markedly reduced
novel immunoglobin generation and adaptive cell-mediated
immunity.124–143 Type 1 T-helper (TH1) cellular response,
activated macrophage cell killing, is associated with clear­
ance of systemic virus and survival in animal models.
Elegant studies by Suzuki et al. demonstrated that, post­
burn, chemokine CCL2 (a.k.a. monocyte chemoattractant
protein-1) stimulates a subset of natural killer T cells to
produce interleukin-4, an early signal in a cascade ulti­
mately producing TH2 cytokines and abolishing the ben­
eficial TH1 response.144–159 This situation leads to increased
susceptibility to Herpesviridae. Herpetic keratitis (reactiva­
tion) in burned patients is both a sight-threatening problem
and a marker of profoundly altered immunity. Dendritic
(branching) epithelial defects and stromal infiltrates are
typical of herpetic keratopathy (Fig. 43.1D). Allowed to
progress, these enlarge forming a “geographic” corneal
ulcer with an irregular border. Real-time polymerase chain
reaction testing of corneal swab specimens is invaluable
for diagnosis, providing rapid (within hours) information
about the presence and type of Herpesviridae infection.160
Although tear specimens have also been studied, the diag­
nostic yield is substantially lower.
ORBITAL COMPARTMENT SYNDROME
Orbital compartment syndrome (OCS) presents when the
globe is compressed by swelling of the orbital contents and
is unable to decompress itself. The natural variation in
eyelid laxity provides a variable individual susceptibility to
this problem; if the globe is able to be moved anteriorly to
accommodate the swelling, intraocular hypertension may
not develop. Acute intraocular hypertension can lead to
anterior ischemic optic neuropathy (AION), with loss of
vision. In the setting of severe burns, it can rapidly cause
complete loss of vision bilaterally.161 Decreased arterial
these enzymes has also been observed in the tear fluid from
ocular burn and infectious ulceration patients.107 Altered
capillary permeability and the evolving wound-healing
response occur in a manner akin to skin wound healing.
This includes phagocytic infiltration, tissue destruction and
pathogen clearance, reepithelialization, and myofibroblast-
mediated scar formation. The disorganized collagen formed
as part of scar formation lacks the regular arrangement
and spacing of a healthy, clear corneal stroma. As a result,
it appears white/gray and reflects rather than transmits
visible light, causing vision loss. Transparency can also be
lost due to corneal endothelial dysfunction. Impaired func­
tion of the endothelial adenosine triphosphate (ATP)-
dependent transport of solute from the stroma into the
aqueous humor causes abnormally increased hydration of
stromal proteins. The associated epithelial defect should be
measured daily at a minimum on magnified exam because
stability and reepithelialization indicate treatment response.
Inhibition of serine proteases may slow epithelial migra­
tion, although inhibition of MMPs may actually facilitate
reepithelialization.108–112 The majority of corneal ulcers can
be prevented in burned patients via early release and skin
grafting of full-thickness eyelid burns.113 Most corneal
ulcers in burned patients are sterile, but the occurrence of
bacterial superinfection is not uncommon.114 For this
reason, and because treatment of infectious corneal ulcers
is aided by the provision of directed antibiotics, swab or
scraping culture of corneal ulcers is a routine part of our
diagnostic protocol. Corneal scraping is accomplished with
ophthalmic tetracaine drops, sedation (usually intravenous
ketamine), loupe magnification, adequate lighting, and
either a #69 or the rounded belly of a #15 blade. Carefully,
the margin of the corneal ulcer is scraped, maintaining the
edge of the blade almost parallel to the corneal surface to
avoid any penetrating injury. The specimen, often visible
only with loupes, is plated on blood and chocolate agars (for
the broadest spectrum of bacterial growth), Sabouraud’s
agar (for fungal organisms), and several glass slides, for
Gram’s stain (for bacteria), Giemsa stain (for cellular fea­
tures and viral cytopathic effect), and potassium hydroxide
stain (for fungal elements).115 Rapid review of the slide
specimens, if positive, enables immediate initiation of
directed topical antimicrobial agents.116–118 Initial response
to treatment is nonprogression (stabilization) in the size of
the epithelial defect and underlying stromal infiltrate.
With continued healing, these gradually become smaller.
Therefore every follow-up examination should scrupu­
lously document the sizes of the epithelial defect and
stromal infiltrate.
BACTERIAL KERATITIS
Bacterial corneal ulcers can occur in otherwise healthy
patients, as with prolonged use of contact lenses, but
burned patients are at particular risk because of lost eyelid
function, ocular surface exposure, local contamination
from colonized/infected skin wounds, and disruption of
host immunity, among other factors.119 Acinetobacter spp.
have been reported, as well as Staphylococcus spp. and Pseu­
domonas spp.120,121 Pathogen virulence factors play impor­
tant roles in the outcome of these infections, and more
virulent bacteria may be selected during the recovery of

43  •  Burn Injuries of the Eye
440
tarsorrhaphy) if eyelid destruction and ocular surface
exposure are present. In cases where vision is unilater­
ally affected, it is possible to intermittently patch, or treat
with cycloplegics, the “good” eye, in an attempt to prevent
amblyopia.169 Involving an ophthalmology consultant is
prudent when vision-preserving eyelid procedures raise
concerns for iatrogenic amblyopia.
DESCEMETOCELE, CORNEAL PERFORATION,
AND OPEN GLOBE
The posterior 50 µm of corneal stroma is Descemet’s mem­
brane. This posterior layer of corneal stroma, while thin,
possesses a high degree of strength. When stromal destruc­
tion is near full thickness, the aqueous humor of the ante­
rior chamber may be contained by this structure alone.
Termed a descemetocele, it is a sign of an impending corneal
perforation (Fig. 43.1G). Often an aqueous leak can be
appreciated if fluorescein dye is applied over the area; the
leaking aqueous humor dilutes and carries the dye into the
tear lake (positive Seidel test). Corneal perforations (Fig.
43.1H) and lacerations (Figs. 43.2A and B) can be similarly
recognized if the aqueous leak is not massive. With a
massive loss of aqueous humor, the eye loses intraocular
pressure, becoming “flat.” Loss of intraocular pressure, or
marked intraocular hypotension below 8 mm Hg, can result
in choroidal detachment and loss of retinal function. Early
application of tissue adhesive to descemetocele or acute per­
foration reduces the rate of eventual enucleation.170,171
Interventions
Topical lubricants provide protection to an at-risk ocular
surface. We generally prefer petroleum-based or water-
based ointments. The preservative present (a mild chemical
toxin) in multidose artificial tear formulations can cause or
exacerbate corneal injury if used more frequently than four
times a day.
Topical antimicrobials are recommended if clinical find­
ings or confirmatory microbiologic evidence exists of ocular
pressure further compounds the risk of AION infarction.
Orbital compartment syndromes are occasionally observed
in the first 24–96 hours after severe burn injury requiring
large-volume resuscitation.162 The development of com­
partment syndromes in unburned extremities or abdomen
should prompt evaluation of the intraocular pressure;
urgency is increased if there is concomitant arterial hypo­
tension. Burns of the face and periorbita can lead to prodi­
gious swelling and OCS in the absence of massive fluid
resuscitation.163 Full-thickness flame burns (charring) of
the periorbital skin can prevent the normal swelling of the
underlying tissues, thus facilitating OCS. Intraocular pres­
sure can be evaluated grossly by direct palpation of the
globe, by evaluating the mobility of the globe against the
lower lid (the globe is tightly pressed against the conjuncti­
val surface of the lower lid in OCS), or more exactly with a
tonopen or Schioetz tonometer. Intraocular pressure is sen­
sitive to extrinsic forces, so it is essential that the technique
used to open the lids not compress the globe or a falsely
elevated intraocular pressure reading may result. Measured
at the cornea, intraocular pressures of 30 mm Hg or higher
are cause for concern and frequent reevaluation. Avoiding
excessive fluid/volume expansion and elevation of the head
of the bed can help reduce intraocular pressure. If the globe
is hard on palpation, the lower lid tightly apposed to the
globe, or intraocular pressure remains at 30 mm Hg or
higher, release of OCS is indicated to preserve vision and
prevent AION. The intraocular pressure threshold for
release should be somewhat lower when patients have
ongoing arterial hypotension because tissue perfusion is a
balance between arterial and tissue hydrostatic pressures.
AMBLYOPIA
Amblyopia is concerning in the burn unit primarily when
prolonged eyelid closure or near-closure is requisite to
treat ocular surface lesions in prepubertal children. Loss
of visual stimuli leads to loss of capacity to perceive visual
stimuli.164–169 Amblyopia presents with decreased visual
acuity in the absence of structural or refractive lesions.
In practice, it is better to treat both eyes equally (e.g.,
A
B
Fig. 43.2  A, Corneal laceration. B, Scleral laceration.

43  •  Burn Injuries of the Eye
441
surface infection. For limited burns, erythromycin ointment
provides antimicrobial coverage and lubrication. In major
burns or with severe associated facial burns, high colony
count, not infrequently Gram-negative, colonization often
occurs of the eyelids and surrounding skin. In these patients,
our first-line preference is bacitracin/polymyxin B oint­
ment. We provide empiric coverage of corneal ulcers and
significant epithelial defects with quinolone drops (moxi­
floxacin is preferred but more expensive) while culture data
are pending. Fortified antibiotics (vancomycin, ceftazidime,
or tobramycin) are used on a case-by-case basis, generally
when positive culture data are available or pending, and
clinical progression is observed while on empiric treatment.
Fungal keratitis occurs infrequently, but, in severe burns,
when culture data suggest yeast colonization of facial
wounds near the eyes, we provide natamycin prophylaxis.
Voriconazole eyedrops can similarly be compounded to for­
tified antibiotic drops and may be useful in the treatment of
documented fungal keratitis. Herpetic keratitis in burned
patients is treated with systemic antivirals; topical antivi­
rals (ganciclovir or trifluridine) can be added to more quickly
halt the progression of corneal injury. A direct comparison
between systemic and topical treatments has not, to our
knowledge, been performed in burn patients.172 Due to
altered host immunity discussed earlier, burn patients are
in jeopardy of developing disseminated Herpesviridae, and
topical monotherapy is not generally employed.
BANDAGE CONTACT LENS
Lenses useful as corneal bandages are characterized by low
diopteric power, soft structure, and high gas permeability,
and are often labeled “extended-wear” (e.g., Bausch and
Lomb Night and Day or Acuvue Oasis). These are occa­
sionally useful in facilitating reepithelialization and pro­
tecting corneas damaged by exposure. Once in place, these
lenses should be evaluated frequently and discontinued or
replaced when no longer effective. Due to risk of infection
and other complications, it is prudent to involve an oph­
thalmology consultant when bandage contact lenses are
employed.173–177
LATERAL CANTHOTOMY
Lateral canthotomy should be performed in cases of OCS,
described earlier. Structure is provided to the lids by the
canthal tendons, inserting on the upper and lower tarsi
medially and laterally. The lateral origin is palpable as a
bony prominence at the lateral orbital rim, called Whitnall’s
tubercle. Lateral canthotomy is performed by dividing the
skin and lateral canthal tendon, freeing the lower lid from
its bony attachment. Lidocaine 1% or 2% with epinephrine
is infiltrated lateral to the lateral canthus and the skin is
clamped parallel to the palpebral fissure, then divided with
scissors anteroposteriorly. The lower lid is grasped and
pulled away from the globe, placing the lateral canthal
tendon on stretch, making it easier to locate and divide. The
canthal tendon is divided with scissors anteriorly to Whit­
nall’s tubercle on the orbital rim.178,179 A successful lateral
canthotomy leaves the lower lid freely mobile and no longer
apposed to the globe. Afterward, the intraocular pressure
should be reevaluated.
EYELID CLOSURE AND RECONSTRUCTION
Because the vast majority of burn-related eye disease results
from exposure of the ocular surface, techniques facilitating
eyelid closure are of central import. Temporary closure can
be accomplished with Steri-Strips and cyanoacrylate skin
adhesive; this closure may last 24–48 hours. Cyanoacrylate
adhesive can also be used to temporarily close the lids by
joining the lashes and eyelid margins of the lateral parts of
lids;180–186 in practice, this method of temporary eyelid
closure lasts a few days. A temporary suture tarsorrhaphy
can be constructed either with bedside sedation and local
anesthesia or in the operating room. Tarsorrhaphy increases
the rate of corneal epithelial wound healing.174,187–189
Several techniques have been described; some permit facile
reopening and reclosure if frequent eye examination is
deemed necessary.190–206 Chromic gut sutures often do not
require removal and are occasionally used in our prac­
tice.207 A tarsorrhaphy becomes progressively more “per­
manent” as deepithelialized surfaces of the eyelids are
apposed. Several methods exist to create what we term
“semi-permanent” tarsorrhaphy; these are indicated when
large areas of full-thickness injury to the eyelids necessitate
multiple reconstructive operations or after the failure of
previous temporary suture tarsorrhaphy.208 Less durable
outcomes are associated with mattress sutures or bolster
techniques than an internal fixation technique by which
the gray line is split in the region of the planned tarsorrha­
phy and the posterior and anterior laminae of the upper
and lower lids are sutured to each other.209 It is vitally
important to avoid placing knots in contact with the corneal
surface because these can cause abrasion injuries and
corneal ulcers.
The forces of scar contraction powerfully influence eyelid
function and, when tarsorrhaphy (including temporary) is
indicated, often eyelid release and tissue interposition will
also be required to preserve sight (Figs. 43.3A and B).113
Essentially the procedure is a reverse blepharoplasty: the
skin and scar of the lid is incised in the tarsal crease, and
the upper lid mobilized inferiorly. Overcorrection is needed
at the time of surgery because recurrent contraction in 2–3
weeks is the rule. The resulting defect can be covered with
a split-thickness skin graft and secured with a combination
of fibrin glue, sutures, or cyanoacrylate adhesive. If neces­
sary, a secondary procedure is employed for the lower lids,
although full-thickness skin autografts may be substituted
to close the defect after release.210 While release and skin
graft interposition may protect a fresh tarsorrhaphy from
disruption due to scar contraction at the eyelids, these grafts
eventually contract despite all efforts at preservation.211–215
Contraction and recurrence of cicatricial ectropion neces­
sitate a series of repeated releases until both ocular surface
and eyelid function stabilize. In cases of massive burns, when
eyelid release is required and no sufficient donor site for
sheet grafting of the upper lids can be spared, it is possible,
despite burned skin, to mobilize the midportion of the brow
and upper lid inferiorly from the medial and lateral brow in
a myocutaneous V-Y inferior advancement flap, akin to this
flap’s utilization in oncological reconstruction.216–218 This
procedure may provide the release needed to allow forma­
tion of a stable tarsorrhaphy for ocular surface protection
in critically injured patients.

43  •  Burn Injuries of the Eye
442
oculi myocutaneous flap from the lower lid with a laterally
based pedicle (Fig. 43.5A–C).220,221 The lower lid donor site
defect of the latter may be closed with the previously dis­
cussed nasolabial fold island pedicle flap. Occasionally the
tissue destruction resulting from burn injury is so severe
that the structural integrity of the tarsal plate is compro­
mised. This leads to lid dysfunction often recalcitrant to the
preceding methods of treatment.222 To address this, tarsal
compromise must first be recognized. It can be replaced
Huang et al. suggest use of local skin flaps, when possi­
ble, to overcome the difficulty of autograft contraction and
recurrent cicatricial ectropion. The lower lid may be treated
with a superomedially based island pedicle flap from the
nasolabial fold (Figs. 43.4A–C). This flap is quite durable,
and the donor site heals with little morbidity.219 If burn scar
of the skin surrounding the donor site precludes closure, a
split-thickness autograft can be used. Flaps available for the
upper lid include paramedian forehead flap and orbicularis
A
B
Fig. 43.3  A, Upper eyelid release, grafting, and lateral tarsorrhaphy. B, Follow-up.
A
C
B
Fig. 43.4  Cicatricial ectropion of the lower lid; reconstruction with nasolabial island pedicle flap. A, Flap dissection. B, Flap inset. C, Follow-up.

43  •  Burn Injuries of the Eye
443
entire corneal surface, beginning through a transverse inci­
sion of the conjunctiva in the superior fornix. After the
superior bulbar conjunctival flap is raised, a perilimbal
peritomy is performed, the cornea deepithelialized, and the
flap brought down over the cornea by securing its inferior
edge between the 4 and 7 o’clock positions of the periot­
omy.229,230 The superior aspect of the flap is sutured to
Tenon’s capsule between the 10 and 2 o’clock positions of
the peritomy, and the entire superior surface of the globe is
left denuded of conjunctiva, which rapidly reepithelializes.
This flap is useful if performed with scrupulous avoidance
of “buttonholing,” as holes created in the flap invariably
expand and allow corneal exposure. The goal of a Gunder­
sen flap is to provide long-term corneal coverage, prevent
perforation, and preserve an intact globe for later vision
restoration.231
using suitable cartilage, often harvested from the conchal
bowl. Placed in a preseptal location223 during eyelid con­
tracture release and covered with a skin flap, this technique
can be used in cases of subtotal eyelid loss so long as intact
palpebral conjunctiva remains. Replacing lost conjunctival
tissue is infrequently necessary postburn. This deformity
can present with entropion and significant ocular surface
injury and is frequently seen after Stevens–Johnson syn­
drome or TEN. We have successfully employed the tech­
nique of preseptal cartilage graft with skin resection
(blepharoplasty) to rotate the lash line and scarred/
keratinized mucocutaneous junction away from the corneal
surface.224 We have not yet had occasion to resort to con­
junctival replacement procedures, such as buccal or nasal
mucosal free grafts or nasal septal composite cartilage-
mucosa grafts.225,226
CONJUNCTIVAL (GUNDERSEN) FLAPS
When corneal ulceration and epithelial loss are catastrophic
and refractory to the previously described therapeutic mea­
sures, it is possible to mobilize the bulbar conjunctiva over
the cornea (Fig. 43.6). These flaps provide a supply of vas­
cularized tissue to create scar, deliver systemic antimicro­
bial therapy to the wound, and stabilize an impending
perforation (e.g., descemetocele). A fornix flap is constructed
by suture of the mobile conjunctiva in the inferior and supe­
rior fornices.227 This flap may last 1–2 weeks before retract­
ing and does not require any dissection. If small strips of
apposing conjunctiva are excised, a more durable fornix flap
may be held in place by adhesions similar to those formed
via semipermanent tarsorrhaphy. Khodadoust described a
microsurgical conjunctival flap, but its placement is more
demanding than other options.228 The classic Gundersen
flap mobilizes the superior bulbar conjunctiva over the
A
C
B
Fig. 43.5  Cicatricial ectropion; reconstruction with myocutaneous orbicularis flap and nasolabial flap. A, Flap dissection. B, Flaps inset. C, Follow-up.
Fig. 43.6  Gundersen (conjunctival) flap.

43  •  Burn Injuries of the Eye
444
and in a stable, if scarred, state. Corneal neovascularization
frequently follows healing of corneal ulcers. If present, it
will increase the risk of corneal allograft rejection, as does
the presence of nonnative immune surveillance (Langer­
hans) cells.237–239 Herpetic keratopathy is a further risk
factor for rejection.240 Thus a lamellar graft (partial-
thickness corneal allograft) is preferred, because it preserves
the patient’s native endothelium from graft rejection.241–245
Lamellar grafts are also more tolerant of elevated intraocu­
lar pressure, although they can undergo epithelial or
stromal rejection.246–249 As a salvage procedure, tectonic
grafts can be used in the setting of frank perforation or
descemetocele.250–253 The purpose of these procedures is to
maintain a closed globe and intraocular pressure. Amniotic
membrane multilayer grafts may be useful as a temporizing
measure and may play an antiinflammatory role in decreas­
ing the rate of rejection of allografts placed in an emergent
setting.254–256 Rarely destruction of the eyelids, ocular
surface, and/or ocular surface may lead to the situation in
which the potential for vision exists, but no native recon­
structive options exist. These cases may benefit from evalu­
ation by centers experienced in the performance of and
postoperative care for keratoprosthesis surgery.257–300
Complete references available online at

RECONSTRUCTION OF THE LACRIMAL
APPARATUS
Rarely burn injury or resulting scarring compromises the
normal flow of tears through the lacrimal system. Although
a Jones tube or lacrimal stent may be useful in other set­
tings, in the burned patient, scarring and markedly abnor­
mal function of the eyelids combined with discharge due to
chronic conjunctivitis render these tubes prone to clogging.
The foreign body may also trigger local infectious complica­
tions.232 Instead we employ a conjunctival mucosal flap to
create a fistulous tract for tear drainage.233 In cases where
the punctum and upper lacrimal drainage apparatus are
destroyed, this flap can be placed within the lacrimal sac,
termed mucosal conjunctivodacryocystostomy. When the
upper and lower lacrimal drainage structures are dysfunc­
tional, the mucosal flap can be drained directly into the
nasal or maxillary sinus cavities, mucosal conjunctivorhi­
nostomy, and mucosal conjunctivoantrostomy, respectively.
Refractory epiphora has been amenable to these treatments
in 16 of 17 reported cases.234
CORNEAL TRANSPLANTATION
A stable ocular surface is generally requisite to achieve a
successful corneal transplant.235,236 Eyelid malposition must
be corrected and epithelial defects and corneal ulcers closed

444.e1
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286. Klufas MA, Yannuzzi NA, D’Amico DJ, Kiss S. Vitreoretinal aspects of
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287. Charoenrook V, Michael R, de la Paz MF, et al. Osteokeratoprosthe­
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288. Iyer G, Srinivasan B, Agarwal S. Rachapalle SR. Laminar resorp­
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289. Lee RM, Ong GL, Lam FC, et al. Optical functional performance of the
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290. Lim LS, Ang CL, Wong E, Wong DW, Tan DT. Vitreoretinal compli­
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291. Weisshuhn K, Berg I, Tinner D, et al. Osteo-odonto-keratoprosthesis
(OOKP) and the testing of three different adhesives for bonding
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292. Avadhanam VS, Liu CS. A brief review of Boston type-1 and osteo-
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293. Berg BI, Dagassan-Berndt D, Goldblum D, Kunz C. Cone-beam com­
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294. Iyer G, Srinivasan B, Agarwal S, et al. Bone augmentation of the
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445
The Burn Problem:
A Pathologist’s Perspective
HAL K. HAWKINS
44 
reaction. In the skin, the tissues at the base of the zone of
necrosis become acutely inflamed. Cytokines released by
inflammatory cells and surviving cells in the tissue have
effects throughout the body. In addition, in endothelial cells
injured by hypoxia, the enzyme xanthine dehydrogenase is
converted to xanthine oxidase, which releases superoxide
during degradation of adenosine, which in turn is released
by necrotic cells.7,8 Superoxide, released into the circulation
by this metabolic process and by neutrophils, can injure the
lung by damaging both endothelial and epithelial cells and
allowing protein-rich fluid to exude into alveoli. In experi­
mental models of burn injury, as well as in models of
ischemia–reperfusion injury, the lungs have been shown to
be injured by these processes.9,10 Ischemia caused by reduced
perfusion may lead to necrosis of pancreatic acinar epithe­
lium and acute pancreatitis. Thermal injury to skeletal
muscle, or lack of perfusion of muscle, may lead to local
exudation of fluid and development of such high pressures
in fascial compartments that arterial perfusion is prevented.
This “compartment syndrome,” unless relieved by prompt
surgical intervention, leads to necrosis of muscle through­
out the entire compartment.11 The consequences of massive
necrosis of muscle often include secondary injury to the
lungs, owing to release of reactive oxygen species, and myo­
globinuria with secondary renal damage.12 At the time of
injury, patients frequently inhale carbon monoxide, which
compromises the oxygen-carrying capacity of the blood.
The resultant tissue hypoxia can cause death at the scene,
and if the patient survives, it can be sufficient to lead to
irreversible neuronal injury, cerebral edema, and brain
death days later. Hypoxemia, sometimes related to carbon
monoxide intoxication, also contributes to cardiac and
renal injury. In addition, when fires occur in closed spaces,
the “flashover” process consumes all available oxygen so
that the patient’s environment may contain too little oxygen
to sustain life. Occasionally, a burn victim is found without
pulse or respiratory effort, probably as a consequence of
hypoxia, and is revived by cardiopulmonary resuscitation
(CPR). In such cases, ischemic and hypoxic injury may be
profound in multiple organs.
INFECTION
Necrotic skin provides an excellent environment for prolif­
eration of bacteria and fungi, and as long as necrotic tissue
remains, the risk of infection remains high. Immunosup­
pression contributes to this risk, and burn patients develop
serious infections with agents usually encountered only in
patients treated with immunosuppressive drugs. The mech­
anisms of this immunosuppression are still under investiga­
tion but include excessive secretion of glucocorticoids,
Videos available at
Introduction
A large burn is not a simple injury but a very complicated
disease. This statement, restated from its publication in
1840, holds true with additional force in 2016.1 Massive
destruction of skin tissue by burns stimulates many complex
reactions that are still only partly understood. Malfunction
of every organ system complicates the responses of patients
to large burns. These malfunctions can be clarified by exam­
ination of the body after death. Postmortem examination
also may reveal unsuspected infections or adverse effects of
therapy. In addition, postmortem examination leads to
review of the circumstances of injury and of the causal
sequence in which complications occurred. Analysis of an
entire case from the point of view of pathogenesis often
clarifies the nature of the patient’s most significant prob­
lems. The manner of death is accident in most cases, but
collection of additional information on the circumstances
of the initial injury sometimes reveals evidence of homi­
cide. After presentation of the major systemic problems that
occur in burn patients, this chapter reviews some of the
observations made at autopsy organized by organ system.
It also surveys experimental evidence that bears on patho­
genic mechanisms relevant to disease processes seen at
autopsy. The observations reviewed here are drawn from
the experience of more than 300 autopsies performed on
burned children who died at the Shriners Burns Hospital in
Galveston, Texas, from 1971 to the present.
Systemic Reactions to Burns
HYPOXIA AND ISCHEMIA
Immediately after burn injury, massive loss of intravascular
fluid into the burned tissue begins to occur.2,3 Unless this
fluid loss is replaced very promptly and carefully, serious
hypovolemia develops.4–6 Hypovolemia and the resulting
reduction of tissue perfusion to levels less than that neces­
sary for cellular survival, which is defined as ischemia,
causes necrosis of certain cells. Typically, the cells first
affected by ischemia are those with the greatest oxygen
demand, including neurons in the brain, cardiac myocytes,
intestinal epithelial cells, and proximal tubular epithelial
cells in the kidney. After the death of selected cell types or
whole segments of organs (infarcts), responses are gener­
ated that often lead to further injury of remote organs. Cel­
lular necrosis stimulates an intense acute inflammatory

44  •  The Burn Problem: A Pathologist’s Perspective
446
abnormal cytokine signaling, and altered maturation of
neutrophils and macrophages. When burn wounds become
infected and large numbers of bacteria accumulate, those
with high pathogenic capacity invade the adjacent viable
tissue, produce further necrosis, and gain access to the cir­
culation. This is the condition of burn wound sepsis, which
historically has been the leading cause of death in burn
patients. In Linares’ series of 115 autopsies, sepsis was
present in 73%, as documented by positive blood culture
and demonstration of invasive infection of viable tissue.13
When pneumonia was found at autopsy in such a case, the
cause of death was classified as burn wound sepsis, with
pneumonia as a contributing cause. In more recent cases,
pneumonia has been considered the primary cause of
death. In 80% of these fatal cases of sepsis, the burn wound
was the source of the infection. The most important patho­
gens were Pseudomonas aeruginosa, Staphylococcus aureus,
Klebsiella pneumoniae, Escherichia coli, Enterobacter spp., and
Candida spp. More recently, antibiotic-resistant Acinetobacter
has emerged as a frequent cause of fatal sepsis. Burn wound
sepsis is recognized clinically when a burn wound is the site
of proliferating microorganisms exceeding 105/g of tissue
and there is histologic evidence of active invasion of subja­
cent unburned tissue.14
It is important to assess the presence and extent of infec­
tion within the burn wound, both by careful clinical exami­
nation of wounds and by biopsy of suspicious areas. A high
index of suspicion serves burn patients well. All biopsy and
excision specimens in our institution are sampled and
studied histologically using special stain, a tissue Gram
stain for bacteria, and methenamine silver for fungi. In
large excision specimens, samples are taken from sites of
especially deep tissue injury and sites that show abnormal
discoloration of dermal or subcutaneous tissue. When
infectious microorganisms are found, it is important to
determine their location with respect to the boundary
between living and necrotic tissue. This boundary may be
irregular but is generally distinct and marked by inflamma­
tion in wounds that are several days old, and it may be
indistinct in very fresh specimens because karyolysis takes
some time to develop in burn wounds.
Wound infections generally begin with colonization of
the skin surface and proliferation of organisms on the
surface, often with extension into hair follicles followed by
growth within the necrotic tissue. Growth within necrotic
tissue is considered evidence of tissue infection, however,
and is potentially more dangerous than growth on the
surface of necrotic skin. Even when quantitative cultures
show more than 105 bacteria per gram of tissue, when
careful histologic study shows that the organisms are
limited to the skin surface or the superficial necrotic tissue,
the risk of sepsis appears to be low. Such growth on or in
necrotic tissue, however, sets the stage for invasion of viable
tissue. The finding of clusters of bacteria or fungi within
viable tissue implies a serious risk of sepsis and further
tissue invasion. Bacterial invasion of viable tissue is readily
apparent by histologic study of appropriate tissue samples
(Fig. 44.1). Invasive fungal infection presents a somewhat
different pattern in that there is often a wavefront of necro­
sis that accompanies fungal invasion (Fig. 44.2). Thus, the
presence of fungal hyphae extending to a boundary between
necrotic and viable tissue is considered evidence of fungal
invasion of viable tissue. On this basis, infections identified
within burn wounds are reported as surface colonization;
invasion of necrotic tissue, which may be superficial or
deep; and invasion of viable tissue. The responsible surgeon
is called immediately when invasion of viable tissue is
found. If the level of clinical suspicion is high, cryosection­
ing techniques can be useful. We use a tape transfer device
to facilitate handling of these specimens, since cryosections
of adipose tissue and necrotic tissue adhere poorly to slides.
The results are confirmed with routine sections on the fol­
lowing day. Diagnosis of viral infection of the skin is
achieved most efficiently by sampling freshly opened vesicu­
lar lesions or the bases of recently ruptured vesicles and
molecular testing by polymerase chain reaction (PCR).
When septicemia occurs, there is a generalized reaction,
which often includes hypotension, tachycardia, increased
Fig. 44.1  Micrograph showing a dense cluster of filamentous Gram-
negative rods within necrotic skin in a patient with severe wound infec­
tion from whom Pseudomonas aeruginosa was recovered in culture.
Tissue Gram stain.
Fig. 44.2  Micrograph showing fungal hyphae within necrotic tissue
extending close to the boundary with intact, viable dermal tissue. Peri­
odic acid–Schiff stain.

44  •  The Burn Problem: A Pathologist’s Perspective
447
are caused by endogenous flora and many derive from
wound infections present at the time of admission, nosoco­
mial infection is a constant hazard.20,21 The problem of
burn wound sepsis is amenable to therapy. The strategy of
excision of the potentially infected burn wound as early as
possible, together with judicious administration of effective
antibiotics, can reduce the number of deaths caused by
infection. After the institution of early excision and grafting
of burn patients in our institution, the incidence of burn
wound sepsis as a cause of death declined dramatically, but
the problem of sepsis persists. Organisms resistant to all
available antibiotics are seen in burn patients with increas­
ing frequency, and development of new antibiotics has not
kept pace.22 Patients who are referred for therapy more than
1 week after burn injury often have extensive invasive
wound infection and sepsis caused by antibiotic-resistant
organisms. Other microorganisms also can cause life-
threatening infections in burn patients. Fungal infection is a
continuing problem in patients with large burns.23 Diagno­
sis of specific fungal infections by histopathology is difficult
because important morphologic features that allow identi­
fication in culture do not occur in tissues, and fungi may
display unexpected structural features in injured tissues.
Pigmented fungal species generally do not show invasive
behavior, and saprophytic species can mimic Zygomycetes.
In one recent case of apparent systemic fungal infection,
invasive and systemic dissemination of a pseudofungus of
the genus Oomycetes was demonstrated.24 Molecular
methods (reverse transcriptase PCR) were used to identify
the organism in this case. Zygomycetes have recently been
recognized as dangerous burn wound pathogens.25 It seems
likely that the increased availability of molecular diagnostic
testing of infectious agents may lead to recognition of addi­
tional previously unrecognized causes of invasive infection
in burn patients as well as allowing more precise and rapid
diagnosis of infection. Viral infections may also complicate
burns. We have also experienced cases in which acquisition
or reactivation of herpes virus infections led to major tissue
injury. The risks of infection of a victim of a large burn are
somewhat similar to those of an immunosuppressed trans­
plant patient. Recent studies have illustrated the usefulness
of the study of autopsy tissue in generating hypotheses to
be tested in the laboratory.26,27
COAGULOPATHY
The burn wound has procoagulant effects and may induce
coagulation throughout the circulation (disseminated
intravascular coagulation [DIC]).28,29 Tissue necrosis can
lead to coagulopathy. Generation of thrombin within the
circulation leads to generation of fibrin peptides and stimu­
lates acute inflammatory reactions, including increased
vascular permeability and upregulation of adhesion mol­
ecules on neutrophils and endothelial cells (Fig. 44.4).30
Generation of fibrin degradation products may interfere
with normal thrombosis, and thrombocytopenia can
develop.31 Activation of the kinin system can stimulate
further abnormal vascular permeability and hypotension.32
Consumption of coagulation factors can lead to abnormal
bleeding, which can cause extensive tissue injury second­
arily. It is important to note that the acute-phase response
to burn injury includes increased synthesis of fibrinogen
hyperthermia or hypothermia, and poor perfusion of the
intestines and other viscera.15 Coagulopathy is also an
important complication of sepsis.16 In addition, after bacte­
ria have gained entrance to the general circulation, tissue
infection may develop at distant sites. This is most likely to
occur in the lungs. One recent case demonstrated clearly
the route of dissemination of fatal burn wound sepsis. The
patient was admitted in a clinically septic condition 2 weeks
after sustaining a large burn and died despite aggressive
therapy. At the time of autopsy, there were many areas
of bacterial proliferation within the burn wound, invasion
of viable tissue deep to the burn eschar, and thrombosis of
blood vessels invaded by bacteria at the margin of the
necrotic zone. Bacteria were especially numerous within
the smooth muscle of veins in the dermis, suggestive of
biofilm formation. Septic emboli with fibrous organization
were seen in pulmonary artery branches in all lobes of the
lungs. There were foci of necrosis throughout the lungs in
which bacterial proliferation was visible within the walls of
arteries, and these necrotic areas were surrounded by
massive pulmonary hemorrhage and edema. Very little
acute inflammatory reaction was seen around the many
foci of bland necrosis in the lungs. A direct hematogenous
route of spread of infection from the skin to the lungs
seemed clear in this case. This pattern is similar to that of
ecthyma gangrenosum of the skin, which is also character­
ized by bland necrosis thought to be caused by ischemia.17,18
A similar angioinvasive pattern of pulmonary infection can
be seen with generalized infection caused by Aspergillus spp.
or similar filamentous fungi. On the other hand, airway
obstruction is known to predispose to pneumonia acquired
through the airways by preventing normal clearance of
bacteria from the airways and by providing a favorable
medium for bacterial growth. Multiple foci of airway
obstruction are almost always seen at autopsy in burn
patients.19 In another recent case, although pneumonia
was not present, there was invasion of antibiotic-resistant
Pseudomonas spp. directly into the wall of a bronchus (Fig.
44.3). Although many serious infections in burn patients
Fig. 44.3  Photograph showing a slice of the upper lobe of the lung
taken at autopsy from a patient who showed clinical signs of sepsis
when he developed disseminated infection after multiple wound cul­
tures of open wounds yielded multiple antibiotic-resistant Pseudomo­
nas spp.

44  •  The Burn Problem: A Pathologist’s Perspective
448
evidence that neutrophils contribute to this process of burn
wound extension (Fig. 44.5).37
A fortunately rare complication involving the skin of
patients with large burns is the development of squamous
cell carcinoma during the late phase of recovery. This so-
called “Marjolin ulcer” shows extensive local invasion but
generally can be controlled with adequate local excision.38–40
RESPIRATORY SYSTEM
Respiratory failure, defined as the inability to maintain
adequate oxygen saturation while 100% oxygen is given via
ventilator, is the immediate cause of death in some burn
patients. The causes and mechanisms of respiratory failure
are multiple and will be addressed separately, although
often more than one mechanism operates. Direct thermal
injury to the trachea and bronchi probably does not occur,
except in patients exposed to large amounts of steam. In
addition to the problems listed below, patients may develop
problems related to the airways such as pneumothorax or
interstitial emphysema, aspiration of gastric contents, pul­
monary embolism, and nonspecific pulmonary edema
related to increased venous pressure. Lesions of the lungs,
which may be multiple, are often found at autopsy in burn
patients.41
Diffuse alveolar damage, the histopathologic correlate of
acute respiratory distress syndrome, affects the pulmo­
nary parenchyma in all lobes, although it is often patchy
in distribution, and begins with exudation of protein-rich
fluid into alveolar spaces. This exudate is a consequence
of damage to or increased permeability of both capillary
endothelial cells and the epithelial type I cells of the alveo­
lar lining. Within hours, the exudates form hyaline mem­
branes, which are a histologic hallmark of this disease
process (Fig. 44.6). Within a few days, the exudate begins
to undergo organization by spindle-shaped fibroblasts
within alveolar spaces (Fig. 44.7), and collagenous fibro­
sis develops, which obliterates alveoli and greatly thickens
the septa between alveoli and extends between capillaries
and the alveolar surface. Macrophages accumulate within
alveoli, and alveolar epithelial type II cells multiply. In the
and factor VIII. During the first 3–10 days after burn injury,
patients often have greater than normal clotting activity.
When DIC occurs, coagulation factors, including anti­
thrombin, are depleted.33,34 When DIC occurs in the patient’s
terminal course, microscopic fibrin thrombi are seen in
many organs at the time of autopsy, most commonly in the
lungs, the skin, the kidneys, and the gastrointestinal (GI)
tract.13,35
Review of Organ Systems
Affected by Burns
INTEGUMENTARY SYSTEM
The skin is the site of initial injury in burn patients, and
many of the events that lead to dysfunction or failure of
other organs begin in the skin. Thermal injury rapidly pro­
duces irreversible injury and cell death in all tissues in the
skin. In many cases, a burn wound excised within 48 hours
of injury shows that the entire dermis and all of the hair
follicles are necrotic, but much of the subcutaneous adipose
tissue remains viable. It appears that the greater insulating
capacity of adipose tissue protects it. In some cases, however,
necrosis extends deep into the subcutaneous tissue. Fre­
quently a bandlike infiltrate of degenerating polymorpho­
nuclear neutrophils is seen in histologic sections in the
midst of a totally necrotic dermis. This suggests that the
boundary between necrotic and viable tissue may have
extended deeper after the initial burn injury and its inflam­
matory response. There is experimental evidence that burn
wounds often evolve from an initial level of necrosis to a
deeper level, even from second to third degree, as a result of
poor perfusion of the tissue immediately deep to the initial
burn injury.36 This process of vascular stasis deep to the
burn is undoubtedly due in part to the rapid loss of intra­
vascular fluid from the damaged capillaries and venules just
below the necrotic burn wound. In addition, there is
Fig. 44.4  Micrograph, taken at low magnification, showing a small
round pale area of necrotic lung tissue in which no nuclei are staining,
surrounded by a zone of congestion and hemorrhage, with very little
acute inflammatory reaction. Hematoxylin and eosin stain.
Fig. 44.5  High-magnification micrograph showing short Gram-nega­
tive rods growing profusely within the wall of a small pulmonary artery
branch. Brown–Hopps tissue Gram stain.

44  •  The Burn Problem: A Pathologist’s Perspective
449
the circulation. This process is greatly enhanced if the
patient’s course is complicated by ischemic injury to muscle
compartments, limbs, or other organs. Lipid peroxidation
is a recognized consequence of burn injury. Superoxide
can also react with nitric oxide, produced in the wound or
the lung, to form peroxynitrite, a highly toxic substance.46
Thrombin peptides, released during thrombosis of blood
vessels in the wound, can also activate neutrophils and
stimulate endothelial cells to express adhesion molecules.47
The kinin system can be activated during thermal injury,
with its systemic consequences. When patients develop
sepsis, additional pulmonary damage may be produced by
release of proinflammatory cytokines and augmentation
of the processes that lead to inflammatory injury of the
lung.13,48 Neuropeptides, including substance P and cal­
citonin gene-related peptide (CGRP), may have a role in
increasing vascular leakage in the airways.49,50 Finally, the
presence of oxygen in high concentration can itself lead
to injury manifest as diffuse alveolar damage.51–53 Despite
this plethora of mechanisms that can lead to pulmonary
injury in burn patients, many patients with massive burn
injury do not develop clinically apparent respiratory diffi­
culty. The conditions that seem to be most strongly associ­
ated with this form of pulmonary injury are delayed fluid
resuscitation, limb ischemia, and sepsis. A recent publica­
tion noted that although diffuse alveolar damage has been
found less frequently than infection as a cause of death at
autopsy in recent years, the histologic changes of diffuse
alveolar damage are frequently identified at the time of
autopsy.54
Smoke inhalation injury commonly complicates burns
that occur in burning buildings. The toxic effects of prod­
ucts of combustion directly injure tissues in the airways and
lead to lung injury after a phase characterized by airway
inflammation and exudation. These patients are recognized
during bronchoscopy by observing hyperemia of the tra­
cheobronchial mucosa and small particles of carbonaceous
soot within the airways. Associated findings include facial
burns and singed nasal hairs. These patients usually do not
require ventilator therapy for several days but are at high
risk of developing respiratory failure, which responds poorly
to ventilator therapy and may prove fatal even when the
burn injury is small. The mortality rate of burn injury has
been found to be greatly increased when inhalation injury
also is present.55–59 Experimental studies in sheep and dogs
have partially clarified the mechanisms of smoke inhalation
injury.60–63 In animals, the immediate reactions to inhala­
tion of toxic smoke include detachment of numerous cili­
ated columnar cells from the tracheobronchial epithelium,
massive secretion of mucus by secretory cells, and a more
than 10-fold increase in tracheobronchial blood flow.64–66
Within a few hours, an intense acute inflammatory reac­
tion develops in the airways, with exudation of numerous
neutrophils and release of protein-rich fluid that may coag­
ulate within airways, forming occlusive “casts” (Fig. 44.8).
After 48 hours, the exudate of neutrophils fills many termi­
nal bronchioles and begins to extend into the lung paren­
chyma (Fig. 44.9). Studies using markers of upper airway
mucus, including Alcian blue staining and immunostaining
for Muc5B, demonstrate the presence of this material in
small peripheral airways and alveoli, showing that the
obstructive material moves from larger to smaller, more
late stages, there is severe interstitial fibrosis. Multiple
pathogenetic mechanisms are involved for this process, and
it is not yet clear which of these are most significant in
patients with burn injury.42,43 The burn injury stimulates
activation of complement, which could stimulate vascu­
lar leakage in the pulmonary bed. These and many other
peptides are thought to activate circulating neutrophils,
which produce secondary injury to the vascular and epi­
thelial membranes in the lung.44,45 Conversion of xanthine
dehydrogenase to xanthine oxidase in the burn wound
can cause release of superoxide into the venous circula­
tion, stimulating endothelial injury and oxidative stress
in the lung.7 The neutrophils reacting to the burn wound
undergo an oxidative burst, with release of superoxide into
Fig. 44.6  Section of lung tissue showing bright pink, homogeneous
hyaline membranes attached to alveolar walls and septa of alveolar
ducts. This is from a 2-year-old patient who died 8 days after a large
scald burn. This represents the exudative phase of diffuse alveolar
damage, which may be seen in the absence of smoke inhalation injury.
Hematoxylin and eosin stain.
Fig. 44.7  Micrograph showing numerous elongated cells resembling
fibroblasts occupying alveolar spaces and secreting connective tissue
matrix. This abnormality represents the proliferative phase of diffuse
alveolar damage. This patient died 1 month after a large flame burn
and had clinical evidence of smoke inhalation injury and acute respira­
tory distress syndrome. Hematoxylin and eosin stain.

44  •  The Burn Problem: A Pathologist’s Perspective
450
of vagal reflexes and activation of proinflammatory proc­
esses in reaction to injury to the airway mucosa, particu­
larly local production of interleukin (IL)-8.68–71 Local
production of nitric oxide and other reactive nitrogen
species has significant deleterious effects in this form of
acute lung injury, according to large animal experi­
ments.72,73 Local activation of thrombin during the forma­
tion of fibrin clots and local production of endothelin-1
may further enhance the inflammatory reaction in the
airways.74,75 Experimental studies in sheep have demon­
strated that activation of poly-adenosyl-ribose polymerase
(PARP) contributes to lung injury after burn and smoke
inhalation injury.76 Obstruction of small bronchi and bron­
chioles is thought to lead to failure of ventilation of multiple
small segments of lung tissue, and inappropriate vasodila­
tion in these poorly ventilated segments caused by the vas­
cular effects of nitric oxide may well contribute to the failure
of adequate oxygenation.26 Treatment with nebulized
heparin or tissue plasminogen activator has been found to
reduce the degree of airway injury in the ovine model, dem­
onstrating the importance of fibrin polymerization in this
model.77,78 Segmental atelectasis and prominent vasodila­
tion in focal areas are features of smoke inhalation injury
seen in experimental animals and in patients examined at
autopsy after burn injury and smoke inhalation injury.
Obstruction of bronchi and bronchioles by mucus, fibrin,
and cell debris contributes to respiratory malfunction in
experimental animals, and similar obstructive material is
seen in human lung tissue at autopsy.19,26,62,67,79 A recent
review of more than 40 years’ experience at the Shriners
Burns Hospital in Galveston found that although clinical
evidence of smoke inhalation injury was present in only
14% of patients admitted for recent burns, such evidence
was recorded in 66% of the patients who died. Although
autopsy cases in which death is attributable to smoke inha­
lation injury without infection have become uncommon,
histologic evidence of diffuse alveolar damage is still com­
monly seen in lung tissue sampled at autopsy.54
peripheral airways.26 This inflammatory reaction resolves
in the experimental animal, and the epithelium slowly
regenerates. However, autopsy evidence suggests that exu­
dation of neutrophils and protein into the airways resolves
poorly in humans and may persist for weeks (Fig. 44.10).
The loss of airway epithelium, which may be extensive, does
not regenerate for long periods. Perhaps because of failure
of the mucociliary escalator, mucus can be seen to accumu­
late around terminal bronchioles focally.19 Failure of muco­
ciliary clearance would be expected to increase the risk of
pneumonia in burn patients. Multiple mechanisms may be
responsible for the respiratory disease evoked by inhalation
of toxic smoke.67 Factors that may be likely to lead to selec­
tive damage to the airways include local release of neuro­
peptides by afferent C-fibers in the airways and activation
Fig. 44.8  Micrograph of a sheep trachea sampled 3 hours after experi­
mental smoke inhalation injury by insufflation of cooled cotton smoke
under anesthesia. Numerous polymorphonuclear neutrophils appear
to be flowing into the tracheal lumen from a gap in the epithelial lining.
Hematoxylin and eosin stain.
Fig. 44.9  Micrograph showing polymorphonuclear neutrophils filling
the lumen of a small bronchiole in a sheep 48 hours after experimental
smoke inhalation injury. Hematoxylin and eosin stain.
Fig. 44.10  Micrograph showing a bronchiole in human lung tissue
obtained at autopsy 7 days after a large flame burn. The lumen is
almost completely obstructed by a mixture of fibrin, mucus, and neu­
trophils. Hematoxylin and eosin stain.

44  •  The Burn Problem: A Pathologist’s Perspective
451
sometimes the only evidence of myocardial injury. These
lesions may represent poor perfusion of a tissue with high
metabolic demands during terminal episodes of hypoten­
sion. In some cases, they may represent the effects of endog­
enous or exogenous adrenergic agents.81,82 This mode of
injury is potentially preventable in burn patients.
URINARY SYSTEM
Patients with extensive burn injury, if resuscitated ade­
quately during the first few hours, may have normal renal
function throughout their hospital courses. However, when
the initial fluid resuscitation was not optimal or when
patients develop episodes of sepsis, acute renal failure may
develop. In such cases the autopsy may reveal acute tubular
necrosis.41,83 Clinical renal failure was an independent
factor associated with increased mortality rate in the analy­
sis of prognostic factors in patients with greater than 80%
total body surface burns in our institution.84 Patients with
renal failure seem to be at especially high risk for the infec­
tious complications of burn injury.
DIGESTIVE SYSTEM AND
HEPATOBILIARY TRACT
The association of duodenal ulcers with burn injury,
described by Curling, is a classic lesion that still occurs in
patients with burn injury, although its incidence is low,
probably as a result of routine treatment of burn patients
with inhibitors of gastric acid secretion.85 Local mucosal
necrosis and hemorrhage or erosion, an early manifestation
of this process, are seen in some cases.
The intestinal tract is especially susceptible to ischemic
and hypoxic injury, and lesions related to poor perfusion are
often found at the time of autopsy. Decreased blood flow in
the splanchnic circulation is a well-established physiologic
consequence of endotoxemia.14,86 Thus, sepsis is associated
with an increased risk of intestinal injury. Hypoxic or ische­
mic injury of the intestinal epithelium can lead to translo­
cation of intestinal flora into the mesenteric lymphatic
circulation and into the portal venous circulation.87,88
Alterations in the bacterial ecology of the gut can favor the
escape of bacteria from the intestine.89 Thus, hypotension
and hypoxia can also be causes of sepsis. In our autopsy
experience, abscesses or foci of tissue infection in the intes­
tinal tract were uncommon. The intestinal lesion most com­
monly seen at autopsy is transverse streaks of hemorrhage
in the small intestine in a “ladder” pattern, associated with
focal necrosis of folds of mucosa. This is called superficial
hemorrhagic necrosis (Fig. 44.13).90 Perforation of the
intestinal tract is an uncommon occurrence in patients
with burn injury. Occasional patients develop pseudomem­
branous colitis or “typhlitis,” typically a consequence of
infection by toxin-producing Clostridium difficile (Fig.
44.14). This complication can be minimized by screening
for the toxin in the stool. Rarely, ischemic injury in the
intestinal tract is sufficient to yield zones of transmural
necrosis.
The liver is enlarged in most autopsies of children who
succumb to burn injury, often to double or triple its normal
weight. Such massive hepatomegaly can compromise ven­
tilation.91 Steatosis is often found at autopsy (Fig. 44.15).
CARDIOVASCULAR SYSTEM
Despite the tachycardia and increased output common to
patients with burn injury, structural lesions of the heart
have been uncommon in our autopsy series, which repre­
sents a pediatric population. However, cardiac hypertrophy
is a consistent finding.80 Cardiac dilation and clinical evi­
dence of poor myocardial contractility develop in some
patients after burn injury. Bacterial endocarditis occurs in
occasional patients with sepsis complicating burn injury.
Nonbacterial thrombotic endocarditis (marantic endocar­
ditis) has also been seen and may also give rise to embolic
complications (Fig. 44.11). When the endocardial region of
the left ventricle is examined at autopsy, small foci of necro­
sis associated with local hemorrhage are often observed
(Fig. 44.12). Contraction band necrosis in these foci is
Fig. 44.11  Micrograph of a hematoxylin and eosin-stained cardiac
valve showing a deposit of fibrin on the tricuspid valve of a patient who
died of sepsis and had nonbacterial thrombotic (marantic) endocarditis
diagnosed at autopsy. Gram stains did not reveal any bacteria.
Fig. 44.12  High-magnification micrograph of heart tissue showing the
presence of multiple contraction bands in cardiac myocytes, seen as
refractile dark red bands running across muscle fibers. This is an early
irreversible change that is seen early after ischemic injury causes lethal
cell injury, especially when the tissue is reperfused with blood. It can
also be seen in the setting of β-adrenergic toxicity. Hematoxylin and
eosin stain.

44  •  The Burn Problem: A Pathologist’s Perspective
452
Acute pancreatitis is found at autopsy in a sizable minor­
ity of cases of fatal burns. Often necrosis and hemorrhage
appear out of proportion to the extent of acute inflamma­
tion. The pancreas is particularly vulnerable to the reduced
splanchnic blood flow that accompanies sepsis (Fig. 44.16).
Increased clinical suspicion of pancreatitis has led to assess­
ment of circulating amylase and lipase. On this basis, clini­
cal pancreatitis is not rare in our patient population but is
often transient.
LYMPHOID SYSTEM
Depletion of lymphocytes from lymphoid tissues through­
out the body is a consistent feature seen at autopsy in
patients with burn injuries. The abnormalities were well
described by Linares in 1978.95 The thymus is consistently
The degree of steatosis is often mild, however, even in the
presence of massive hepatomegaly. Analysis of the lipid
content of liver obtained at autopsy documented the pres­
ence of excess lipid but showed that its quantity was far too
small to account for the increase in weight of the liver.92
Congestion of the liver is also frequently seen at autopsy,
often with centrilobular necrosis, which may be a conse­
quence of reduced splanchnic blood flow in patients with
sepsis and elevated venous pressure. Intracellular cholesta­
sis is commonly observed in patients with burn injury. The
basis for this abnormality is not clear, although multiple
physiologic derangements could be expected to lead to
cholestasis.93,94
Fig. 44.13  Low-power micrograph showing a transverse mucosal fold
in the jejunum of a patient who was septic and hypotensive for several
days before death. Whereas the mucosal fold at the top is necrotic and
shows no nuclear staining, the remainder of the intestinal mucosa and
wall are intact but show submucosal hemorrhage. Hematoxylin and
eosin stain.
Fig. 44.14  Photograph showing dark green to black discoloration of
patches elevated above the surrounding mucosa in the cecum of a
patient who had intestinal distension and occult blood in the stools.
This is a typical appearance of pseudomembranous colitis. Hematoxy­
lin and eosin stain.
Fig. 44.15  Micrograph showing liver tissue in which almost every cell
contains one or several large pale vacuoles that are the sites where lipid
was stored within hepatocytes. Steatosis or fatty metamorphosis is
consistently seen in the liver at autopsy but may not account for the
increase in size and mass of the liver. This patient was 6 years old and
lived for 1 month after injury. His liver was 2.2 times the normal weight.
Hematoxylin and eosin stain.
Fig. 44.16  A cross-section of the pancreas obtained at autopsy. The
patient died after a long course of sepsis. The bright yellow flecks
represent fat necrosis with saponification of fatty acids liberated by
pancreatic lipases, and patchy hemorrhage is visible within and around
the gland.

44  •  The Burn Problem: A Pathologist’s Perspective
453
likely to disseminate. Atrophy of skeletal muscle occurs as
part of the catabolic state of burn patients and represents
a challenge for those involved in rehabilitative efforts.
CENTRAL NERVOUS SYSTEM
When the brain and spinal cord are examined carefully at
autopsy, abnormalities can be found in the great majority
of patients who die after burn injury. The commonest lesion
is degeneration or loss of neurons in the portions of the
cortex most susceptible to hypoxic and ischemic injury.
These lesions can be a result of hypovolemia during resus­
citation, shock developing as part of the syndrome of sepsis,
or as a consequence of respiratory failure. Of course, exten­
sive hypoxic brain injury may occur in patients who are
asphyxiated during the initial burn injury. Some patients,
especially those who require CPR at the scene of injury,
develop massive cerebral edema and brain death several
days after the initial injury, reflecting development of
massive cerebral edema in response to extensive hypoxic–
ischemic injury in the brain. Severe hypoxic brain injury
also can occur in burn patients who are deprived of oxygen
during the progress of a house fire or who are poisoned by
carbon monoxide at the scene of the burn. Direct thermal
injury to the brain occurs occasionally in young children;
can be detected by radiologic imaging studies; and is repre­
sented at autopsy by small foci of tissue necrosis on the
cortical surface, surrounded by hyperemia.
The Burn Autopsy
As long as patients develop complications of burn injury
that are difficult to manage, especially when the pathogen­
esis of these complications remains uncertain, careful post­
mortem examination of patients who do not survive will
continue to contribute to patient care. The major medical
very small, even in young children. The lymph nodes often
lack germinal centers and may be strikingly depleted of
lymphocytes. Sinus histiocytosis is often present, and pyro­
ninophilic cells resembling plasma cells are often prominent
in the portions of the node normally occupied by B cells.
The splenic white pulp is deficient, sometimes strikingly so.
The GI lymphoid tissue of the terminal ileum is generally
atrophic, despite its normal prominence in children, and the
appendix often shows a striking lack of normal lymphoid
tissue in its wall (Fig. 44.17). These abnormalities of lym­
phoid tissue correlate with the deficient immune response
typical of patients with extensive burn injury. To some
extent, they may represent the effects of high levels of
endogenous glucocorticoids in burn patients.
ENDOCRINE SYSTEM
Excessive secretion of glucocorticoids and of epinephrine by
the adrenal gland is characteristic of the prolonged hyper­
metabolic response to burns. Morphologic evidence of lipid
depletion of the adrenal cortex has not been seen in our
experience. In one interesting case, reactivation of neonatal
infection with herpes simplex virus type II occurred in a
young child with a large burn, leading to extensive skin
injury and graft loss. Focal necrotic lesions were found in
the adrenal cortex that were labeled by an immunostain for
herpes simplex, indicating that dissemination of the infec­
tion had occurred (Fig. 44.18).
MUSCULOSKELETAL SYSTEM
Lesions of skeletal muscle are uncommon in burn patients
but are ominous when they occur. Occasionally, direct
thermal or electrical injury extends into deep muscle, and
at times, this injury can be so severe that adequate debride­
ment is not practical. When invasive bacterial or fungal
infection extends into muscle, again, it may not be feasible
to treat adequately by excision of the infected tissue, and
the infection may be resistant to antibiotic therapy and
Fig. 44.17  Low-magnification micrograph showing a cross-section of
the appendix. There is striking depletion of the amount of blue-stain­
ing lymphoid tissue that normally makes up the bulk of the surface of
a section of the appendix. Hematoxylin and eosin stain.
Fig. 44.18  Micrograph that is an immunohistochemical stain for
herpes simplex virus type II of the adrenal cortex of a child who had
extensive skin infection and injury caused by reactivation of a neonatal
herpes infection. The dark brown material is reaction product that was
not seen when the antibody was omitted. Multiple small necrotic
lesions were seen in the liver and adrenal glands.

44  •  The Burn Problem: A Pathologist’s Perspective
454
the patient’s course. Of course, the circumstances of burn
injury may have legal implications.97 Documentation of the
patient’s injuries and careful interpretation of the hospital
course can provide factual evidence when only supposition
would be available otherwise. Several recent publications
have confirmed the continuing usefulness of autopsies,
especially in the setting of burn trauma.98–102 We advocate
a policy of carrying out complete autopsies on all patients
who die after burn injury whenever possible in collabora­
tion with the local medical examiner or coroner.
Complete references available online at

Further Reading
Barrow RE, Hawkins HK, Aarsland A, et al. Identification of factors con­
tributing to hepatomegaly in severely burned children. Shock.
2005;24(6):523-528.
Cox RA, Mlcak RP, Chinkes DL, et al. Upper airway mucus deposition in
lung tissue of burn trauma victims. Shock. 2008;29(3):356-361.
Kallinen O, Partanen TA, Maisniemi K, et al. Comparison of premortem
clinical diagnosis and autopsy findings in patients with burns. Burns.
2008;34(5):595-602.
Linares HA. A report of 115 consecutive autopsies in burned children:
1966–80. Burns. 1981;8:263-270.
Pereira CT, Barrow RE, Sterns AM, et al. Age-dependent differences
in survival after severe burns: a unicentric review of 1,674 patients
and 179 autopsies over 15 years. J Am Coll Surg. 2006;202(3):536-
548.
problems that complicate burn injury are summarized in
the next few paragraphs. There is no disease with more
complex clinical and physiopathologic derangements than
an extensive burn. Observations made at the time of autopsy
often clarify the nature of the problems that have led to the
patient’s demise. Sometimes the findings lead to suggestions
for changes in procedure that may lead to improved patient
safety. Very often a review of recent deaths effectively
reminds the staff of the importance of measures to prevent
wound infection. Often a causal sequence of events can be
reconstructed by including the clinical evidence, including
cultures with sensitivity testing and metabolic profiling,
and the autopsy findings. Infectious processes, for example,
often can be traced from their sites of origin, in the skin or
elsewhere, to the fatal conclusion. Dangers caused by the
emergence of highly resistant bacterial strains can be
traced. The autopsy should always be approached from the
point of view of using both clinical and autopsy evidence
to better understand the reactions of the patient to the burn
injury and to the treatments provided. In other words, the
burn autopsy can provide not only an appropriate morpho­
logic analysis but also a dynamic interpretation of the
pathogenesis of the disease processes of importance in an
individual patient. When approached in this way, investiga­
tion of patient deaths becomes a valuable learning experi­
ence for all those who participate.96 Often, unexpected
lesions are found that were likely to have been significant in

454.e1
44  •  The Burn Problem: A Pathologist’s Perspective
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contributing to hepatomegaly in severely burned children. Shock.
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The massive hepatomegaly that is consistently found at autopsy in
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100. Kallinen O, Partanen TA, Maisniemi K, et al. Comparison of premor­
tem clinical diagnosis and autopsy findings in patients with burns.
Burns. 2008;34(5):595-602.
This paper from Finland compares clinical diagnoses with autopsy find­
ings in burn patients and emphasizes the value of a high autopsy rate in
these cases.
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455
Molecular and Cellular Basis of
Hypertrophic Scarring
PETER KWAN, ALEXIS DESMOULIÈRE, and EDWARD E. TREDGET
45 
skin the majority of collagen is type I (80%) with smaller
amounts of type III (10–15%) and type V (minimal), result­
ing in thick, regular collagen fibril bundles running parallel
to the skin surface.6 In contrast, HTS is composed of greatly
increased amounts of type III (33%)7 and type V (10%)8
collagen, which drastically alters collagen fibrils, making
them thinner6 and disorganized.9 In normal wound healing,
type III collagen appears early then gradually disappears as
the scar is remodeled and matures,10 but this does not occur
in HTS, where persistently high levels reflect biological
immaturity.11
Classic histologic descriptions of HTS highlight “whorls”
and “nodules” of poorly organized collagen encapsulated in
more normal-appearing collagen fibrils,6 as seen in Fig.
45.6. However not only are collagen fibril composition and
morphology altered in HTS, but interfibrillar spacing is also
irregular and greatly increased.12 This space is filled with
proteoglycans and glycoproteins whose composition is
markedly different from normal skin and mature scar.
PROTEOGLYCANS AND GLYCOPROTEINS
Proteoglycans are responsible for physical properties of skin
such as turgor, resilience, and resistance to compression,
resulting from their interaction with collagen. Proteogly­
cans also modulate the activities of multiple growth factors
and cytokines. Glycoproteins, such as fibronectin, are gen­
erally involved in cell–matrix adhesion and influence cell
behavior via this mechanism. Together proteoglycans and
glycoproteins are major constituents of skin, both physi­
cally and functionally.
Proteoglycans are formed by a protein core, often with
repeating units such as leucine in decorin, and glycosami­
noglycan side chains.13 These side chains are ionized and
hydrophilic and thus mainly responsible for tissue water
retention.14 Early studies of HTS demonstrated elevated
glycosaminoglycan levels,15 which are responsible for the
hyperhydrated state of HTS that leads to its classically
increased turgor. These levels of glycosaminoglycan are
not uniformly elevated. Instead certain proteoglycans are
downregulated and others upregulated, with unique impli­
cations for HTS.
Decorin is a prototypical small, leucine-rich proteoglycan
(SLRP) produced in abundance in normal skin and mature
scar but reduced by 75% in HTS.3 Originally named for
“decorating” collagen fibrils, decorin affects wound healing
via several distinct and complementary pathways. Decorin
binds to collagen fibrils, controlling their diameter, mor­
phology,16 and interfibrillar distance.17 In decorin knock­
out mice collagen fibrils are irregular in morphology and
have highly variable diameters.18 Decorin binds to and
Introduction
Clinically postburn hypertrophic scars (HTS) are elevated,
erythematous, pruritic, and inelastic.1 In addition to poor
cosmesis, these scars typically form contractures resulting
in dysfunction and discomfort, leading to significant mor­
bidity for burn patients (Fig. 45.1). HTS is fundamentally
different from normal skin and mature scar in several key
ways: (1) the extracellular matrix (ECM) of HTS is signifi­
cantly altered in both composition and architecture, (2) the
behavior of keratinocytes and fibroblasts present in HTS is
profibrotic compared to mature scar, and (3) many profi­
brotic cytokines are upregulated and their expression pro­
longed. Generally, HTS undergoes some remodeling and
maturation over time, and this may account for the vari­
ability in descriptions of HTS. Many features of HTS are
shared by other fibroproliferative disorders, including renal
fibrosis, pulmonary fibrosis, and scleroderma.2 Thus under­
standing the pathophysiology of HTS applies to other areas
of medicine, and developments in treating various fibropro­
liferative diseases can directly affect scar management.
Since an exhaustive discussion of every nuance of abnor­
mal wound healing is impossible, we focus on aspects of
HTS formation highlighting well understood pathways or
novel developments. It is our hope that a deeper under­
standing of abnormal wound healing pathophysiology and
fibrosis will lead to nonsurgical treatments that improve life
not only for burn patients, but for the many patients suffer­
ing fibrotic diseases.
Extracellular Matrix
ECM in healing wounds is laid down by fibroblasts and sub­
sequently remodeled as the scar matures. The ECM in HTS
displays significant differences from mature scar and normal
skin, most notably in the arrangement and composition of
collagen bundles and in the relative proportions of several
proteoglycans.3 Owing to the interaction of fibroblasts and
ECM, these differences not only result from abnormal fibro­
blast behavior but also contribute to it.4
COLLAGEN
Collagen is the major constituent of ECM, providing a scaf­
fold for cells and mechanical strength to tissues. In HTS the
quantity of collagen per unit surface area is increased;5
however the relative proportion of collagen in HTS is
decreased compared to normal skin, owing to much greater
increases in proteoglycans and glycoproteins.3 In normal

45  •  Molecular and Cellular Basis of Hypertrophic Scarring
456
inactivates the profibrotic cytokines transforming growth
factor-β (TGF-β)19 and platelet-derived growth factor
(PDGF).20 The effects of this inactivation are most readily
visible in fibroblast-populated collagen lattices where
decorin significantly reduces contraction by normal and
HTS fibroblasts.21,22 Decorin also binds to and antagonisti­
cally downregulates several cell surface receptor tyrosine
kinases: epidermal growth factor receptor (EGFR),23 hepa­
tocyte growth factor receptor (HGFR),24 and insulin-like
growth factor 1 receptor (IGF1R),25 which reduces cellular
proliferation and migration. Decorin production increases
significantly as scars mature.26 In a mouse model of diabe­
tes, renal fibrosis and nephropathy developed significantly
faster in decorin knockout than in wild-type mice.27 Simi­
larly upregulating decorin production via an adenoviral
vector in mouse models of bleomycin-induced pulmonary
fibrosis reduced fibrosis.28
In contrast to decorin downregulation, two other pro­
teoglycans, biglycan and versican, are significantly upregu­
lated in HTS. Biglycan is 57% similar to decorin in amino
acid sequence but with two dermatan sulfate chains and
is believed to have originated as a gene duplication of
decorin.29 Despite these similarities, biglycan and decorin
have significantly different functions in vivo. Biglycan is
minimally present in normal skin but significantly up-
regulated in fibrosis, yet it does not compensate for the lack
of decorin.29,30 Versican is also significantly upregulated in
HTS, up to six times higher than in normal skin,3 where
it is normally confined to the proliferating epidermis.31
As a large proteoglycan with 12–30 glycosaminoglycans
D
C
B
A
Fig. 45.1  Hypertrophic scarring in a 34-year-old white man, 8 months following a 60% total body surface area burn involving the face, upper extremi­
ties, and hands. (From Scott PG, Ghahary A, Chambers MM, Tredget EE. Biological basis of hypertrophic scarring. In: Malhotra SK, ed., Advances in Structural
Biology, vol. 3. Greenwich, CT: JAI Press, 1994: 157–202.)

45  •  Molecular and Cellular Basis of Hypertrophic Scarring
457
with the tendency of HTS to form following deep partial- to
full-thickness burns suggests two possible theories of HTS
formation: (1) selective proliferation of deep dermal fibro­
blasts after fibrogenic cytokine stimulation, or (2) destruc­
tion of superficial dermal fibroblasts by thermal injury,
leaving only deep dermal fibroblasts to repopulate the
wound.38 Both theories are consistent with an experimental
model in which human skin was grafted onto the backs of
nude mice and subsequently injured. In this model, deep
dermal fibroblasts closed wounds and superficial dermal
fibroblasts then remodeled them.39 It is possible that in deep
burns superficial fibroblasts are not present to initiate this
remodeling process, leaving the healing wound in a hyper­
active state (Fig. 45.2).
ROLE OF MYOFIBROBLASTS IN NORMAL AND
PATHOLOGICAL SITUATIONS
Myofibroblasts are cells that have acquired a phenotype
intermediate between fibroblasts and smooth muscle cells.
Presently it is accepted that myofibroblast modulation of
fibroblastic cells begins with the appearance of precursor
proto-myofibroblasts whose stress fibers contain only β- and
γ-cytoplasmic actins. These proto-myofibroblasts acquire
de novo contractile bundles whose stress fibers generate
sufficient forces to pull cells forward to populate tissue
spaces in a migration process and to pre-remodel the ECM.
Proto-myofibroblasts evolve, but not necessarily always,
into the differentiated myofibroblast.40 Fully differentiated
myofibroblasts express α-smooth muscle actin (α-SMA), the
actin isoform present in typical contractile vascular smooth
muscle cells (Fig. 45.3). The presence of α-SMA is directly
related to the contractile activity of myofibroblasts. A direct
correlation has been demonstrated both in vitro and in vivo
between the level of α-SMA expression and myofibroblast
contraction.41,42 Myofibroblasts also exhibit some simi­
larities with pericytes.43 In physiological conditions, after
healing, myofibroblasts undergo apoptosis,44 and only a few
fibroblasts are left to ensure renewal of the ECM.
Among the soluble factors, TGF-β1 is a potent inducer of
myofibroblast differentiation.45,46 TGF-β1 action on myofi­
broblast differentiation is only possible in the presence of
ED-A fibronectin, which underlines the fact that ECM com­
ponents play an important role in soluble factor activity.47
Granulocyte–macrophage colony-stimulating factor stimu­
lates macrophage proliferation and myofibroblast differen­
tiation, thereby promoting granulation tissue formation.48,49
Endothelin has also a positive effect on differentiation and
activation of myofibroblasts. This peptide also induces myo­
fibroblast contraction and migration.50 More recently it has
been shown that granulation tissue formation is modified
by chemical denervation.51 This peripheral nervous system
involvement in tissue repair has likewise been shown in the
liver; in this organ, in an experimental model of fibrosis
chains, versican is most likely responsible for the increased
hydration and turgor leading to the increased volume
of HTS.5
The most common glycoprotein in ECM is fibronectin,
which has effects on cell–matrix interaction via its interac­
tion with integrins. Although the role of fibronectin in HTS
is unclear, its upregulation in HTS,32 influence on the
assembly of other ECM proteins, and interaction with cel­
lular integrins33 suggest that it, too, plays a role in fibroblast
behavior and HTS formation.
Cellular Contributions to
Hypertrophic Scar
HYPERTROPHIC SCAR FIBROBLASTS
Fibroblasts are the cells primarily responsible for ECM pro­
duction and remodeling in wound healing. Numerous
studies have demonstrated that dermal fibroblasts can be
divided into distinct subpopulations—superficial (papillary)
and deep (reticular)—based on both physical location and
phenotype.34–36 When characteristics of superficial dermal,
deep dermal, and HTS fibroblasts are compared, as in Table
45.1, it becomes clear that HTS fibroblasts most closely
resemble deep dermal fibroblasts.36 These in vitro results
correlate directly with a clinically relevant dermal scratch
model developed by Dunkin and colleagues.37 In this model
a linear skin wound is created with depth that increases
along its length from no injury to full-thickness penetra­
tion. This results in regeneration in the superficial portion
(depth ≤0.56 mm) with minimal scar; whereas HTS forma­
tion occurs in the deeper portion of the wound.37
Combining these basic science and clinical observations
Table 45.1  Superficial and Deep Dermal Fibroblasts
Compared to Hypertrophic Scar Fibroblasts
Superficial
Dermal
Fibroblasts
Deep
Dermal
Fibroblasts
Hypertrophic
Scar
Fibroblasts
Collagen production
↓
↑
↑
Collagenase
production
↑
↓
↓
Decorin production
↑
↓
↓
TGF-β production
↓
↑
↑
CTGF production
↓
↑
↑
Keratinocyte
proliferation
↑
↓
↓
Capillary formation
↑
↓
↓
Scarring
Regeneration
Critical depth
Superficial
fibroblasts
Deep
fibroblasts
Fig. 45.2  Injury below a critical depth in skin leads to scarring. (From Kwan P, Hori K, Ding J, Tredget EE. Scar and contracture: biological principles. Hand
Clin. 2009;25[4]: 11–528.)

45  •  Molecular and Cellular Basis of Hypertrophic Scarring
458
increases, a sudden change in cell morphology occurs and
stress fibers appear.54,55 Shear forces exerted by fluid flow are
also able to induce TGF-β1 production and differentiation
of fibroblasts cultured in collagen gels in the absence of
other external stimuli, such as cytokine treatment.56 Inter­
cellular mechanical coupling of stress fibers via adherens
junctions improves contraction of collagen gels by myofi­
broblasts.57 By assessing spontaneous intracellular Ca2+
oscillations, Follonier et al. have shown that intracellular
Ca2+ oscillations are coordinated between contacting myo­
fibroblasts via adherens junctions, but randomly between
fibroblasts and noncontacting cells.58 They propose the fol­
lowing model of mechanical coupling for myofibroblasts:
individual cell contraction is transmitted via adherens junc­
tions and leads to opening of mechanosensitive ion chan­
nels in adjacent cells. The resulting Ca2+ influx induces a
contraction that can feed back on the first cell and/or stimu­
late other contacting cells, working like a syncytium. This
mechanism could improve the remodeling of cell-dense
tissue by coordinating the activity of myofibroblasts.59
PATHOLOGICAL REPAIR (HYPERTROPHIC SCARS
AND KELOIDS)
Pathological wound healing can result from impaired
remodeling of the granulation tissue leading to abnor­
mal cutaneous repair in hypertrophic or keloid scars
(Fig. 45.5). Keloid and HTS differ in their expression of α-
SMA; indeed, in keloids, no α-SMA is observed, although
proto-myofibroblasts could account for large amounts of
extracellular matrix but are unable to contract, whereas
numerous myofibroblasts express this protein in HTS, thus
explaining the fact that contracture often appears specifi­
cally in HTS.38,60 Thus the use of α-SMA to differentiate
HTS and keloids has been proposed.61 The presence of con­
tractile myofibroblasts in HTS is responsible for the forma­
tion of contractures that interfere with function and may
require extensive reconstructive surgery (Fig. 45.6). More­
over, keloids contain thick collagen fibers, whereas HTS
contain thin fibers organized in nodules.60,62 It emphasizes
that the different processes involved in collagen matura­
tion together with the effects of the matrix metalloprotein­
ase (MMP)/tissue inhibitor of MMP (TIMP) system play an
important role in excessive scar formation. The expression
of lysyl hydroxylase-2b (LH-2b), a splice variant of LH-2,
an enzyme involved in the cross-linking of the collagen
fibrils, has been linked to fibrotic development occurring
in pathologic situations.63 Animal models mimicking this
specific expression of LH-2b are available and could be used
to test new antiscarring therapies based on the inhibition
of LH-2b.64 In these lesions, the normal healing process
cannot be achieved and granulation tissue continues to
grow owing to an abnormal and excessive secretion of
growth factors and/or lack of molecules inducing apopto­
sis or ECM remodeling. Interestingly HTS have an excess of
microvessels, most of which are partially or totally occluded
due to a functional regression of endothelial cells induced
by (myo)fibroblast hyperactivity.65 In excessive scarring,
a focal upregulation of p53 expression, which probably
inhibits apoptosis, has been observed. ECM modifications
also seem to be an important factor in induction of the
apoptotic process. In vivo, covering granulation tissue by
using carbon tetrachloride treatment, chemical denerva­
tion significantly reduces matrix deposition and myofibro­
blast differentiation.52
ROLE OF MECHANICAL STRESS AND
MYOFIBROBLASTS
Myofibroblast cells, because of their contractile properties
and privileged relationships with ECM, can modify their
activity depending on the mechanical environment. It has
been shown, in gingival fibroblasts, that α-SMA expression
induced by TGF-β1 is regulated by the compliance of col­
lagen gels on or in which they are cultured.53 The direct
effects of mechanical stress on fibroblasts can be easily
shown in culture using stressed fibroblast-populated colla­
gen lattices (Fig. 45.4). Moreover, myofibroblast differentia­
tion features, such as stress fibers, ED-A fibronectin, or
α-SMA expression, appear earlier in granulation tissue sub­
jected to increased mechanical tension by splinting of the
full-thickness wound with a plastic frame than in normally
healing wounds.42 It has also been shown that fibroblasts
cultured on substrates of variable stiffness present different
phenotypes. Cultured fibroblasts do not express stress fibers
on soft surfaces, but, when the stiffness of the substrate
Protomyofibroblast
Stress fibers expressing
β- and γ-cytoplasmic actins
Proliferation and migration
Myofibroblast
Stress fibers expressing
α-smooth muscle actin
Contraction and ECM
deposition
Fibroblast
Deactivation
Apoptosis
ECM
MMPs and
TIMPs/remodeling
Soluble factors
and ECM
components
Mechanical
stress
?
Fig. 45.3  Schematic illustration showing the evolution of the (myo)
fibroblast phenotype. The myofibroblast modulation of fibroblastic
cells begins with the appearance of the proto-myofibroblast, whose
stress fibers contain only β- and γ-cytoplasmic actins and evolves, but
not necessarily always, into the appearance of the differentiated myo­
fibroblast, the most common variant of this cell, with stress fibers con­
taining α-smooth muscle actin. Myofibroblasts present a well-developed
rough endoplasmic reticulum and are responsible for (excessive) depo­
sition of extracellular matrix (ECM); they also secrete matrix metallo­
proteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs)
and are involved in granulation tissue remodeling. Soluble factors,
particularly transforming growth factor-β1, associated with ECM com­
ponents (e.g., fibronectin ED-A), play important roles during myofibro­
blast differentiation. Mechanical stress is also importantly involved in
myofibroblast differentiation. The myofibroblast can undergo apopto­
sis; the deactivation leading to a quiescent phenotype has not been
clearly demonstrated at least in vivo. (From Desmoulière A.)

45  •  Molecular and Cellular Basis of Hypertrophic Scarring
459
F
E
D
C
B
A
Fig. 45.4  Myofibroblast evolution in collagen gels. When myofibroblasts previously cultured in plastic dishes are incorporated in a floating collagen
gel, a high proportion rapidly undergo apoptosis (arrows). In contrast, when incorporated in an attached collagen gel, they show a typical elongated
morphology, express high amounts of α-smooth muscle actin, and proliferate. (From Coulomb B, Inserm U970, Université Paris Descartes, France and
Desmoulière A, unpublished data.)

45  •  Molecular and Cellular Basis of Hypertrophic Scarring
460
stages of fibrosis.71 The epithelium could also be involved
in the development of excessive scarring.72 Hakvoort et al.
have shown that, in HTS, keratinocytes expressed an acti­
vated CD36+ phenotype.73 They suggest that HTS formation
is not only due to dermal dysfunction, but is also the result
of a perturbation affecting dermal–epidermal interactions
involving neurohormonal factors. Indeed, a “neurogenic
inflammation hypothesis” has been suggested.74 Mechani­
cal stress stimulates mechanosensitive nociceptors in skin
sensory fibers, which release neuropeptides involved in
vessel modifications and fibroblast activation.
ORIGIN OF (MYO)FIBROBLASTS
It is now accepted that myofibroblasts can originate from
various cell types, as illustrated in Fig. 45.7. The majority
of these cells originate from local recruitment of connective
tissue fibroblasts. For example, in skin, dermal fibroblasts
located in the edges of the wound can acquire a myofibro­
blast phenotype and participate in tissue repair.75,76 In
diffuse cutaneous systemic sclerosis, microvascular peri­
cytes constitute a cellular link between microvascular
damage and fibrosis by transdifferentiating into myofibro­
blasts.77 In the liver, the role of hepatic perisinusoidal
hepatic stellate cells has been widely studied, and their key
role during fibrogenesis has been clearly demonstrated.78
Recently it has also been shown that portal fibroblasts are
involved in the formation of portal septa.79 Vascular smooth
muscle cells residing in the walls of portal vein branches
and portal arteries have been implicated in fibrosis observed
in chronic schistosomiasis.80 In the kidney, both mesangial
cells and interstitial fibroblasts of the medulla can acquire
a myofibroblast phenotype and participate in ECM deposi­
tion after damage.81,82 Moreover the involvement in tissue
repair of local mesenchymal stem cells is becoming better
understood. These progenitor cells have been described in
the dermal sheath that surrounds the outside of the hair
follicle facing the epithelial stem cells, constituting a niche
of stem cells. They are involved in the regeneration of the
dermal papilla and can also become wound healing (myo)
fibroblasts after an injury.83 This concept of a cell associa­
tion able to reconstitute the different organ cell populations
and constituting a niche of stem cells is currently discussed
in diverse organs, notably the liver, in the periportal zone
containing Hering’s canals.84,85 Recent data have shown
the implication of circulating cells, called fibrocytes, in the
tissue repair process88 tissue repair process, another type of
circulating cell originating from bone marrow participates
in tissue repair. These mesenchymal stem cells are bone
marrow-derived nonhematopoietic precursor cells89,90 that
contribute to the maintenance and regeneration of connec­
tive tissues through engraftment. Indeed, they have the
capacity to engraft into several organs and to differentiate
into wound-healing myofibroblasts. However, recently it
has been suggested that fibroblasts/myofibroblasts that
participate in cutaneous wound healing are not derived
from circulating progenitor cells.91 Finally, epithelial- and
endothelial-to-mesenchymal transition (EMT), a process by
which differentiated (or malignant) epithelial cells and
endothelial cells undergo a phenotypic conversion that
gives rise to the matrix-producing fibroblasts and myofibro­
blasts, is increasingly recognized as an integral part of
tissue fibrogenesis after injury, particularly in the kidney92
a vascularized skin flap induces an upregulation of MMP
together with a decrease in TIMP, leading to a rapid loss of
granulation tissue cells by apoptosis.66 In vitro, the matrix
environment can modulate fibroblast apoptosis. Further­
more, in HTS, the mechanical forces obtained by compres­
sion of the scar are able to restore the classic organization
observed in normal wounds and trigger the disappearance
of myofibroblasts by apoptosis.67 Thus mechanical stress can
maintain myofibroblast differentiation. It has been shown
that mechanical loading early in the proliferative phase of
wound healing produces HTS by inhibiting cellular apopto­
sis.68 In contrast, it is suggested that mechanical challenge
could be a clinically relevant strategy to improve ischemic
and chronic wound healing by supporting myofibroblast for­
mation.69 Interestingly oncogenic-Ras-transformed human
fibroblasts lose growth factor selectivity and cell matrix
density-dependent inhibition of migration.70 In the liver
and certain other organs, stiffness appears to result from
matrix cross-linking and possibly other unknown variables
in addition to matrix quantity, suggesting that increased
stiffness may play an important role in initiating the early
Epithelial cells
BM
Fibroblasts
Myofibroblasts
Growing and
migrating
epithelial cells
Abnormal
epithelial
cells?
Interaction
ECM
Resolution
(apoptosis and
matrix remodeling)
α-SMA
Repair
Scarring
Chronicity
Fig. 45.5  Processes leading to normal repair or pathological scarring.
In normal tissue repair, myofibroblasts disappear by apoptosis during
the transition between granulation tissue and scar. In pathological situ­
ations, myofibroblasts proliferate and participate in the excessive
deposition of extracellular matrix. In all these situations, not only inter­
action between fibroblasts/myofibroblasts and extracellular matrix,
but also the dialogue between epithelial cells and mesenchymal cells
play a major role. BM: basement membrane; SMA: smooth muscle
actin; ECM: extracellular matrix. (Modified from Sarrazy et al. Wound
repair and regeneration: mechanisms of pathological scarring: role of
myofibroblasts and current developments. Wound Repair Regen. 2011;19[1]:
s10–s15.)

45  •  Molecular and Cellular Basis of Hypertrophic Scarring
461
wounds via a secondary lymphoid chemokine gradient,
and differentiate under the influence of T cells and TGF-
β.86 It has been noted that CD4+ T cells producing TGF-β
are present in high levels in burn wounds,99 where fibrocyte
levels in burn patients are also increased.100 In contrast,
Pilling et al. demonstrated that fibrocyte differentiation is
blocked by serum amyloid P (SAP), a constitutive plasma
protein related to C-reactive protein, by using SAP to inhibit
fibrocytes in a mouse bleomycin-induced pulmonary fibro­
sis model.101 It appears that fibrocytes contribute to ECM
formation and fibrosis through two mechanisms. Exposure
to profibrotic cytokines causes fibrocytes to secrete colla­
gen and differentiate into myofibroblasts via Smad2/3 and
SAPK/JNK MAPK pathway activation.102 Fibrocytes also
modulate the activity of local fibroblasts in burn wounds
via secretion of TGF-β and connective tissue growth factor
(CTGF)103 and may serve as a crucial link between healing
wounds and the immune system. Like leukocytes, fibrocytes
can act as antigen-presenting cells to prime naïve T cells104
and also express Toll-like receptors, allowing them to func­
tion as part of the innate immune system.105 Fibrocytes
also induce revascularization of wounds through MMP-9
secretion, which degrades ECM and promotes endothelial
invasion and the production of vascular endothelial growth
and during stroma reaction formation. However the degree
to which this process contributes to fibrosis and stroma
reaction in the skin remains a matter of intense debate and
is likely to be context dependent. Altogether mesenchymal
stem cells, fibrocytes, bone marrow-derived cells, and cells
derived from EMT may represent alternative sources of
myofibroblasts when local fibroblasts are not able to respond.
These diverse cell types probably contribute to the appear­
ance of myofibroblast subpopulations whose phenotype
can be modulated by their interactions with neighboring
cells and ECM.93,94
THE ROLE OF FIBROCYTES IN
HYPERTROPHIC SCAR
Fibrocytes are a bloodborne, CD14+ monocyte subpopula­
tion86 that mediate wound healing, first identified in 1994
by Bucala et al. in mouse wound chambers.95 Although
originally defined as collagen+/vimentin+/CD34+ cells, other
accepted markers include combinations of collagen+ and
CD45+ or LSP1+ markers.87,96 Fibrocytes have been found
in normal wound healing86 and also in a wide variety of
fibrotic diseases, including pulmonary fibrosis,97 renal fibro­
sis,98 and hypertrophic burn scars.87 Fibrocytes traffic to
D
C
B
A
Fig. 45.6  Myofibroblasts in hypertrophic scars. In hypertrophic scar nodules myofibroblasts express large amounts of α-smooth muscle actin (A,B,
immunohistochemistry for α-smooth muscle actin) and develop huge contractile activity in scars after burn injury (C,D) (From Desmoulière A; C,D are
from Casoli P, Plastic Surgery and Burns Unit, University Hospital of Bordeaux, France.)

45  •  Molecular and Cellular Basis of Hypertrophic Scarring
462
via factors such as stratifin.114 In contrast, keratinocytes
from HTS promote increased fibrosis in normal dermal
fibroblasts,72 display an activated phenotype similar to early
wound-healing keratinocytes,115 and have higher prolifera­
tion rates in the basal layer many months after reepithelial­
ization is complete.116 This may be due, in part, to elevated
PDGF production by HTS keratinocytes.117 This suggests
that normal keratinocytes promote normal wound healing
and abnormal keratinocytes promote HTS formation. It is
also possible that HTS fibroblasts alter the normal wound-
healing keratinocyte phenotype to a HTS phenotype, and
these HTS keratinocytes in turn reinforce the HTS fibroblast
phenotype. Thus therapies for HTS must address not only
wound fibroblasts but also wound keratinocytes.
The Role of Cytokines in
Hypertrophic Scar
Cytokines serve as signals for communication between
cells, in paracrine signaling, and for cells to signal them­
selves in autocrine signaling. While the number of cyto­
kines, and hence the diversity of signals, is immense, there
are several key cytokines whose prototypic role in fibrosis
and HTS has been extensively studied and whose actions
account for a wide variety of fibroses. The roles of these
cytokines are illustrated in Fig. 45.8.
TGF-β
TGF-β is one of the most studied profibrotic cytokines and
belongs to a large superfamily of related proteins regulating
processes as diverse as embryonic development, chemotaxis,
Epithelial cells
Local
epithelial
stem cells
Local
MSC
‘Niche’
(hair follicle)
Local fibroblast
subpopulations
Endothelial
cells
Pericytes
EMT
Fibrocytes and
bone marrow-
derived MSC
Myofibroblasts
α-SMA
ECM
BM
Fibroblasts
Fig. 45.7  Schematic illustration showing the different origins of the
myofibroblast cells. Various cell types can acquire a myofibroblast phe­
notype; these diverse origins lead to distinct myofibroblast subpopula­
tions. Circulating fibrocytes and bone marrow-derived mesenchymal
stem cells (MSCs) are important sources of myofibroblasts when the
dermis, source of local fibroblasts, is destroyed (second- and third-
degree burns). A local source can also be local stem cells (both epithe­
lial stem cells and MSCs forming a niche located at the level of hair
follicles). The hypothesis suggesting that a major source of fibrosis- and
tumor-associated myofibroblasts is through transdifferentiation from
nonmalignant epithelial cells, from epithelial-derived carcinoma cells
or from endothelial cells through epithelial- and endothelial-to-mesen­
chymal transition (EMT), requires further studies. SMA: smooth muscle
actin; ECM: extracellular matrix. (From Desmoulière A.)
Platelets
Proliferation
Proteoglycans
Fibronectin
Collagen
Macrophages
Lymphocytes
γ IFN(–)
α IFN(–)
IGF-1
Serum
Dermal keratinocytes
Glandular cells
(sweat glands)
Macrophages
TGF-β
(active)
TGF-β(+)
(latent)
PDGF(+)
+
–
+
Fig. 45.8  Balance of pro- and antifibrotic cytokines in wound healing.
The fibrogenic and antifibrogenic factors that modulate fibroblast
function during wound healing. (From Tredget EE, Nedelec B, Scott PG,
Ghahary A, Hypertrophic scars, keloids and molecular basis for therapy.
Surg Clin N Am. 1997;77:701–730.)
factor.106 Our understanding of fibrocytes as profibrotic
mediators of wound healing continues to evolve, with
several recent descriptions of alternate fibrocyte subpopu­
lations107 and the ability to reprogram fibrocytes into an
antifibrotic phenotype.108 Although this appears to compli­
cate the fibrocyte picture, it does highlight the importance
of systemic responses to wound healing and suggests that
the initial cytokine signals that bone marrow-derived cells
receive as they leave the circulation can have a significant
impact on their role in HTS formation.
HYPERTROPHIC SCAR KERATINOCYTES
Keratinocytes are an important component of wound
healing. Classically the remodeling phase of wound healing
begins once reepithelialization of the wound is complete,109
and wounds taking longer than 2 weeks to reepithelialize
are more likely to form HTS.110 Keratinocytes regulate fibro­
blast activity and vice versa,109 suggesting that they play
key roles in normal wound healing and HTS formation.111
Experiments with keratinocyte-conditioned media in skin-
equivalent models show that keratinocytes downregulate
fibroblast production of the profibrotic cytokines TGF-β and
CTGF.112 Normally keratinocytes increase fibroblast prolif­
eration but simultaneously reduce collagen production113
and increase collagen breakdown by upregulating MMP-1

45  •  Molecular and Cellular Basis of Hypertrophic Scarring
463
PLATELET-DERIVED GROWTH FACTOR
PDGF is delivered to wounds by platelets from injured capil­
lary vessels and is also produced by local fibroblasts.139
There are four isoforms of PDGF: A, B, C, and D, which form
dimers to activate two structurally related tyrosine kinase
receptors140 leading to fibroblast proliferation and actin fila­
ment reorganization that induces a transformation into
myofibroblasts.45 PDGF also increases ECM production and
inhibits myofibroblast apoptosis.141 PDGF activity contrib­
utes to pulmonary fibrosis, hepatic fibrosis, renal fibrosis,
and scleroderma.142 PDGF has been shown to upregulate
TGF-β receptors in scleroderma fibroblasts,139 and its mul­
tiple effects are magnified in HTS and keloid fibroblasts.143
Recent research into the causes of nephrogenic systemic
fibrosis, a disorder of dermal fibrosis occurring after gado­
linium contrast administration in patients with impaired
renal function, shows that blocking PDGF receptors using
antibodies inhibits the proliferative effects of gadolinium on
fibroblasts.144 Other researchers have shown that blocking
PDGF action using tyrosine kinase inhibitors reduces fibro­
sis in murine models of radiation-induced pulmonary fibro­
sis145 and scleroderma.146 Thus although PDGF is an
independently profibrotic cytokine, it also serves to rein­
force and magnify the effects of TGF-β, and blocking its
activity can reduce fibrosis.
INSULIN-LIKE GROWTH FACTOR 1
Insulin-like growth factor 1 (IGF-1) was originally described
in chondrocytes, where it regulates glycosaminoglycan pro­
duction.147 IGF-1 is a mitogen for fibroblasts148 and endo­
thelial cells,149 and it induces collagen production in
pulmonary150 and dermal151 fibroblasts. IGF-1 upregulates
TGF-β gene transcription in fibroblasts, accounting for
observed similarities in their profibrotic actions.151 It has
been shown that IGF-1 also downregulates collagenase
mRNA levels and activity in dermal fibroblasts.152 This
increase in collagen production and decrease in breakdown
shift the balance of ECM remodeling toward fibrosis. IGF-1
is upregulated in a number of fibrotic conditions, including
post-burn HTS,153 scleroderma, pulmonary fibrosis, and
hepatic fibrosis.5 Interestingly in unwounded skin IGF-1 is
produced exclusively in epidermal sweat and sebaceous
glands and is thus sequestered from dermal fibroblasts.153
One may hypothesize that when these structures are dis­
rupted, as in burns and other wounds, dermal fibroblasts
are then directly exposed to IGF-1. Prolonged inflammation
and delayed re-epithelialization would increase the dura­
tion of fibroblast stimulation with IGF-1 and could help
explain the formation of HTS. Although IGF-1 is certainly
not the only cause of HTS, its relationship to TGF-β and its
unique distribution in skin suggest a key role in the patho­
genesis of abnormal scarring.
INTERFERONS
HTS is not simply the result of overexpression of profi­
brotic signals, but also results from a disturbance in the
delicate balance between pro- and antifibrotic cytokines.
The interferons (IFN) are cytokines classically produced by
immune cells to activate the host defense system.154 IFNs
cell cycle, homeostasis, and wound healing. When pro­
duced by cells, TGF-β is secreted in an inactive form bound
to latent TGF-β-binding protein. This bond is subsequently
cleaved by enzymes in the milieu of healing wounds, includ­
ing several matrix metalloproteinases (MMP-2, MMP-9)
and plasmin (present in blood). Mammals produce three
known isoforms: TGF-β1, TGF-β2, and TGF-β3.118 These are
produced by many cells involved in wound healing, includ­
ing degranulating platelets, macrophages, T lymphocytes,
endothelial cells, fibroblasts, and keratinocytes.119 The
actions of TGF-β1 and -β2 are mediated by the intracel­
lular Smad pathway and have directly profibrotic actions
on mesenchymal cells.120 TGF-β is upregulated locally in
wounds and systemically in the blood of burn patients with
HTS.121 HTS fibroblasts produce greater amounts of TGF-β
than normal fibroblasts122 and regenerative fetal fibro­
blasts.123 In fact, normally regenerative fetal fibroblasts can
be induced to form scar following TGF-β exposure.123 TGF-β
has direct effects on the ECM by upregulating collagen pro­
duction124 and downregulating decorin production125 by
fibroblasts. This decrease in dermal decorin is profibrotic
because decorin binds to TGF-β in the ECM, blocking its
activity.126 TGF-β promotes not only the transformation of
fibroblasts into myofibroblasts46 but also the transdifferen­
tiation of epithelial cells into mesenchymal cells,127 and it
reduces apoptosis in the healing wound.128 In this context,
TGF-β is a highly profibrotic cytokine playing a unique
role in HTS initiation. Interestingly, it has been suggested
that the isoform TGF-β3 acts as an antifibrotic cytokine.
Clinical trials of TGF-β3 have shown promise in improving
wound healing,129 and it is noteworthy that TGF-β3, which
is upregulated in the remodeling phase of wound healing,
reduces ECM deposition.130 Many effects of other cytokines
in wound healing can be directly related to activation by or
interaction with TGF-β.
CTGF/CCN2
Connective tissue growth factor (CTGF or CCN2) is a
prototypic member of the CCN family of cytokines. The
CCN family motif consists of four linked regions: an
IGF-binding domain, a von Willebrand type C domain, a
thrombospondin-1 domain, and a cysteine knot heparin-
binding domain.131 This configuration and multiple studies
suggest that CTGF does not act simply as a growth factor,
but rather as an important cofactor for TGF-β and as an
interface between cells and the ECM by binding to cellu­
lar integrins and matrix proteoglycans.132 Independent
stimulation by TGF-β or CTGF alone induces only transient
fibrotic upregulation in fibroblasts, whereas co-stimulation
by both cytokines leads to prolonged fibrosis,133 and in
chronic fibrosis CTGF remains elevated after TGF-β returns
to basal levels.134 Thus one can surmise that TGF-β serves
to initiate fibrosis and CTGF serves to continue the process
as a downstream mediator of TGF-β.124 In keeping with this
hypothesis, CTGF is upregulated in HTS, scleroderma,135
and other fibrotic diseases.136 TGF-β induces CTGF through
the Ras/MEK/ERK pathway, and blocking this activation
with iloprost (a synthetic prostacyclin PGI2 analog) reduces
fibrosis.137 Other methods of targeting CTGF, such as anti-
CTGF antibodies and CTGF siRNA, have also proved effec­
tive in reducing fibrosis.138

45  •  Molecular and Cellular Basis of Hypertrophic Scarring
464
between pro- and antifibrotic cytokines and suggests pos­
sible therapeutic treatments for HTS.
The Immune System Regulates
Wound Healing
Mast cells, neutrophils, and macrophages have long been
recognized as playing important roles in the inflammatory
phase of wound healing.162 Macrophages produce classic
immune cytokines interleukin-1 (IL-1), IL-6, and tumor
necrosis factor-α (TNF-α), which stimulate keratinocytes
and fibroblasts,45 and classic profibrotic cytokines TGF-β,
PDGF, and IGF-1.163 Recently the importance of the immune
response type rather than degree of inflammation in deter­
mining the risk of HTS formation has been recognized. HTS
are highly infiltrated by lymphocytes,6 of which activated
CD4+ T-helper (TH) cells are an important subgroup.99 These
TH cells can be generally classified as one of at least four
groups: TH1, TH2, TH17, and T-regulatory cells, based on
cytokine production patterns.164 Of these, the TH1–TH2 axis
in wound healing and burn patients is the most studied. TH1
cells produce IFN-γ, IL-2, and TNF-β and are involved in
cell-mediated immunity, whereas TH2 cells produce IL-4,
IL-5, and IL-10 and are involved in antibody-mediated
can be divided into type I (IFN-α and IFN-β produced by
leukocytes and fibroblasts, respectively) and type II (IFN-γ
produced by activated T lymphocytes).154 Of these, the two
antifibrotic cytokines whose roles in wound healing and
HTS have been best studied are IFN-α2b and IFN-γ. Treat­
ment of fibroblasts with these IFNs inhibits cell prolifera­
tion and also downregulates collagen,155 fibronectin,155 and
TGF-β production.121 IFN-α2b also upregulates collagenase
production and reduces TIMP-1,156 making it a good candi­
date to promote scar remodeling.121 IFN-α2b reduces in vitro
collagen lattice contraction rates157 and in vivo wound con­
traction in guinea pigs.158 IFN-α2b also reduces myofibro­
blast populations and increases the numbers of apoptotic
fibroblasts in later stages of wound healing,158 a finding
also demonstrated in several other cell types.159,160 A pro­
spective clinical trial of IFN-α2b in post-burn HTS patients
demonstrated reductions in scar volume, normalized TGF-β
levels, and reduced scar angiogenesis.121 It is suggested that
abnormal scar results, at least in part, from reduced levels
of endogenous IFN in burn patients. An examination of
the peripheral blood mononuclear cells (PBMCs) of patients
forming keloids after trauma compared to those with normal
scarring showed decreased production of IFN-α and IFN-
γ,161 which is consistent with this hypothesis. Therefore an
understanding of IFNs highlights the important balance
IL-4 percent positive cells
Time postburn (months)
HSc
noHSc
0.25
0.50
0.75
1
2
6
12
12+
2
6
12
12+
0
20
15
10
5
IFN-γ percent positive
Time postburn (months)
0.25
0.50
0.75
1
2
6
12
12+
0
20
15
10
5
IL-10 (pg/mL)
IL-12 (pg/mL)
Time postburn (months)
1
0
16
12
8
4
0
16
12
8
4
2
6
12
12+
Time postburn (months)
1
A
B
C
D
Fig. 45.9  Cytokine production in burn patients. Cytokine production by lymphocytes from burn patients as a function of time after injury. The percent­
ages of lymphocytes producing IFN-γ (A) or IL-4 (C) were estimated by flow cytometry analysis of cells stained for intracellular cytokines using fluores­
cent-labeled antibodies (n = 22). Panels B and D show the time course of IL-12 (B) and IL-10 (D) production by peripheral blood mononuclear cells
(PBMCs) cultured from burn patients who developed hypertrophic scar (HSc) and those who did not (noHSc), measured by enzyme-linked immuno­
sorbent assay (ELISA: n = 16). The values measured for cells from normal human volunteers are shown in the shaded boxes (mean ± SD). (From Tredget
EE, Nedelec B, Ghahary A. Hypertrophic scar, keloids and contracture: The cellular and molecular basis for therapy. Surg Clin N Am. 1997;77(3):701–730.)

45  •  Molecular and Cellular Basis of Hypertrophic Scarring
465
cellular phenotypes, and cytokine messages displayed. This
results in a mass of disorganized connective tissue with
thin, irregular collagen bundles in whorls and nodules
instead of thick, organized fibers parallel to the surface. The
concomitant decrease in decorin and increase in other pro­
teoglycans not only contributes to this disorganized ECM
but also allows profibrotic signals to propagate in the dermis.
The fibrotic, hypercellular nature of HTS both contributes
to and results from elevated profibrotic (e.g., TGF-β, CTGF)
and decreased antifibrotic (IFN-γ) cytokine levels. The
resulting local HTS fibroblast is modulated by systemic
fibrocytes and TH cells, which migrate to the wound. The
resulting pathogenesis of HTS is complex, with many
aspects that serve to reinforce the fibrotic process. Although
this complexity makes elucidating the mechanisms of HTS
formation difficult, it also provides multiple targets for
medical therapy. It is our hope that this will provide thera­
pies to improve the quality of life for both burn patients and
others with fibroproliferative conditions.
Complete references available online at

Further Reading
Desmoulière A, Chaponnier C, Gabbiani G. Tissue repair, contraction, and
the myofibroblast. Wound Repair Regen. 2005;13(1):7-12.
Dunkin CSJ, Pleat JM, Gillespie PH, et al. Scarring occurs at a critical depth
of skin injury: precise measurement in a graduated dermal scratch in
human volunteers. Plast Reconstr Surg. 2007;119(6):1722-1732.
Ignotz RA, Massague J. Transforming growth factor-beta stimulates the
expression of fibronectin and collagen and their incorporation into the
extracellular matrix. J Biol Chem. 1986;261(9):4337-4345.
Leask A, Abraham DJ. TGF-beta signaling and the fibrotic response. FASEB
J. 2004;18(7):816-827.
Schmidt M, Sun G, Stacey MA, et al. Identification of circulating fibrocytes
as precursors of bronchial myofibroblasts in asthma. J Immunol.
2003;171(1):380-389.
Tredget EE, Yang L, Delehanty M, et al. Polarized Th2 cytokine production
in patients with hypertrophic scar following thermal injury. J Interferon
Cytokine Res. 2006;26(3):179-189.
Wang J, Dodd C, Shankowsky HA, et al. Deep dermal fibroblasts contribute
to hypertrophic scarring. Lab Invest. 2008;88(12):1278-1290.
immunity.165 Interestingly these cytokine profiles are
involved not only in specific immune responses, but are also
anti- or profibrotic.166 The TH2 cytokine IL-10 stimulates
activated naïve TH cells to secrete TGF-β, and this is more
pronounced in IFN-γ (TH1) knockout mice and reduced in
IL-4 (TH2) knockout mice.167 In a burn mouse model TH2
cytokines (IL-5) were upregulated and TH1 cytokines (IFN-γ
and IL-2) were coordinately downregulated.168 A similar
TH2 type response is seen in human burn patients using
stimulated PBMC from those with burns of 25% or more
total body surface area (TBSA),169 a finding confirmed by
another study in burn and major trauma patients.170 The
severity of fibrosis in animal models has also been linked to
the type of TH-cell response. In a model of liver fibrosis
BALB/c mice developed a TH2 response to chemically
induced liver injury and displayed more severe fibrosis than
did C57BL/6 mice, which developed a TH1 response. This
effect was abrogated by administration of IL-4 antibodies or
IFN-γ, which induced a TH1 response in the BALB/c mice.171
A longitudinal study of recovering burn patients demon­
strated a predominant TH2 response to burn injury, as dem­
onstrated by increased IL-4 and IL-10 levels from PBMC and
in scar tissue (Fig. 45.9). Interestingly this response was
significantly higher in burn patients who went on to develop
HTS than in those who developed normal scars, whereas
those patients developing normal scar had higher levels of
IFN-γ-producing PBMC.172 Recently it was found that IFN-α
blocks TH2 development and inhibits cytokine secretion by
committed TH2 cells.164 This suggests that IFN-α2b has
effects not only on fibroblasts, as discussed previously, but
also the TH2 cells that modulate them.
Conclusion
HTS is a fibrotic disorder resulting from derangement of the
normal wound-healing process and shares many common
features with other fibrotic diseases. As discussed, HTS is
markedly different from normal skin and mature scar in
terms of the structure and composition of ECM, active

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466
Pathophysiology of the
Burn Scar
HAL K. HAWKINS, JAYSON JAY, and CELESTE C. FINNERTY
46 
inflammatory and reparative events are prolonged and
more prominent. Extensive leakage of blood plasma by
damaged small blood vessels maintains an outward flow
that serves to keep the wound clean but causes deposition
of coagulated fibrin and other desiccated proteins on the
wound surface. Conversion of fibrinogen into fibrin fills the
gap in the epidermis and provides a gelatinous matrix
capable of sustaining migrating cells. Thrombin stimulates
expression of interleukin-6 (IL-6) in connective tissue cells.5
Degranulation of platelets releases platelet-derived growth
factor (PDGF) and other proinflammatory cytokines.6 Fibrin
degradation releases peptides that stimulate fibroblast pro­
liferation and secretion, division of vascular endothelial
cells, and production of cytokines by other cells.7–9 Dermal
fibroblasts, together with circulating stem cells, divide
rapidly in the wound bed and secrete large quantities of
collagen and proteoglycans, with predominance of type III
collagen.10,11 Simultaneously the endothelial cells of small
blood vessels proliferate rapidly and form numerous small
capillary loops that extend upward toward the surface.
Together these cells form a mass of granulation tissue that
covers the wound. These activities of fibroblasts and endo­
thelial cells are stimulated by cytokines and other peptides,
largely secreted by monocytes and lymphoid cells that infil­
trate the wound bed. Certain proteins and peptides that are
normally present in blood plasma also stimulate and enable
formation of the wound matrix, notably fibronectin and
vitronectin.12–14 Polymorphonuclear neutrophils also enter
the wound bed in large numbers where they phagocytize
and kill bacteria and fungi that gained entry to the dermis
and subcutis through the open wound. Next the fibroblasts
develop interconnections among themselves and produce
and assemble the contractile machinery of actin and myosin
within the cytoplasm of each cell.15 These interconnected
myofibroblasts contract to shrink the size of the open
wound, pulling adjacent intact skin to cover the wound bed.
Wound contraction is most dramatic in experimental
wounds of rodents; however the effects of wound contrac­
ture in applying tension to surrounding tissues can be seen
in humans as well. Simultaneously with these processes,
the basal keratinocytes of the cut edges of the epidermis
proliferate and change to a migratory and secretory pheno­
type and begin to invade the wound bed between the granu­
lation tissue layer and the scab of dried proteins on the
surface.16 Once they make contact to seal the center of the
wound, the migrating keratinocytes change phenotype
again and restore the normal laminated structure of the
epidermis and produce a new basal lamina.17,18 Melano­
cytes also migrate during healing of large wounds and
establish a degree of pigmentation in the healed wound that
approximates the pigmentation of the uninjured skin. It
Introduction
PREHISTORIC AND HISTORIC PERSPECTIVES
Wounds due to combat, hunting injuries, accidents, and
thermal injuries have been the leading causes of death in
humans for millennia, whereas prolonged survival of large
full-thickness wounds is a recent phenomenon. Complex
biological responses to cutaneous injury have evolved over
time without evolutionary pressure to evolve appropriate
healing responses to large wounds. There are records of
human attempts to improve wound healing in ancient texts
from Mesopotamia and Egypt. Guido Majno has explored
what can be learned from archeology and paleontology
regarding wounds and their treatment in ancient times and
provides an accurate description of the wound healing
process in lay terms.1 In the development of modern medi­
cine, the advances in wound treatment advocated by
Ambroise Pare (1520–1590) stand out, together with the
antisepsis campaign of Joseph Lister (1827–1912) and the
development of antibiotics and other modern methods of
treatment described in this book.
INCISIONAL WOUNDS WITH PRIMARY CLOSURE
The essential components of wound healing are easily
understood. They are: (1) activation of tissue repair in the
wound by fibroblasts and small blood vessels and an inflam­
matory response initiated by vascular leakage and (2) entry
into the wound of circulating polymorphonuclear neutro­
phils, lymphocytes, and macrophages.2 When a sharp inci­
sion is closed while still sterile, minimal vascular leakage and
inflammation occur, and the predominant reaction to injury
occurs in the fibroblasts present in the dermis and subcuta­
neous tissue. These resting connective tissue cells are rapidly
activated to secrete collagen, which quickly bridges the small
remaining gap to restore the resistance of the skin to tearing.
Vascular continuity is restored by budding and remodeling
of blood vessels, and the basal keratinocytes of the epidermis
divide briefly to restore the complete structure of the epider­
mal barrier. All that remains to indicate the site of injury is a
linear ribbon of dense collagen with little flexibility that
marks the site of the incision, as well as small scars that mark
the suture sites. This process of incisional wound healing
was well described in humans by Ross and colleagues.3,4
DELAYED WOUND CLOSURE “BY SECOND
INTENTION” AND WOUND CONTRACTION
If the epidermis and dermis are incised or removed and the
edges of the wound remain separated, then the resultant