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CLINICAL REVIEW
Pediatric Dermatology
Vol.
15
No.
3 169-183, 1998
Acute InfectiousPathogenesis and
Gary
L.
Department
o
Pediatrics, Children’s Hospital and
PurpuraFulminans:Medical Management
Darmstadt,
M.D.
Regional Medical Center, University
of
Washington School
of
Medicine, Seattle, Washington
Abstract:
Purpura fulminans (PF) is a potentially disabling and life-threatening disorder characterized by acute onset of progressive cutane-ous hemorrhage and necrosis, and disseminated intravascular necrosis.Acute infectious PF occurs most commonly in the setting of meningo-coccemia due to elaboration of endotoxin. Presence of purpura, particu-larly when generalized, is an important predictor of
a
poor outcome fol-lowing meningococcal infection. Histopathologic hallmarks of acuteinfectious PF are dermal vascular thrombosis and secondary hemor-rhagic necrosis, findings which are identical to those of the Shwartzmanreaction. Acute infectious PF and the Shwartzman reaction have a com-mon pathogenesis, involving a disturbance in the balance of anticoagu-lant and procoagulant activities of endothelial cells. This disturbance,which
is
triggered by endotoxin, appears to be mediated by cytokines,particularly interleukin-1
2,
interferon-?, tumor necrosis factor-a, and in-terleukin-1, leading to the consumption of proteins
C
andSand anti-thrombin
111.
State-of-the-art therapeutic interventions based on recentadvances in our understanding
of
the pathogenesis of acute infectious PFare discussed.
Purpura fulminans (PF)
is
a potentially disabling andlife-threatening disorder characterized by acute onset ofprogressive cutaneous hemorrhage and necrosis due todermal vascular thrombosis, and disseminated intravas-cular necrosis (DIC). It occurs predominantly in threeclinical settings (Table 1): (1) in the neonatal period as amanifestation
of
inherited, homozygous protein
C
or,rarely, protein
S
deficiency;
(2)
approximately
7
to 10days after a relatively benign antecedent infection, usu-ally involving the skin, such as varicella or scarlet fever(i.e., “idiopathic”
PF)
(Table
2);
and
(3)
in conjunctionwith an acute infectious illness (i.e., acute infectious
PF),
particularly sepsis with endotoxin [lipopolysaccharide](LPS)-producing gram-negative bacteria (e.g.,
Neisseriameningitidis)
(1). All cases involve dysfunction of he-mostasis, with a shift from a quiescent state favoringanticoagulation to a disease state of overwhelming pro-coagulation.Significant strides have been made in the management
of
hereditary neonatal PF because
of
advances in ourunderstanding of its pathogenesis (e.g., protein
C
defi-ciency) and the availability of new therapeutic products(e.g., protein C concentrate)
(2,3).
Idiopathic PF is anuncommon entity that has been reported in less than 100children
(4,5).
It
develops while the patient is not acutelyill, typically during the postinfectious convalescent phase
Address correspondence to
Gary
L.
Darmstadt, M.D., Division
of
Infectious Disease, Department
of
Pediatrics
CH-32,
Children’s
Hos-
pital and Regional Medical Center,
4800
Sand Point
Way
NE,
eattle,
WA
98105,
or
e-mail: gdarms@chmc.org.
169
 
170
Pediatric Dermatology Vol.
15
No.
3
May/June 1998
TABLE
1.
Classification
of
Purpura Fulminans
I. Hemostasis initiatedA. Protein
C
anticoagulant system dysfunction
1.
Hereditary
2.
Acquired
1.
Antithrombin
I11
a.
Homozygous protein
C
deficiency
b.
Homozygous protein
S
deficiencya. Disseminated intravascular coagulation
B.
Disorder of other hemostasis regulatory systems
11.
Idiopathic
111.
Acute infectious
A.
Postinfectious
B.
Unknown etiology
of varicella, group
A
streptococcal infection, or a non-specific viral exanthematous illness. Some cases havefollowed conditions that apparently were not infectious,such as cutaneous hypersensitivity reaction or stomatitis.Idiopathic PF differs from the acute infectious form inthat microthrombi and clinically significant thrombo-hemorrhagic manifestations in organs other than the skingenerally are lacking; distal vascular beds (i.e., extremi-ties) typically are spared; and circulatory collapse
is
notpresent initially, although hypovolemic shock and tissuehypoperfusion may develop due to extravasation ofblood into the skin. These differences are reflected in thelower mortality rate associated with idiopathic PF (ap-proximately
15%)
compared to acute infectious PF.The majority of cases of PF develop in childhoodduring an acute infection, particularly meningococcalsepsis. This review describes our current knowledge ofthe pathogenesis
of
acute infectious PF. Based on this
TABLE
2.
Infectious Causes
of
Purpura Fulminans
I.
11.
Idiopathic (postinfectious) purpura fulminansVaricellaScarlet feverStreptococcal tonsillopharyngitisViral exanthemRubellaMeaslesUpper respiratory tract infectionGastroenteritisAcute infectious purpura fulminans
Neisseria meningitidisStreptococcus pneumoniaeStreptococcus agalactaeae
(groupBstreptococcus)
Haemophilus influenzae
type
b
Rickettsia rickettsiiStreptococcus pyogenes
(group A streptococcus)
Staphylococcus aureusKlebsiella pneumoniaeEscherichia coliProteus mirabilisEnterobacter
spp.
Neisseria catarrhalisHaemophilus aegypticusCapnocytophaga canimorsus
knowledge, the application
of
new, potentially more ef-fective approaches
to
its medical management will bediscussed.
EPIDEMIOLOGY
Purpura fulminans develops in
15%
to 25% of those withmeningococcemia
(6-9).
It can develop during infectionwith any of the meningococcal serogroups; endotoxinproduction, however, appears to be highest among sero-group
C
isolates
(10).
Purpura fulminans occurs onlyrarely in the course of infection with other organisms,even in the setting of sepsis with
DIC.
In one series ofpatients with pneumococcal sepsis, however,
6%
(101
165)
developed symmetrical peripheral gangrene
(1
1).
In
the neonate, acute infectious
PF
may be due to group
B
streptococcus.Although several factors have been identified as pre-dictive of
a
poor outcome from meningococcemia, size
of
skin hemorrhage increases with disease severity (12),and the presence of purpura, particularly when general-ized, is associated with high morbidity and mortality, asit reflects a profound disturbance in hemostatic mecha-nisms (8,13-21). While the overall fatality rate in chil-dren with meningococcemia in the United States is lessthan
15%,
development of PF heralds mortality in 20%to
60%
of cases.
Of
those who survive, the majority havecutaneous and skeletal deformities due to gangrene(22,23). The presence of petechiae signals septicemia,and onset within 12 hours of initial medical evaluationhas been associated with poor outcome in some studies(24,25) but not in others
(6,8,17).
Thus
PF,
distinct frompetechiae or other cutaneous manifestations of meningo-coccemia such as
a
maculopapular eruption, is an impor-tant marker
of
a poor outcome.
CLINICAL
CHARACTERISTICS
Lesions of PF are similar regardless of the precipitatingcondition. Cutaneous discomfort develops first, followedby development of erythema with or without edema andpetechiae. Sites of involvement appear transiently likeecchymoses, and up to this point the pathologic processin the skin is reversible without progression to necrosis.Lesions evolve rapidly into painful, indurated, well-demarcated, irregularly bordered purpuric papules andplaques which are surrounded by
a
thin, advancing ery-thematous border (Figs.
1
and 2). Late findings in ne-crotic areas are the formation of vesicles and bullae (Fig.3), which mark the development of hemorrhagic necro-sis, and finally firm eschar which ultimately sloughs.Gangrenous necrosis often extends into subcutaneous tis-sue, and occasionally involves muscle and/or bone (Fig.4); epiphyseal growth plate necrosis in the growing child
 
Darmstadt: Acute Infectious Purpura Fulminans
17
1
Figure
1.
Well-defined, irregularly bordered purpuricplaques on the arm of a child with early acute infectiouspurpura fulminans due to
Neisseria meningitidis.
Figure
3.
Purpuric plaques and hemorrhagic bullae on theleg of a child with severe, advanced purpura fulminansdue
to
Neisseria meningitidis.
Figure
2.
Well-defined, purpuric plaques on the arm of achild, late in the course of meningococcemia.
may lead to limb foreshortening. The distal extremitiesare often most severely involved, usually in a symmetricmanner, probably due to the presence of fewer collateralchannels for tissue perfusion, and the relatively greaterimpact of circulatory collapse on perfusion of distal vas-cular beds. This differs from idiopathic or postinfectiousPF, which typically begins in the skin of the thighs, legs,buttocks, and lower trunk. Acute infectious PF fre-quently progresses proximally and ultimately may formpurpuric plaques of various sizes and shapes in
a
diffuse,patchy distribution.Development of systemic consumptive coagulopathy(i.e., DIC) is a defining feature of PF, which distin-guishes it from other forms of skin necrosis due to der-mal vascular occlusion such as warfarin- or heparin-induced skin necrosis, thrombotic thrombocytopenicpurpura, cryoglobulinemia, antiphospholipid syndrome,or paroxysmal noctural hemoglobinuria. Shock may oc-cur in all forms of PF, but is most characteristic of acuteinfectious PF. Thrombohemorrhagic manifestations maybe found in multiple vascular beds and organ systems,
Figure
4.
Gangrenous fifth fingertip due
to
Neisseria men-ingitidis.
and multiple organ dysfunction syndrome is common.Fibrinogen, coagulation factors (e.g., factor V and factorVIII), and platelets are consumed in ongoing thrombosisand fibrinolysis. Prothrombin time (PT) and partialthromboplastin time (PTT) are prolonged; fibrin degra-dation products (e.g., D-dimers) are elevated; and protein
C,
protein
S,
and antithrombin I11 levels are reduced.The histopathologic hallmarks of PF are dermal vas-cular thrombosis and secondary hemorrhagic necrosis(Fig. 5a)
(26).
Vascular changes are widespread, involv-ing multiple organ systems, particularly the adrenalglands
(Waterhouse-Friderichsen
syndrome), lungs, andkidneys. The cutaneous vessels most affected are thepostcapillary venules in the subpapillary plexus
of
thepapillary dermis, where blood flow velocity is slowest.
of 00

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