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Purpura

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73 Purpura

Melissa A. Reyes and Lawrence F. Eichenfeld

Purpura can be a signicant nding, especially as it is associatedwith multiple infectious etiologies, some of which are life-threatening. Purpura results from trauma to blood vessels in theskin leading to hemorrhage into the surrounding tissue. Vesseldamage can be the result of direct trauma (physical, chemical,infectious/toxic), vessel occlusion, immune complex deposition,platelet depletion or dysfunction, or other conditions that causevascular leakage of erythrocytes into the skin, mucous membranes,conjunctivae, or retina. The clinical appearance of purpuric lesions

depends on the size of the affected vessels, location of the vessels,extent of hemorrhage, and the coagulation status of the patient.There are a substantial number of noninfectious causes of purpura.Morphology and clinical presentation can be useful in discrimi-nating among likely etiologies. Purpuric lesions can be dividedinto six subtypes based on size and morphology of the lesions1:petechiae, macular purpura, ecchymoses, palpable purpura, non-inammatory retiform purpura, and inammatory retiform purpura.

TYPES OF PURPURIC LESIONS

AND PATHOGENESIS

Petechiae, macular purpura, and ecchymoses are all supercial atcutaneous lesions of varying sizes, 4 mm, 5 to 9 mm, and 1 cm,respectively. Palpable purpura is raised, partially blanching, ery-thematous to purple, typically round lesions. Retiform purpura

appears lace-like in pattern as the affected vessels are larger andexist in the dermis and subcutis. Inammatory retiform purpurainitially is erythematous before evolving into purpura. All purpu-ric lesions share similar changes in color based on the age of thelesion. Lesions initially are bright red or deep red and becomepurple as the heme pigments break down and progress to greenand yellow-brown before fading. The amount of time to fadingdepends on the amount of extravasated blood.

Petechiae, macular purpura, and ecchymoses are consideredmacular orat purpura and result from simple extravasation ofblood into the skin. Histologically, there is minimal inamma-tion, in contrast to the inammatory hemorrhage seen in micro-vascular occlusion or cutaneous small-vessel vasculitis, which

results in palpable purpura.1Inammatory purpura occurs secondaryto occlusion by a clot with resulting ischemia and necrosis of thevessel, in the case of microvascular occlusion syndromes. Vasculitisis caused by immune complexes deposited on the vessel lumen,which attracts neutrophils that destroy the complexes as well asinjure the vessel wall. Retiform purpura and inammatory retiformpurpura result from both occlusion and vasculitis, respectively, oflarger, slow-ow vessels.

In patients with septicemia, purpura can arise from ve main

etiologies: (1) disseminated intravascular coagulation (DIC) andcoagulopathy, (2) direct vascular invasion and occlusion by organ-isms, (3) infective vasculitis, (4) emboli, such as seen with endo-carditis, and (5) vascular changes due to toxins.2 Many infectionsare associated with thrombocytopenia with development ofpetechiae or ecchymoses, with or without DIC. Invasion of micro-organisms into capillaries can occur especially with bloodstreaminfection (BSI) due toNeisseria meningitidis, Neisseria gonorrhoeae,and Pseudomonas aeruginosa (Figure 73-1). Diffuse vasculitis withpathologic evidence ofRickettsiae in vascular endothelial cells isseen with Rocky Mountain spotted fever (RMSF) and epidemictyphus. Immune mediated vasculitis is associated with a broad setof petechial rashes associated with atypical measles, hepatitis B,and chronic meningococcemia. Intravascular catheter-associatedinfections and acute and subacute endocarditis can manifest withinfectious embolization, complicated by infarction, tissue hemor-

rhage, and necrosis. Endocarditis also can be associated withimmune-mediated vasculitis and petechiae. The scarlatiniformpetechial eruptions ofStreptococcus pyogenes (group A streptococ-cus, GAS) are an example of toxin-mediated rashes, also knownas toxic erythemas.

CAUSES OF PURPURA

Petechiae and Macular Purpura

Petechiae are small, 4 mm in diameter, non-blanching purpuricmacules that can appear on the skin, conjunctiva, retina, andmucous membranes. Lesions of macular purpura are larger than

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Figure 73-1. Skin manifestations of meningococcemia. Rapidly progressive disease with rst examination showing one patient with petechiae on the arm with

exaggeration distal to the site of a tourniquet (A) and petechiae and purpura on the back(B); and another patient with a purpuric plaque on the distal leg (C).

Purpuric lesions around the knee in a patient at the time of admission (D) and 4 days later (E). Early manifestations of rapidly progressive, fatal meningococcemia

with predominantly non-petechial, macular lesions (F). (A, B, D, and E, courtesy of J.H. Brien; C and F, courtesy of S.S. Long.)

A

B

C D

E

F

petechiae but smaller than ecchymoses. Both are the result ofextravasation of blood from capillaries. For the remainder of thechapter, petechiae will be used to include all macular purpuriclesions

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Purpura

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aMost common.

BOX 73-1. MajorInfectiousCausesofPurpurainChildrenandNeonates

CHILDREN

Bacteria

Arcanobacterium haemolyticum, Bacteroides ragilis,

Bartonella hensleae, Borrelia spp., Brucella spp.,

Campylobacter jejuni, Capnocytophaga canimorsus,a

Enterococcus spp., Escherichia coli, Francisella tularensis,

Haemophilus infuenzae type b, Klebsiella spp., Leptospira spp.,Listeria monocytogenes, Moraxella catarrhalis, Mycobacterium

leprae, Mycobacterium tuberculosis, Neisseria meningitidis,a

Neisseria gonorrhoeae,aPseudomonas aeruginosa,aSalmonella

typhimurium, Staphylococcus aureus, Streptobacillus

moniliormis, Streptococcus pneumoniae, Streptococcus

pyogenes,a

viridans streptococci, Yersinia pestis, Yersinia enterocolitica

Fungus

Candida, Aspergillus, Rhizopus, Fusarium species and agents of

mucormycosis

Helminths

Ascaris spp., Strongyloides stercoralis (hyperinfection syndrome),

Trichinella spiralis

Mycoplasma

Mycoplasma pneumoniae

Protozoa

Plasmodium alciparum

Rickettsiae

Ehrlichia canis, Ehrlichia chaeensis, Ehrlichia equi, Anaplasma

phagocytophilum, Rickettsia akari, Rickettsia prowazekii

(epidemic typhus),aRickettsia rickettsii(Rocky Mountain spotted

fever),aRickettsia typhi

Viruses

Adenoviruses; Colorado tick fever virus; coxsackievirus A4, A9,B2B5; cytomegalovirus,a echovirus 3, 4, 7, 9, 18; dengue fever

virus; EpsteinBarr virus; hantavirus; hepatitis virus A, B,a C;a

human immunodeciency virus; parvovirus B19; respiratory

syncytial virus; rotavirus; rubella virus; rubeola virus (typical and

atypical measles); varicella-zoster virus; yellow fever and other

hemorrhagic fever viruses (e.g., Ebola, Marburg and Lassa

viruses)

NEONATES

Bacteria

Gram-positive and gram-negative bacteria associated with

septicemiaa

Treponema pallidum

Protozoa

Toxoplasma gondii

Viruses

Enteroviruses; cytomegalovirus; herpes simplex virus types 1, 2;

rubella virus

(15% with a conrmed viral etiology) had higher white blood cellcounts (WBCs) and absolute band counts. Another prospectivestudy attempted to capture a broader cohort of patients by evaluat-ing 411 consecutive pediatric patients presenting to a hospitalemergency department with both fever and petechiae.3 Of the 53ill-appearing patients (toxic appearance, inconsolable crying orscreaming, or lethargy), 6 had invasive bacteremial infection whilenone of the 357 well-appearing children had positive blood cul-tures or cerebrospinal uid bacterial cultures. In this study of 411patients with fever and petechiae, only 2 patients hadN. meningi-tidis (0.5%), 2 had Streptococcus pneumoniae, and 1 had GAS inva-sive infection. The study also found that WBCs 15,000 waspredictive of severe BSI. Thus, a febrile patient with petechiae whois well-appearing, has normal laboratory workup, petechiae abovethe nipple line, and documented streptococcal pharyngitis has lowrisk of invasive bacterial disease. Petechiae in febrile patients ismore commonly associated with viral infections, given their highprevalence, but also because viruses tend to damage small cutane-ous vessels.9

Petechiae on the palate are characteristic of streptococcal phar-yngitis,10 but also can be seen in EpsteinBarr virus infection,Arcanobacterium haemolyticum pharyngitis, rubella, roseola, viral

hemorrhagic fevers, thrombocytopenia, and palatal trauma.10Palmar and plantar petechiae can be seen in the gloves and sockssyndrome caused by parvovirus B19. In this condition, there isconuent erythema of the distal extremities with pinpoint maculesevolving into petechiae on the palms and soles with concurrentfever and leukopenia.11 Parvovirus B19 also has been reported tocause a generalized petechial eruption,12 and petechiae in abathing suit distribution.13 Clusters of patients with generalizedpetechial eruptions are reported during community outbreaks oferythema infectiosum, apparently associated with the viremicphase of parvovirus B19 infection.14 Other reported infectiouscauses of generalized petechiae include scarlet fever, RMSF, para-inuenza, inuenza, respiratory syncytial virus, enterovirus,

rotavirus, atypical measles, rubella, dengue, and adenovirusinfections.6

Petechiae or purpura also can be due to noninfectious causes,such as secondary to drug eruptions, acute leukemia,6 low plateletcount, and mechanical causes (Box 73-2). Severe coughing orvomiting can increase intrathoracic pressure, causing petechiae inareas perfused by the superior vena cava, approximately corr-esponding to skin above the nipple line. This distribution ofpetechiae is not always benign a reported 25% of patients withfever and petechiae conned to the upper torso had bacterialinfection in one study.7 Petechiae also can form distal to tourni-quet placement and are of no clinical signicance without otherndings. In contrast, the tourniquet test can cause distal petechiaein patients with dengue fever and is positive in most patients withdengue hemorrhagic fever.15 In newborns, petechiae can occur atsites of pressure as they progress through the birth canal, butpetechiae also can result from acquired infection or maternalantiplatelet antibodies; thus appropriate evaluation should be per-formed. Older children with petechiae and no fever should beevaluated for blood dyscrasias.

EcchymosesEcchymoses are purpuric at patches on the skin, commonly knownas bruises. Ecchymoses typically are 1 cm in size and are causedby a greater volume of extravasated blood than in petechiae. Thus,ecchymoses tend to take longer to resolve (1 to 3 weeks). Petechiaein a patient with an underlying coagulopathy can quickly evolveinto ecchymoses, sometimes within minutes.

Ecchymoses resulting from infection are uncommon in chil-dren. When ecchymoses occur, they are most frequently due toN. meningitidis BSI with coagulopathy.16 Other reported causesinclude other gram-negative bacteria, gram-positive bacteria(Staphylococcus aureus, S. pyogenes, and S. pneumoniae), viruses

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patches and eschars.3 Purpura fulminans is caused by abnormali-ties in coagulation secondary to infection. Purpura can occur 7 to10 days after an otherwise benign infection (idiopathic purpurafulminans) and in the setting of acute infection such as gram-negative infection caused byN. meningitidis.16 Idiopathic purpurafulminans has been associated with varicella, scarlet fever, strep-tococcal tonsillopharyngitis, viral exanthem, rubella, measles,upper respiratory tract infection, and gastroenteritis.16 A variantcalled symmetric peripheral gangrene results in ischemic necrosisof the distal parts of two or more extremities without large-vessel

obstruction. This variant is associated with higher mortality andmorbidity, such as amputation, in patients with purpura fulmin-ans.20 Both purpura fulminans and symmetric peripheral gangreneoccur more frequently in infants and children than in older indi-viduals.2 In neonates, purpura fulminans can be a manifestationof inherited homozygous protein C, or rarely protein S, deciency.In older children, BSIs in patients with these underlying decien-cies (as well as properdin deciency, splenic dysfunction, or neu-tropenia) can lead to purpura fulminans.

Palpable Purpura

Unlike, petechiae and ecchymoses, palpable purpura are raised pur-puric papules and plaques that can range in size from a few mil-limeters to a few centimeters. Palpable purpura favors dependentareas such as the lower extremities, but in the supine patient can

occur on the back, buttocks, and distal arms. Palpable purpura canevolve into nodular, vesicular, pustular, necrotic, or ulcerativelesions.

Palpable purpura is classically associated with leukocytoclasticvasculitis, an inammatory process injuring the vessel.21 His-topathologically, brin deposition in vessel walls, neutrophilicdebris, and perivascular lymphocytes are present. Palpable purpuraalso can occur with S. aureus BSI or bacterial endocarditis as theresult of infectious microemboli occluding the vascular lumen.Osler nodes and Janeway lesions found in bacterial endocarditisare types of microembolic-induced palpable purpura. Osler nodesare tender nodules on the palms, soles, and pads of the ngers/toes. Janeway lesions are nontender, purpuric macules, papules ornodules usually on the palms and soles. Lesions similar to Oslernodes have been reported in typhoid fever, polyarteritis nodosa,systemic lupus erythematosus, ChurgStrauss syndrome, mixedcryoglobulinemia, and Wegener granulomatosis.1,2

Palpable purpura can have a variety of causes, including infec-tion (10% to 15%), drug exposure, immunization, and autoim-mune disease. The most common infectious causes of palpablepurpura includeN. meningitidis, S. aureus, andN. gonorrhoeae butcases have been reported due to Mycobacterium, Rickettsia, Myco-plasma, and rarely Bartonella, Treponema pallidum, Salmonella,Campylobacter, Yersinia, and Brucella species. Viral causes includehepatitis viruses (hepatitis C more common than hepatitis B, andhepatitis B more common than hepatitis A), hepatitis virus vac-cines, HIV, parvovirus, and rarely cytomegalovirus, varicella, andinuenza.1

Retiform Purpura

Retiform purpura is due to occlusion of dermal and subcutaneousvessels, which causes a lace-like pattern of purpura, also known

as livedo reticularis. A complete reticulate pattern is not usuallyseen, but rather a puzzle piece-like or branching patternoccurs because of the angulated or sometimes serpentine patternof the purpura. Vascular invasion by fungi (Mucor, Aspergillus inimmunocompromised patients), gram-negative organisms (Pseu-domonas) that multiply in arterioles, and Strongyloides can causenoninammatory retiform purpura while vasculitis during BSI cancause inammatory retiform purpura.1

BOX 73-2. MajorNoninfectiousCausesofPurpura

PLATELET DISORDERSa

Thrombocytopenia

Decreased production of platelets: drugs, marrow inltration or

aplasia, toxins

Decreased survival of platelets: disseminated intravascular

coagulation, drugs, hemolyticuremic syndrome, idiopathic and

autoimmune thrombocytopenic purpura, prosthetic heart valve,hypersplenism, sequestration

Platelet dysfunction (inherited or acquired)

Thrombocytosis

VASCULAR DISORDERS

Noninammatory purpura

Amyloidosis, angiokeratoma corporis diffusum, antiphospholipid

syndrome, atrophie blanche, corticosteroid therapy, Cushing

disease, EhlersDanlos syndrome, fat embolism, hereditary

hemorrhagic telangiectasia, increased capillary pressure

(choking, coughing, forced restraint, tourniquet, vomiting),

Langerhans cell histiocytosis, progressive pigmentary

dermatosis (pigmented purpura), scurvy, trauma

Vasculitis and inammatory purpura

Behet disease, ChurgStrauss syndrome, cystic brosis,

dermatomyositis, drug- or toxin-induced hypersensitivity

vasculitis (nonsteroidal anti-inammatory drugs, penicillin,

quinidine, propylthiouracil, sulfonamides, allopurinol,

diphenylhydantoin, phenothiazines, thiazides), dysproteinemias

(Waldenstrm Adom hyperglobulinemic purpura, Waldenstrm

Adom macroglobulinemia, essential mixed cryoglobulinemia,

paraproteinemia), HenochSchnlein purpura, inammatory

bowel disease, Kawasaki syndrome, leukemia, lymphoma,

pityriasis lichenoides, polyarteritis nodosa, pyoderma

gangrenosum, rheumatoid arthritis, sarcoidosis, scleroderma,

primary and acquired immunodeciencies (graft-versus-host

disease, human immunodeciency virus infection), second

component of complement deciency, serum sickness,

Sjgren syndrome, Sweet syndrome (acute febrile neutrophilicdermatosis), systemic lupus erythematosus, urticarial vasculitis,

Wegener granulomatosis

COAGULATION DISORDERSb

Clotting factor deciencies

Depletion of clotting factors through increased use or proteolysis,

inadequate production, presence of inhibitor of coagulation,

synthesis of abnormal form of clotting factor

Thrombotic disorders

Antiphospholipid syndrome, antithrombin III deciency,

plasminogen deciency, protein C deciency, protein S

deciency

bPrimarily ecchymoses.

aPrimarily petechiae.

(dengue and other hemorrhagic fevers), and Rickettsia rickettsii(RMSF).1619

Ecchymosis occurring acutely and in an ill-appearing patientis called purpura fulminans. In this setting, ecchymoses rapidlyevolve, are usually symmetric in distribution, and develop necrotic

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