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Melissa A. Reyes and Lawrence F. Eichenfield

Purpura can be a significant finding, especially as it is associated with multiple infectious etiologies, some of which are lifethreatening. Purpura results from trauma to blood vessels in the skin leading to hemorrhage into the surrounding tissue. Vessel damage can be the result of direct trauma (physical, chemical, infectious/toxic), vessel occlusion, immune complex deposition, platelet depletion or dysfunction, or other conditions that cause vascular 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 discriminating among likely etiologies. Purpuric lesions can be divided into six subtypes based on size and morphology of the lesions1: petechiae, macular purpura, ecchymoses, palpable purpura, noninflammatory retiform purpura, and inflammatory retiform purpura.


Petechiae, macular purpura, and ecchymoses are all superficial flat cutaneous lesions of varying sizes, 4mm, 5 to 9mm, and 1cm, respectively. Palpable purpura is raised, partially blanching, erythematous to purple, typically round lesions. Retiform purpura appears lace-like in pattern as the affected vessels are larger and exist in the dermis and subcutis. Inflammatory retiform purpura initially is erythematous before evolving into purpura. All purpuric lesions share similar changes in color based on the age of the lesion. Lesions initially are bright red or deep red and become purple as the heme pigments break down and progress to green and yellow-brown before fading. The amount of time to fading depends on the amount of extravasated blood. Petechiae, macular purpura, and ecchymoses are considered macular or flat purpura and result from simple extravasation of blood into the skin. Histologically, there is minimal inflammation, in contrast to the inflammatory hemorrhage seen in microvascular occlusion or cutaneous small-vessel vasculitis, which

results in palpable purpura.1 Inflammatory purpura occurs secondary to occlusion by a clot with resulting ischemia and necrosis of the vessel, in the case of microvascular occlusion syndromes. Vasculitis is caused by immune complexes deposited on the vessel lumen, which attracts neutrophils that destroy the complexes as well as injure the vessel wall. Retiform purpura and inflammatory retiform purpura result from both occlusion and vasculitis, respectively, of larger, slow-flow vessels. In patients with septicemia, purpura can arise from five main etiologies: (1) disseminated intravascular coagulation (DIC) and coagulopathy, (2) direct vascular invasion and occlusion by organisms, (3) infective vasculitis, (4) emboli, such as seen with endocarditis, and (5) vascular changes due to toxins.2 Many infections are associated with thrombocytopenia with development of petechiae or ecchymoses, with or without DIC. Invasion of microorganisms into capillaries can occur especially with bloodstream infection (BSI) due to Neisseria meningitidis, Neisseria gonorrhoeae, and Pseudomonas aeruginosa (Figure 73-1). Diffuse vasculitis with pathologic evidence of Rickettsiae in vascular endothelial cells is seen with Rocky Mountain spotted fever (RMSF) and epidemic typhus. Immune mediated vasculitis is associated with a broad set of petechial rashes associated with atypical measles, hepatitis B, and chronic meningococcemia. Intravascular catheter-associated infections and acute and subacute endocarditis can manifest with infectious embolization, complicated by infarction, tissue hemorrhage, and necrosis. Endocarditis also can be associated with immune-mediated vasculitis and petechiae. The scarlatiniform petechial eruptions of Streptococcus pyogenes (group A streptococcus, GAS) are an example of toxin-mediated rashes, also known as toxic erythemas.

CAUSES OF PURPURA Petechiae and Macular Purpura

Petechiae are small, 4mm in diameter, non-blanching purpuric macules that can appear on the skin, conjunctiva, retina, and mucous membranes. Lesions of macular purpura are larger than
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PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION J Skin and Soft-Tissue Infections


Figure 73-1. Skin manifestations of meningococcemia. Rapidly progressive disease with first 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.)

petechiae but smaller than ecchymoses. Both are the result of extravasation of blood from capillaries. For the remainder of the chapter, petechiae will be used to include all macular purpuric lesions <1cm in size. Petechiae resolve in 2 to 3 days also but can evolve into macular purpura, ecchymoses, palpable purpura, vesicles, pustules, or necrotic ulcers, depending on the underlying etiology and clinical course. In certain cases, petechiae can be difficult to differentiate from telangiectases and angiomas. Because these latter lesions are not the result of extravasated blood, applying pressure with a glass slide to blanch the vessels (diascopy) can help differentiate petechiae from other vascular lesions. The appearance of petechiae or purpura in a febrile patient raises the concern for an infectious etiology (Box 73-1). Petechiae can occur in crops, are seen commonly in BSIs, and usually occur with fever and as an early clinical sign in BSI.3 When petechiae occur on the nail bed, they appear as red-brown, longitudinal discolorations under the nail plate and are called splinter hemorrhages.

Historically, the presence of fever and petechiae in a child required evaluation for meningococcal infection. Early studies focused on hospitalized children reported an incidence of meningococcal disease in 7% to 11% of children with fever and petechiae and a case-fatality rate of 10%.4 More recently, it has been recognized that bacterial causes of fever and petechiae are relatively uncommon.5,6 In a retrospective review of 129 hospitalized children with fever and petechiae, 20% had culture-proven bacterial infection, one-half of which was due to N. meningitidis (11%) and a smaller percentage due to Haemophilus influenzae type b (6%).7 The majority of cases, almost 60%, were attributed to viral causes, while the remainder was attributed to other infectious and noninfectious causes. A prospective study including 190 children hospitalized with fever and petechiae documented 7% with meningococcal disease and 10% with GAS disease.8 Three patients had clinical sepsis and purpura fulminans with negative blood cultures. In the study, children with invasive bacterial infections were more likely to appear ill, to have meningeal irritation, and to have petechiae below the nipple line. Non-bacteremic patients




BOX 73-1. Major Infectious Causes of Purpura in Children and Neonates

CHILDREN Bacteria Arcanobacterium haemolyticum, Bacteroides fragilis, Bartonella hensleae, Borrelia spp., Brucella spp., Campylobacter jejuni, Capnocytophaga canimorsus,a Enterococcus spp., Escherichia coli, Francisella tularensis, Haemophilus influenzae type b, Klebsiella spp., Leptospira spp., Listeria monocytogenes, Moraxella catarrhalis, Mycobacterium leprae, Mycobacterium tuberculosis, Neisseria meningitidis,a Neisseria gonorrhoeae,a Pseudomonas aeruginosa,a Salmonella typhimurium, Staphylococcus aureus, Streptobacillus moniliformis, 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 falciparum

Rickettsiae Ehrlichia canis, Ehrlichia chafeensis, Ehrlichia equi, Anaplasma phagocytophilum, Rickettsia akari, Rickettsia prowazekii (epidemic typhus),a Rickettsia rickettsii (Rocky Mountain spotted fever),a Rickettsia 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 immunodeficiency 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

Most common.

(15% with a confirmed viral etiology) had higher white blood cell counts (WBCs) and absolute band counts. Another prospective study attempted to capture a broader cohort of patients by evaluating 411 consecutive pediatric patients presenting to a hospital emergency department with both fever and petechiae.3 Of the 53 ill-appearing patients (toxic appearance, inconsolable crying or screaming, or lethargy), 6 had invasive bacteremial infection while none of the 357 well-appearing children had positive blood cultures or cerebrospinal fluid bacterial cultures. In this study of 411 patients with fever and petechiae, only 2 patients had N. meningitidis (0.5%), 2 had Streptococcus pneumoniae, and 1 had GAS invasive infection. The study also found that WBCs 15,000 was predictive of severe BSI. Thus, a febrile patient with petechiae who is well-appearing, has normal laboratory workup, petechiae above the nipple line, and documented streptococcal pharyngitis has low risk of invasive bacterial disease. Petechiae in febrile patients is more commonly associated with viral infections, given their high prevalence, but also because viruses tend to damage small cutaneous vessels.9 Petechiae on the palate are characteristic of streptococcal pharyngitis,10 but also can be seen in EpsteinBarr virus infection, Arcanobacterium haemolyticum pharyngitis, rubella, roseola, viral hemorrhagic fevers, thrombocytopenia, and palatal trauma.10 Palmar and plantar petechiae can be seen in the gloves and socks syndrome caused by parvovirus B19. In this condition, there is confluent erythema of the distal extremities with pinpoint macules evolving into petechiae on the palms and soles with concurrent fever and leukopenia.11 Parvovirus B19 also has been reported to cause a generalized petechial eruption,12 and petechiae in a bathing suit distribution.13 Clusters of patients with generalized petechial eruptions are reported during community outbreaks of erythema infectiosum, apparently associated with the viremic phase of parvovirus B19 infection.14 Other reported infectious causes of generalized petechiae include scarlet fever, RMSF, para influenza, influenza, respiratory syncytial virus, enterovirus,

rotavirus, atypical measles, rubella, dengue, and adenovirus infections.6 Petechiae or purpura also can be due to noninfectious causes, such as secondary to drug eruptions, acute leukemia,6 low platelet count, and mechanical causes (Box 73-2). Severe coughing or vomiting can increase intrathoracic pressure, causing petechiae in areas perfused by the superior vena cava, approximately corr esponding to skin above the nipple line. This distribution of petechiae is not always benign a reported 25% of patients with fever and petechiae confined to the upper torso had bacterial infection in one study.7 Petechiae also can form distal to tourniquet placement and are of no clinical significance without other findings. In contrast, the tourniquet test can cause distal petechiae in patients with dengue fever and is positive in most patients with dengue hemorrhagic fever.15 In newborns, petechiae can occur at sites of pressure as they progress through the birth canal, but petechiae also can result from acquired infection or maternal antiplatelet antibodies; thus appropriate evaluation should be performed. Older children with petechiae and no fever should be evaluated for blood dyscrasias.

Ecchymoses are purpuric flat patches on the skin, commonly known as bruises. Ecchymoses typically are 1cm in size and are caused by a greater volume of extravasated blood than in petechiae. Thus, ecchymoses tend to take longer to resolve (1 to 3 weeks). Petechiae in a patient with an underlying coagulopathy can quickly evolve into ecchymoses, sometimes within minutes. Ecchymoses resulting from infection are uncommon in children. When ecchymoses occur, they are most frequently due to N. meningitidis BSI with coagulopathy.16 Other reported causes include other gram-negative bacteria, gram-positive bacteria (Staphylococcus aureus, S. pyogenes, and S. pneumoniae), viruses
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PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION J Skin and Soft-Tissue Infections

BOX 73-2. Major Noninfectious Causes of Purpura

PLATELET DISORDERSa Thrombocytopenia Decreased production of platelets: drugs, marrow infiltration 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 Noninflammatory 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 inflammatory purpura Behet disease, ChurgStrauss syndrome, cystic fibrosis, dermatomyositis, drug- or toxin-induced hypersensitivity vasculitis (nonsteroidal anti-inflammatory drugs, penicillin, quinidine, propylthiouracil, sulfonamides, allopurinol, diphenylhydantoin, phenothiazines, thiazides), dysproteinemias (Waldenstrm Adom hyperglobulinemic purpura, Waldenstrm Adom macroglobulinemia, essential mixed cryoglobulinemia, paraproteinemia), HenochSchnlein purpura, inflammatory bowel disease, Kawasaki syndrome, leukemia, lymphoma, pityriasis lichenoides, polyarteritis nodosa, pyoderma gangrenosum, rheumatoid arthritis, sarcoidosis, scleroderma, primary and acquired immunodeficiencies (graft-versus-host disease, human immunodeficiency virus infection), second component of complement deficiency, serum sickness, Sjgren syndrome, Sweet syndrome (acute febrile neutrophilic dermatosis), systemic lupus erythematosus, urticarial vasculitis, Wegener granulomatosis COAGULATION DISORDERSb Clotting factor deficiencies 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 deficiency, plasminogen deficiency, protein C deficiency, protein S deficiency

patches and eschars.3 Purpura fulminans is caused by abnormalities in coagulation secondary to infection. Purpura can occur 7 to 10 days after an otherwise benign infection (idiopathic purpura fulminans) and in the setting of acute infection such as gramnegative infection caused by N. meningitidis.16 Idiopathic purpura fulminans has been associated with varicella, scarlet fever, streptococcal tonsillopharyngitis, viral exanthem, rubella, measles, upper respiratory tract infection, and gastroenteritis.16 A variant called symmetric peripheral gangrene results in ischemic necrosis of the distal parts of two or more extremities without large-vessel obstruction. This variant is associated with higher mortality and morbidity, such as amputation, in patients with purpura fulminans.20 Both purpura fulminans and symmetric peripheral gangrene occur more frequently in infants and children than in older individuals.2 In neonates, purpura fulminans can be a manifestation of inherited homozygous protein C, or rarely protein S, deficiency. In older children, BSIs in patients with these underlying deficiencies (as well as properdin deficiency, splenic dysfunction, or neutropenia) can lead to purpura fulminans.

Palpable Purpura
Unlike, petechiae and ecchymoses, palpable purpura are raised purpuric papules and plaques that can range in size from a few millimeters to a few centimeters. Palpable purpura favors dependent areas such as the lower extremities, but in the supine patient can occur on the back, buttocks, and distal arms. Palpable purpura can evolve into nodular, vesicular, pustular, necrotic, or ulcerative lesions. Palpable purpura is classically associated with leukocytoclastic vasculitis, an inflammatory process injuring the vessel.21 Histopathologically, fibrin deposition in vessel walls, neutrophilic debris, and perivascular lymphocytes are present. Palpable purpura also can occur with S. aureus BSI or bacterial endocarditis as the result of infectious microemboli occluding the vascular lumen. Osler nodes and Janeway lesions found in bacterial endocarditis are types of microembolic-induced palpable purpura. Osler nodes are tender nodules on the palms, soles, and pads of the fingers/ toes. Janeway lesions are nontender, purpuric macules, papules or nodules usually on the palms and soles. Lesions similar to Osler nodes have been reported in typhoid fever, polyarteritis nodosa, systemic lupus erythematosus, ChurgStrauss syndrome, mixed cryoglobulinemia, and Wegener granulomatosis.1,2 Palpable purpura can have a variety of causes, including infection (10% to 15%), drug exposure, immunization, and autoimmune disease. The most common infectious causes of palpable purpura include N. meningitidis, S. aureus, and N. gonorrhoeae but cases have been reported due to Mycobacterium, Rickettsia, Mycoplasma, and rarely Bartonella, Treponema pallidum, Salmonella, Campylobacter, Yersinia, and Brucella species. Viral causes include hepatitis viruses (hepatitis C more common than hepatitis B, and hepatitis B more common than hepatitis A), hepatitis virus vaccines, HIV, parvovirus, and rarely cytomegalovirus, varicella, and influenza.1

Retiform Purpura
Retiform purpura is due to occlusion of dermal and subcutaneous vessels, which causes a lace-like pattern of purpura, also known as livedo reticularis. A complete reticulate pattern is not usually seen, but rather a puzzle piece-like or branching pattern occurs because of the angulated or sometimes serpentine pattern of the purpura. Vascular invasion by fungi (Mucor, Aspergillus in immunocompromised patients), gram-negative organisms (Pseudomonas) that multiply in arterioles, and Strongyloides can cause noninflammatory retiform purpura while vasculitis during BSI can cause inflammatory retiform purpura.1

Primarily petechiae. b Primarily ecchymoses.

(dengue and other hemorrhagic fevers), and Rickettsia rickettsii (RMSF).1619 Ecchymosis occurring acutely and in an ill-appearing patient is called purpura fulminans. In this setting, ecchymoses rapidly evolve, are usually symmetric in distribution, and develop necrotic




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