Pyoderma gangrenosum is an idiopathic inflammatory skin condition characterized by early follicular erythematous papules and pustules or tender, fluctuant nodules with surrounding erythema that spread peripherally and ulcerate, surrounded by a violaceous rim (see Fig. 122–7).66 In 50 percent of cases of pyoderma gangrenosum, there is an associated disorder, such as inflammatory bowel disorders (classically ulcerative colitis), arthritis, hematologic disorders, and solid tumors.67 All four main clinical variants (ulcerative, pustular, bullous, and vegetative) share the histopathologic finding of a sterile abscess with central necrotizing neutrophilic infiltration, and a surrounding perivascular and intramural lymphocytic infiltration. First-line treatment involves wound care and immunosuppressants, such as glucocorticoids, cyclosporine, dapsone, azathioprine, and infliximab.68
Also referred to as acute, febrile neutrophilic dermatosis, Sweet syndrome is characterized by the acute manifestation of painful erythematous and violaceous papules, nodules, and plaques accompanied by fever and elevated neutrophil count (Fig. 122–10).69 These papules, which most commonly appear on face, neck, and upper extremities, present a central yellowish discoloration and tend to coalesce, forming well-circumscribed, irregularly bordered plaques. Other organs can be involved, including the central nervous system, kidneys, lungs, and bones.70 Classically more prominent in middle-aged women, this syndrome associates a complex cytokine dysregulation. Other manifestations include respiratory and urinary infections and autoimmune disorders (including rheumatoid arthritis), SLE, inflammatory bowel disease). Histologic analysis shows a distinct nonvasculitic neutrophilic infiltrate in the superficial dermis with dermal edema. Systemic glucocorticoid treatment is the standard treatment, while clofazimine, dapsone, colchicine, indomethacin, and cyclosporine have also been used successfully.71
Sweet syndrome. The lesions are characterized by nonvasculitic neutrophilic infiltration, commonly on the face.
Besides its classification as a neutrophilic dermatosis, Behçet disease is also an inflammatory disorder that affects multiple organ systems. Clinical features include chronic and relapsing cutaneous manifestations, such as palpable purpura, infiltrative erythema, and papulopustular lesions, as well as oral mucosal and genital ulcers, arthralgias, and gastrointestinal and central nervous system involvement.72 Genetic studies show an association between Behçet disease and human leukocyte antigen B51.73 Histologic features include leukocytoclastic or lymphocytic vasculitis, hence its previous classification as a vasculitis. Antitumor necrosis factor-α directed therapies (infliximab, etanercept), interferon-α, immunosuppressive and immunomodulatory agents such as thalidomide, intravenous immunoglobulin, and even stem cell transplantation are used in Behçet disease.74,75
Serum sickness reflects the clinical manifestations of immune complex formation and deposition. Cutaneous lesions such as urticarial and morbilliform eruptions predominate, though palpable purpura and erythema multiforme can also be encountered. Serum sickness associated with infection or medical therapy can result in specific characteristic lesions. The use of antithymocyte globulin for marrow failure, for instance, results in 75 percent of patients developing serpiginous bands of erythema and purpura on the sides of their hands and feet (Fig. 122–11).76 These characteristic lesions consistently appear 1 to 2 days prior to the onset of systemic symptoms of serum sickness, which include fever and malaise. Analysis of biopsies by direct immunofluorescence reveals deposition of IgM, IgE, IgA, and C3. This deposition appears to activate neutrophils leading to release of lysosomal enzymes and the development of dermal vasculitis.77
Serum sickness caused by antithymocyte globulin. The lesions consist of immunoglobulins and neutrophils.
Henoch-Schönlein purpura (HSP), is a predominantly pediatric vasculitic syndrome characterized by the acute onset of abdominal pain and lower-extremity eruption of diffuse urticarial plaques and palpable purpura. It was first described in 1801 by Dr. William Heberden.78 HSP predominantly affects patients 2 to 20 years of age, 90 percent of patients being younger than 10 years old.79 Several environmental triggers precede HSP onset, such as viral (upper respiratory infections, hepatitis B virus, HCV, parvovirus B19, and HIV) and bacterial (Streptococcus spp., Staphylococcus aureus, and Salmonella spp.) infections in children. Adult disease may be precipitated by medications (nonsteroidal antiinflammatory drugs [NSAIDs], angiotensin-converting enzyme inhibitors, and antibiotics), food allergies, vaccinations, and insect bites.80 The pathogenesis of HSP leukocytoclastic vasculitis is complex. It appears to involve IgA1 immune complex and complement deposition on vessel walls. Elevated values of thrombomodulin, tissue plasminogen activator, and plasminogen activator inhibitor-1 appear to correlate with endothelial injury and fibrinolytic activity in the acute phase of HSP.81
Cutaneous eruptions often begin acutely as urticarial papules and plaques evolving to petechiae, ecchymoses, and palpable and nonpalpable purpura over the lower extremities and buttocks (Fig. 122–12). Palpable purpura is a universal finding, being present in one series in 98.6 percent of patients.82 Clinically, lesions may take the form of retiform or patterned purpura, presence of a retiform edge of various inflammatory lesions, or skin necrosis.83 Other common manifestations include localized subcutaneous edema, glomerulonephritis, arthritis, and (severe) abdominal pain.
Henoch-Schönlein purpura. Urticarial papules and plaques can evolve into palpable purpura. The lesions are characterized by leukocytoclastic vasculitis.
In spite of its chronic relapsing pattern, the long-term evolution is benign in the majority of patients.82 The self-limited course of HSP may be contributed by an enhanced apoptosis of immune cells, which diminishes the severity of the acute inflammatory response.84 Consequently, treatment is frequently supportive. Immunosuppressive drugs, including glucocorticoids, are typically reserved for cases with renal involvement.78 Persistent purpura, severe abdominal symptoms, and diminished plasma coagulation factor XIII activity are predictive of renal involvement, requiring initiation of glucocorticoids.85
Careful analysis of skin lesions of infectious etiology can provide important hints toward identifying the responsible pathogen. Purpura can arise through a variety of pathophysiologic mechanisms associated with infection: (1) vascular effects of toxins, (2) septic emboli, (3) direct invasion of vessels with subsequent vascular occlusion, and (4) immune complex formation.86 Although the morphology of such purpuric lesions may be nonspecific, many pathogens lead to characteristic findings.
Gram-positive and Gram-negative infections may give rise to a large array of purpuric patterns depending on organism virulence and patient immune status. Skin lesions range from simple macules and papules to bullae, ulcers, and necrosis.
Purpura fulminans, a hemorrhagic infarction syndrome consisting of disseminated intravascular coagulation (DIC), acral purpura, and shock may manifest in the setting of bacterial sepsis with encapsulated organisms (Chap. 129).87 Most commonly seen in immunocompromised hosts, purpura fulminans can also be produced by bacterial pathogens in immunocompetent patients.88 This syndrome can be associated with asplenism or functional hyposplenism.89 Although most patients are younger than the age of 10 years, adults can also be affected.90 Retiform purpuric lesions result from fibrin-induced microvascular occlusion, and commonly have a rapid evolution toward necrosis and eschar formation. Adult patients with purpura fulminans as a result of meningococcemia have significantly depressed proteins C and S levels, which may explain the tendency toward fibrin deposition and development of cutaneous ischemic lesions, such as symmetrical peripheral gangrene.91 Facial purpura and livedo reticularis may be seen during fulminant pneumococcal infection in asplenic patients.92 Postinfectious purpura fulminans may also occur after infections with streptococci or varicella zoster,39 and was associated with development of anti–protein S antibodies. Another characteristic lesion is the development of ecthyma gangrenosum in immunocompromised hosts (Fig. 122–13).
Ecthyma gangrenosum. Associated with Gram-negative sepsis, disseminated fungal infection, or other serious infectious diseases, these hemorrhagic bullae evolve from erythematosus plaques, both of which are shown here.
In children, more than 20 percent of cases admitted to the hospital with petechiae and fever were found to have invasive bacterial infections (Neisseria meningitidis, Haemophilus influenzae type B, and Streptococcus pneumoniae), and approximately 7 percent of cases were diagnosed with meningiococcemia.93 Sepsis secondary to N. meningitidis can produce a characteristic pattern of purpuric lesions. Erythematous papules can quickly progress to numerous petechiae combined with violaceous reticular purpuric lesions.94 A retiform aspect can be seen during progression of the infection to purpura fulminans. The finding of petechiae on a patient with symptoms and signs of bacterial meningitis is predictive of meningococcal meningitis.95
Borrelia burgdorferi infection gives rise to erythema migrans, the characteristic lesion of Lyme disease. Skin lesion is classically a nonpruritic annular erythematous expanding plaque, occasionally including a central hemorrhagic bullae (Fig. 122–14). Other reported cutaneous findings associated with this infection include papular urticaria, Henoch-Schönlein–like purpura, and morphea.96
Lyme disease. Erythema migrans with a central hemorrhagic bulla is the characteristic lesion.
Purpuric lesions can also be a manifestation of a viral infection. For example, the adenoviruses and enteroviruses have been associated with fever and petechiae in children.97 Similarly, parvovirus B19 can produce a syndrome of petechiae or purpuric papules progressing to confluent purpuric papules or plaques in a sharply demarcated glove-and-sock distribution.98 In addition to the cutaneous findings, the “gloves-and-socks syndrome” is characterized by fever and occasionally leukopenia, and can also be produced by the measles virus.99 Purpura in the axilla and chest also has been described during parvovirus B19 infection (Fig. 122–15).100 Histopathologic analysis of these purpuric lesions show an evolution from superficial perivascular lymphocytic infiltrate to a dermatitis accompanied by necrotic keratinocytes and hemorrhage.101 Hantavirus causes a syndrome of hemorrhagic fever and renal failure accompanied by headache, cutaneous and mucosal petechiae, and purpuric lesions.102
Parvovirus B19 erythema and petechiae. The classic slapped-cheek rash on the face can appear on other areas of the body, sometimes punctuated with petechiae of unclear etiology.
Fungal infections in the immunocompromised population are a growing medical issue, given the increasing number of patients receiving immunosuppressants for organ transplantation or malignancy. Disseminated or locally invasive infections can give rise to petechiae and hemorrhagic necrosis. Common fungal pathogens in disseminated disease includes Candida (Fig. 122–16), Aspergillus (Fig. 122–17), Histoplasma, and Fusarium.103 Disseminated candidiasis can manifest as ecthyma gangrenosum in immunocompromised patients, suggesting consideration for a skin biopsy.104 Cutaneous aspergillosis can also occur in immunocompetent individuals, and manifest as eruptive maculopapules, necrotizing plaques, or subcutaneous granulomas.105
Disseminated candidiasis. Purpuric nodules in a patient with acute myelogenous leukemia. Ecthyma gangrenosum can also occur in this disease.
Aspergillosis: primary cutaneous inoculation from contaminated armboard.
Immunocompromised patients are at risk of developing purpuric lesions secondary to parasitic infections, such as Pneumocystis jiroveci. Disseminated strongyloidiasis is characterized by larva currens, a serpiginous urticarial eruption caused by the migration of filiform larvae through the dermis.106 Other cutaneous lesions include generalized petechiae and widespread reticular purpura of the arms, legs, and abdomen (Fig. 122–18), with a characteristic thumbprint periumbilical distribution.107
Infections caused by Rickettsia species can also lead to purpuric lesions as a result of their direct invasion of endothelial cells. This is followed by medial and intimal necrosis with subsequent thrombosis and hemorrhage.86 Cutaneous lesions in Rocky Mountain spotted fever range from petechiae to acral purpuric lesions and hemorrhagic necrosis (Fig. 122–19). Maculopapular and vesicular rashes along with lower-extremity eschars produced by Rickettsia africae may also occur in travelers to sub-Saharan Africa.108
Rocky Mountain spotted fever. This rickettsial disorder can present with petechiae on the dorsum of the hand.
Erythema multiforme (EM) is a cutaneous disorder characterized by the development of crops of well-demarcated, erythematous target lesions with central clearing,109 most commonly representing a hypersensitivity reaction triggered by infection or drug exposure (Fig. 122–20). The severity of this disorder ranges from mild (EM minor), to severe (EM major or Stevens-Johnson syndrome). EM has been reported to be triggered by a number of viruses (most commonly herpes simplex, but also adenovirus, cytomegalovirus, and HIV),110,111 and medications (sulfonamides, penicillins, bupropion, phenylbutazone, phenytoin, NSAIDs, adalimumab).112 A cellular allergic reaction coupled with impaired histamine metabolism because of a decrease in histamine-N-methyltransferase activity may be causative.113 Treatment for mild cases is supportive, while the use of glucocorticoids is warranted in severe cases.
Erythema multiforme. This hypersensitivity reaction, usually to one of various drugs, characteristically presents with targetoid lesions.
CUTANEOUS POLYARTERITIS NODOSA
Classic polyarteritis nodosa represents a systemic small- and medium-size vessel vasculitis most commonly involving the skin, heart, liver, and kidneys. A relatively benign cutaneous form exists that lacks significant systemic involvement114 and consistently involves the deep dermis and panniculus.115 Lesions develop as tender erythematous nodules116 with occasional retiform purpura and livedo reticularis localized to the upper and lower extremities, but the trunk, neck, and face can also be involved (Fig. 122–21). The duration of lesions varies from days to a few months.115 Histologic analysis of involved skin shows deep dermal artery necrosis with infiltration of neutrophils and eosinophils, and fibrin deposition. Treatment typically involves the use of NSAIDs and glucocorticoids, alone or in combination. Some cases of cutaneous polyarteritis nodosa are reported to have progressed on long-term followup,117 hence the need for close monitoring of patients diagnosed with an apparently benign, cutaneous form of disease.118
Polyarteritis nodosa. Acral purpura accompanying tender erythematous nodules.
Most common vasculitis associated with neoplasia are cutaneous leukocytoclastic vasculitis, paraneoplastic vasculitis, and HSP.119,120 Paraneoplastic vasculitis is most commonly associated with hematologic neoplasia,121 and is commonly a result of paraproteinemia. However, an association with carcinomas of the lung, colon, breast, and cervix has been observed.122,123,124 Solid tumors predominate in certain types of paraneoplastic vasculitis, such as the HSP.125 Cutaneous manifestations include petechiae, urticaria, and palpable purpura, and are often intensely pruritic. In hematologic disorders, these lesions often precede the development of malignancy by an average of 10 months.126 Histologic examination shows necrotizing leukocytoclastic vasculitis with neutrophilic infiltration.
A long list of drugs are reported to cause a vasculitis resulting in erythematous purpuric lesions. One-fifth of all cutaneous vasculitis are produced by drugs, including allopurinol, cefaclor, colony-stimulating factors, d-penicillamine, furosemide (Fig. 122–22), hydralazine, isotretinoin, methotrexate, phenytoin, minocycline, and propylthiouracil.127
Leukocytoclastic vasculitis secondary to furosemide.
ANTINEUTROPHIL CYTOPLASMIC ANTIBODY–ASSOCIATED VASCULITIS
This small- to medium-vessel vasculitis most commonly affects upper and lower respiratory tracts and kidneys and is strongly associated with the development of circulating antineutrophil cytoplasmic antibodies (ANCAs).128 Skin involvement has been reported in 35 to 50 percent of cases.129 Cutaneous manifestations include a combination of palpable purpura, oral ulcers, and erythematous cutaneous and subcutaneous nodules (Fig. 122–23).130 Necrotizing vasculitis, palisading granulomas, and granulomatous vasculitis are characteristic histologic findings.131
Churg-Strauss syndrome (CSS) is characterized by granulomatous inflammation in the lungs associated with asthma and eosinophilia.132 Cutaneous findings such as ulcers, papules, palpable purpura, cutaneous nodules, and infarcts of fingers and toes are encountered in 50 to 80 percent of cases.130 CSS limited to the skin was described.133 Eosinophilia accompanies elevated IgE levels and a positive perinuclear ANCA. Granulomatous inflammation and necrotizing vasculitis of small- to medium-size blood vessels are present histologically.131