Most wounds are diagnosed as arterial, venous, pressure, neuropathic, surgical, or burn and are treated according to the principles that have been discussed in the previous chapters. If a wound has a different appearance or does not respond to standard care, the clinician is challenged to determine either the factors that are inhibiting healing or to consider a different diagnosis. This chapter reviews the basic morphology of skin disease, red flags of atypical wounds, and characteristics of different diagnostic categories. The pathophysiology, clinical presentation with photographs, differential diagnosis, medical management, and wound management of each wound category are provided to assist the clinician in making sound clinical decisions.

The first indication that a wound is atypical is that little signal in the clinician’s instinct that says, “This is just not quite what it looks to be.” And usually it behooves the clinician to follow those instincts, to at least rule out an atypical diagnosis, and at most to make a differential diagnosis that completely changes the care plan and results in wound healing. TABLE 8-1 provides a list of characteristics that suggest a wound does not fall into the typical categories.^1,2

Many diseases will cause changes in the skin that are predictable and/or suggestive of a certain diagnosis. TABLE 8-2 provides a list of terms and definitions of integumentary characteristics (based on size, texture, and color) that are used to describe abnormal skin appearance.² These terms are used in the following descriptions of atypical wound clinical presentations.

The atypical wounds discussed in this chapter can be categorized into the following groups: allergic reactions, autoimmune disorders, Herpes virus, infected wounds (bacterial and fungal), malignant wounds, and miscellaneous. Some categories will have common signs and symptoms and yet discrete but definite differences, and similar treatment strategies. The list is by no means exhaustive— that would be beyond the scope of this chapter!

Allergic reactions can be either contact (the offending substance touches the skin) or systemic (the offending substance is injected or ingested). In either case, the substance, termed an antigen, causes an immunological response that results in the production of antibodies and a subsequent inflammatory response. The reaction can actually cause wounds to develop, or in the case of existing wounds, prevent healing from progressing.

Contact Dermatitis

Pathophysiology

Contact dermatitis can be either allergic or irritant, depending on the host immune system and the concentration of the irritant.³ In allergic contact dermatitis, the offending substance or contact allergen (ie, a nonprotein chemical called hapten) reacts with the skin barrier to activate the innate immune response. The allergen binds to the carrier protein and creates a sensitizing antigen, the Langerhans cells carry the antigen to the T cells (specifically CD8⁺ T cells that are primed in lymphoid organs during sensitization and recruited in the skin upon re-exposure to the hapten),⁴ and the T cells cause the release of lymphokines.⁵ Thus develops the inflammatory symptoms of erythema, rash, itching, and in some cases vesicular lesions, followed by scaling and dry skin (FIGURES 8-1 and 8-2).⁴ The allergic response can be either immediate or delayed, and can involve both the skin and the subcutaneous tissue. Usually the response increases in severity after repeated exposures; sensitization upon first exposure may last 10–15 days with no clinical consequence and upon re-exposure clinical symptoms may appear within 24–72 hours.⁴

The irritant type of contact dermatitis is not an immunological response but a reaction to a caustic substance and depends on the concentration of the substance, for example, a chemical or topical liquid. Some antiseptics, eg, acetic acid or Dakin’s solution, may cause irritant contact dermatitis if used repeatedly or in strong concentrations.

Patients with chronic leg wounds have an increased susceptibility to allergic contact dermatitis,⁶ especially if they are being treated with compression therapy, a condition sometimes referred to as stasis dermatitis. If contact dermatitis is suspected or if the patient reports a history of allergies to other substances, patch testing can be performed to confirm the diagnosis.⁷ TABLE 8-3 provides a list of common allergens for patients who have wounds.

Clinical Presentation

Signs of dermatitis include erythema, weeping, scaling of the periwound area, and itching. It can occur at any age; however, in the older population it can easily be misdiagnosed. In severe cases, shiny skin and alopecia may develop. A visible determining factor is that the symptoms occur only in areas of direct contact with the irritating material.

Differential Diagnosis

• 
  

  Cellulitis

  
  
• 
  

  Vasculitis

  
  
• 
  

  Atopic dermatitis (chronic dermatitis associated with asthma and inhalant allergies; hereditary)

  
  
• 
  

  Nummular dermatitis (distinct round or oval patches that begin as blisters, often after skin injury; a result of sensitivity to applied topical ointments or metals)

Medical Management

The most important component of treating any dermatitis is the identification and discontinuation of the medication, dressing, or other substance that might be responsible for contact dermatitis. In the acute phase, low-dose topical steroids and antihistamines may help decrease inflammation and discomfort; systemic steroids may be beneficial if there is an extensive area of contact dermatitis. Antibiotics are indicated only if there is evidence of secondary infection.⁵

Wound Management

Patients usually require only supportive care and discontinuation of the irritating topical agent and, in the case of an existing wound, substitution of a dressing that has fewer or no allergens. Nonadherent hypoallergenic dressings are recommended for care of open lesions. Most products that are used for wound care are available in latex-free forms, as both patients and clinicians can suffer from latex allergies. The skin will usually heal in 2 to 3 weeks.

Drug-Induced Hypersensitivity Syndrome

Pathophysiology

Drug-induced hypersensitivity syndrome (DIHS) is an immunologic response to a drug received either orally, by injection, or by IV. Although not fully understood, the process is similar to what occurs with skin allergies except that the immune response is activated by the causative agents and their metabolites rather than by a direct effect on the keratinocytes.⁸ There are numerous syndromes based on severity, types of lesions, and underlying diseases processes; however, all of them produce generalized (rather than localized) skin lesions and systemic symptoms (TABLE 8-4).

Adverse drug reactions have been classified as Type A: those that are predictable and dose-dependent reactions, including overdose, side effects, and drug interactions (eg, a gastrointestinal bleed following treatment with non-steroidal anti-inflammatory drugs [NSAIDs]); and Type B, those that are unpredictable, more likely to be dose independent, and may include immunologically mediated drug hypersensitivity or non-immune-mediated reactions, thus being considered allergic reactions.⁹ The most commonly reported medications that cause DIHS are listed in TABLE 8-5.

Clinical Presentation

Symptoms include generalized rash (with or without vesicles) and any of the following: local eruptions, fever, lymphedema, mucosal lesions, conjunctivitis, and epidermal sloughing (FIGURE 8-3). Onset is usually 1–3 weeks after the first exposure to the offending drug, beginning with a fever or sore throat and progressing to the cutaneous/mucosal involvement. In the younger adult population (20–40 years), the syndrome is termed erythema multiforme.

Differential Diagnosis

• 
  

  Infection

  
  
• 
  

  Vasculitis

  
  
• 
  

  Contact dermatitis

Medical Management

Medical management begins with identification and cessation of the causative agent, which is usually the last one that the patient has initiated taking. Depending on the severity of the symptoms, corticosteroids are used to prevent progression and relieve symptoms, and supportive care is provided in an intensive care unit or a burn unit for more severe cases.

Wound Management

In minor cases, cessation of the medication may be sufficient to reverse symptoms and no wound care is needed. In more severe cases with epidermal sloughing, treatment is similar to that of a deep superficial burn except that debridement of the detached epidermal tissue is usually not advisable because of potential loss of fluids. Nonadherent antimicrobial dressings are recommended to help prevent infection and to avoid further skin tearing with dressing changes. Prevention of fluid loss and infection are paramount, and as the patient improves, dressings to promote re-epithelialization are advised.

Scleroderma

Pathophysiology

Scleroderma (systemic sclerosis) is a chronic autoimmune disease of unknown etiology that usually affects women between the ages of 30 and 50 and results in extensive scarring and disfigurement as it progresses.¹⁵ The skin becomes thick and hard (sclerotic) with a buildup of scar tissue, resulting in loss of skin elasticity, joint range of motion, muscle strength, mobility, and function. There is also damage to internal organs such as the heart and blood vessels, lungs, esophagus, kidneys, and other organs, which is a major factor in determining prognosis for each individual patient.¹⁶

Recent studies suggest both a genetic susceptibility and a predisposition to scleroderma. The most robust associations include genes for B- and T-cell activation and innate immunity; other pathways include genes involved in extracellular matrix deposition, cytokines, and autophagy (the natural, regulated mechanism of cellular activity that allows orderly degradation and recycling of cellular components).¹⁷ The sequence of scleroderma involves the following: arteriole endothelial cells die by apoptosis and are replaced by collagen; inflammatory cells infiltrate the arteriole and cause more damage, resulting in the scarred fibrotic tissue that is the hallmark of scleroderma.^18,19

Clinical Presentation

The two main types of scleroderma are localized and systemic. Localized is further differentiated into morphea with discolored patches on the skin, and linear with streaks or bands of thick hard skin on the arms and legs. Localized scleroderma only affects the skin and not the internal organs. Systemic scleroderma can be limited (affecting only the arms, hands, and face) or diffuse (rapidly progressing, affecting large areas of the skin and one or more organs). Thirty-five percent of the patients with scleroderma develop skin ulcers that are painful, refractory, and usually over bony prominences (FIGURE 8-4). CREST, a limited systemic form of scleroderma, is described in TABLE 8-6; however, it does not reflect the internal organ involvement that may also be present. In addition, patients may experience joint pain, fatigue, depression, reduced libido, and altered body image. A third type is limited systemic sclerosis, also known as sine scleroderma, which includes Raynaud’s phenomenon and internal involvement without sclerotic skin.²⁰

Differential Diagnosis

Other systemic autoimmune diseases, for example, systemic lupus erythematosus and rheumatoid arthritis.

Medical Management

Because the etiology is unknown, treatment of scleroderma centers on alleviating symptoms, preserving skin integrity with protective strategies, preventing infection, and controlling inflammation to minimize severity.²¹ d-penicillamine, colchicine, PUVA, relaxin, cyclosporine, and omega-oil derivatives have been used to treat the skin fibrosis. Immunosuppressive agents such as methotrexate and cyclosporine have been used to treat the systemic disease, and plasmapheresis can be used in severe cases.^1,22

Wound Management

Local wound care is tedious because of the high pain levels associated with open wounds on sclerotic skin, and wound healing is impeded by the scarring of the subcutaneous tissue and the immunosuppressive medications. Enzymatic debridement with collagenase may be helpful with painful wounds, as well as occlusive dressings to help with autolytic debridement. Nonadherent dressings are advised both to minimize pain and avoid tearing skin upon removal. Silicone-backed foam dressings are useful as secondary dressings. Patient education regarding protective measures for skin is crucial, for example, using gloves when doing housework, avoiding caustic liquids, wearing warm clothes to avoid Raynaud’s phenomenon, and using moisturizers to avoid dry skin. As the disease progresses, custom shoes with molded inserts to accommodate changes in the shape of the feet can help maintain independent ambulation.

Vasculitis

Pathophysiology

Vasculitis is an inflammatory disorder of blood vessels, which can ultimately result in organ damage, including the skin. The etiology is often idiopathic—it is a reaction pattern that may be triggered by certain comorbidities including underlying infection, malignancy, medication, and connective tissue diseases such as systemic lupus erythematosus (FIGURE 8-5). Circulating immune complexes (antibody/antigen) deposit in the blood vessel walls, causing inflammation that may be segmental or involve the entire vessel. At the site of inflammation, varying degrees of cellular inflammation and resulting necrosis or scarring occur in one or more layers of the vessel wall, and inflammation in the media of the muscular artery tends to destroy the internal elastic lamina.^23,24

Leukocytoclastic vasculitis, a histopathologic term used to describe findings in small-vessel vasculitis, refers to the breakdown of inflammatory cells that leaves small nuclear fragments in and around the vessels. Vasculitic inflammation tends to be transmural, rarely necrotizing, and nongranulomatous. Resolution of the inflammation tends to result in fibrosis and intimal hypertrophy, which in combination with secondary clot formation can narrow the arterial lumen and account for the ischemia or necrosis of the tissue supplied by the affected vessels.²⁵ Clinical symptoms (ie, tissue loss) depend on the artery or arteries that are involved and the extent of lumen occlusion. Cutaneous vasculitis usually occurs in the lower extremities and feet. Vasculitic syndromes based on the affected vessels are listed in TABLE 8-7.

Clinical Presentation

Clinical presentation of cutaneous vasculitis, which varies depending on the arterial involvement, includes palpable purpura, livedo reticularis, pain, skin lesions with or without nodules, and tissue necrosis. It may present as one large necrotic lesion or several small lesions, but all are full thickness after debridement. Systemic symptoms may also be present and usually relate to kidney, lung, or gastrointestinal tract involvement. On some occasions, signs of vasculitis in other organs may appear at the same time that skin lesions appear (FIGURES 8-6 and 8-7). One very distinctive characteristic for differential diagnosis from chronic venous wounds is the exquisite pain that occurs with vasculitis, making the initial local treatment very tedious.

Differential Diagnosis

• 
  

  Giant cell arteritis

  
  
• 
  

  Primary angiitis of the CNS

  
  
• 
  

  Takayasu arteritis

  
  
• 
  

  Churg–Strauss syndrome

  
  
• 
  

  Immune complex–associated vasculitis

  
  
• 
  

  Microscopic polyangiitis

  
  
• 
  

  Polyarteritis nodosa

  
  
• 
  

  Rheumatoid arthritis

  
  
• 
  

  Wegener granulomatosis

  
  
• 
  

  Henoch–Schönlein purpura

  
  
• 
  

  Chronic venous insufficiency wounds

Medical Management

Treatment of any vasculitis depends on the etiology, extent, and severity of the disease. Ultrasound can be used to detect abnormalities in medium- and large-vessel disease, and to determine distribution or organ involvement in small vessel vasculitides.²⁶ For secondary vasculitic disorders, treating the underlying comorbidity (eg, infection, drug use, cancer, or autoimmune disorder) is crucial.

Remission of life- or organ-threatening disorders is induced by using cytotoxic immunosuppressants (e.g., cyclophosphamide) and high-dose corticosteroids, usually for 3–6 months, until remission occurs or until the disease activity is acceptably reduced. Adjusted treatment to maintain remission takes longer, usually 1–2 years. During this period, the goal is to eliminate corticosteroids, reduce the dosage, or use less potent immunosuppressants as long as needed. After tapering or eliminating corticosteroids, methotrexate or azathioprine can be substituted to maintain remission.²⁷

Wound Management

Initial treatment of wounds caused by vasculitis is extremely difficult because of the pain. The principles of standard wound care (debride necrotic tissue, treat inflammation and infection, apply moist wound dressings, nurture the edges, and ensure optimal oxygen supply, termed TIMEO₂)²⁸ are recommended. Topical lidocaine helps reduce pain during treatments, noncontact low-frequency ultrasound helps mobilize cellular activity and interstitial fluids, and compression therapy helps manage the edema that occurs in the lower extremities as a result of the inflammation and decreased mobility. Nonadherent dressings that promote autolysis of the necrotic tissue (eg, X-Cell, Medline, Mundelein, IL) are excellent initially, especially in reducing pain levels with dressing changes. Silicone-backed foam dressings are helpful in absorbing exudate as well as in reducing pain. If the patient is on steroids, local vitamin A can be used to negate the effects of steroids. As the acute inflammation recedes, pain levels decrease, and wound healing progresses to proliferation, treatment can be more aggressive with the goals of full re-epithelialization and return to prior level of function.

Antiphospholipid Syndrome

Pathophysiology

The antiphospholipid syndrome (APS) is an acquired autoimmune disorder in which antibodies are directed against one or more phospholipid-binding proteins (eg, anti-β2-glycoprotein I, anticardiolipin, and lupus anticoagulant) or their associated plasma proteins, resulting in hypercoagulation within the microvasculature. APS is characterized by elevated titers of different antiphospholipid antibodies.¹⁸ The proteins normally bind to phospholipid membrane constituents and protect them from excessive coagulation activation. The autoantibodies displace the protective proteins and thus produce procoagulant endothelial cell surfaces and cause arterial or venous thrombosis. In vitro clotting tests may paradoxically be prolonged because the antiprotein/phospholipid antibodies interfere with coagulation factor assembly and with activation on the phospholipid components that are added to plasma to initiate the tests.

The lupus anticoagulant is an antiphospholipid autoantibody that binds to protein-phospholipid complexes. It was initially recognized in patients with SLE; however, these patients now account for a minority of patients with the autoantibody. The lupus anticoagulant is suspected if the PTT is prolonged and does not correct immediately upon 1:1 mixing with normal plasma but does return to normal upon the addition of an excessive quantity of phospholipids (done by the hematology laboratory). Antiphospholipid antibodies in the patient plasma are measured by immunoassays of IgG and IgM antibodies that bind to phospholipid-β2-glycoprotein I complexes on microtiter plates.¹⁸ APS can occur with or without associated rheumatic disease (eg, systemic lupus erythematosus).²⁹

Clinical Presentation

The arteriole thrombosis results in venous swelling, creating the typical livedo reticularis skin appearance. In addition, the lower extremities may have purpura, splinter hemorrhages, or superficial thrombophlebitis (FIGURE 8-8). As the disease progresses, skin necrosis may occur, and if the disorder occurs during pregnancy, there will be fetal demise. If the thrombosis is in the venules, the result may be DVT with lower extremity edema, tachypnea due to pulmonary emboli, and ascites.

Differential Diagnosis

• 
  

  Disseminated intravascular coagulation

  
  
• 
  

  Infective endocarditis

  
  
• 
  

  Thrombotic thrombocytopenic purpura

Medical Management

Asymptomatic individuals in whom blood test findings are positive do not require specific treatment.

Prophylactic therapy involves elimination of other risk factors such as oral contraceptives, smoking, hypertension, or hyperlipidemia. For patients with SLE, hydroxychloroquine, an anti-inflammatory that may have intrinsic antithrombotic properties, may be useful. Statins are beneficial for patients with hyperlipidemia. If the patient has a thrombosis, full anticoagulation with intravenous or subcutaneous heparin followed by warfarin therapy is recommended.^18,19,30

Based on the most recent evidence, a reasonable target for the international normalized ratio (INR) is 2.0–3.0 for venous thrombosis and 3.0 for arterial thrombosis. Patients with recurrent thrombotic events, while well maintained on the above regimens, may require an INR of 3.0–4.0. For severe or refractory cases, a combination of warfarin and aspirin may be used. Treatment for significant thrombotic events in patients with APS is generally lifelong. Because cutaneous manifestations are the first sign of APS in up to 41% of patients, a full medical examination is advised for any patient showing the clinical symptoms in order to identify and treat the underlying pathology.^31,32

Wound Management

Conservative wound care is recommended for patients with skin lesions, keeping the wound moist and following wound bed preparation principles. Healing of wounds caused by other etiologies, eg, trauma or spider bites, will be delayed in patients who have APS.

Pemphigus

Pathophysiology

Pemphigus is an autoimmune blistering disease resulting from loss of normal intercellular attachments in the skin and oral mucosal membrane. Circulating antibodies attack the cell surface adhesion molecule desmoglein at the desmosomal cell junction in the suprabasal layer of the epidermis, resulting in the destruction of the adhesion molecules (acantholysis) and initiating an inflammatory response that causes blistering. There are three major forms of pemphigus: pemphigus foliaceus (FIGURE 8-9) and pemphigus vulgaris that have IgG autoantibodies against desmoglein 1 and desmoglein 3, respectively; and paraneoplastic pemphigus that has IgG autoantibodies against plakins and desmogleins (FIGURE 8-10).^33,34

Clinical Presentation

Pemphigus vulgaris, the most common type, involves the mucosa and skin, especially of the scalp, face, axilla, groins, trunk, and points of pressure. Patients usually present with painful oral mucosal erosions and flaccid blisters, erosions, crusts, and macular erythema in areas of skin involvement.^19,30 The primary cell adhesion loss is at the deeper suprabasal layer. (Refer to Chapter 1, Anatomy and Physiology of the Integumentary System, for a review of the skin anatomy.) Pemphigus foliaceus is a milder form of the disease, with the acantholysis occurring more superficially in the epidermis, usually on the face and chest. Paraneoplastic pemphigus, in addition to having different autoantibodies, occurs exclusively on patients who have some type of malignancy, usually a lymphoproliferative disorder (FIGURE 8-10). Because of the malignancy, mortality is high in this type of pemphigus.³⁵

Differential Diagnosis

Diagnosis is confirmed by using immunofluorescence to demonstrate the IgG autoantibodies against the cell surface of intraepidermal keratinocytes.

Medical Management

Medical treatment of all three types consists of high-dose systemic corticosteroids, immunosuppressive agents, and intravenous immune globulin. For patients who have refractory pemphigus vulgaris, a combination of rituximab and intravenous immunoglobulin therapy has been recommended.³³

Wound Management

Wound management is conservative with the goal of preventing infection and promoting reepithelialization in areas where denuding occurs with the blistering. Flat antimicrobial dressings (eg, Acticoat Flex, Smith & Nephew, Largo, FL) are useful over open areas, and hydrotherapy is beneficial when the disease is widespread and in the crusty phase. Secondary dressings are required for most areas, and can include surgical or fish-net garments. Silicone-backed foam dressings without adhesive borders are also recommended for easy removal of loose necrotic tissue without causing painful skin tears.

Bullous Pemphigoid

Pathophysiology

Bullous pemphigoid (BP) is subepidermal autoimmune blistering disease associated with tissue-bound and circulating autoantibodies directed against BP antigen 180 (also known as BPAG 2) and BP antigen 230 (also known as BPAG 1), both components of the basement membrane.^19,36 An immune reaction is initiated by the formation of IgG autoantibodies that target dystonin, a component of the hemidesmosomes, resulting in the infiltration of immune cells to the area. The consequence is separation of the dermal/epidermal junction with fluid collection and blistering or bullae. The severity of the disease is IgE dose dependent and correlates with the degree of eosinophil infiltration in the skin.³⁷

Clinical Presentation

BP occurs most commonly among the elderly, and the most common sites of involvement include inner aspects of thighs, flexor aspects of forearms, axilla, groin, and oral cavity. The extremities can also become involved. Itching is the first dominating symptom of BP, which progresses to urticarial lesions, erythematous edema, papules, eczematous lesions, and typically widespread tense bullae filled with clear fluid (FIGURE 8-11).³⁶

Differential Diagnosis

Histologically, BP is the prototype of a subepidermal bullous disease along with eosinophilic spongiosis. The dermis shows an inflammatory infiltrate composed of neutrophils, lymphocytes, and eosinophils. Diagnosis is confirmed by the presence of linear deposits of IgG and/or C3 along the dermal–epidermal junction on direct immunofluorescence and IgG class circulating autoantibodies that bind to the epidermal (roof) side of the skin basement membrane on indirect immunoflourscence.^18,19,38

Medical Management

Anti-inflammatory agents (corticosteroids, tetracyclines, dapsone) and immunosuppressants (azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide) are the most commonly used medications for BP, usually for 6–60 months, after which most patients will have long-term remission. Longer treatment may be required for patients who have chronic BP.³⁹

Wound Management

Wound management recommendations are the same as for pemphigus, with the goal of minimizing pain, preventing infection, and promoting re-epithelialization.

Cryoglobulinemia

Pathophysiology

Cryoglobulins are abnormal proteins (immunoglobulins), and cryoglobulinemia is the presence of these proteins in the blood. They coagulate or become thick and gel-like in temperatures below body temperature (37°C), thereby clogging the small blood vessels and resulting in vasculitic damage that causes hypoxic skin changes, ischemic wounds, and/or other organ damage (TABLE 8-8). The symptoms may be reversible if the environmental temperature is warmed. The disorder is grouped into three main types, depending on the type of antibody that is produced: Type I (usually with monoclonal IgM) is most often related to cancer of the blood or immune system, for example, multiple myeloma; Types II and III (polyclonal IgG), also referred to as mixed cryoglobulinemia, most often occur in people who have a chronic inflammatory condition, for example, hepatitis C, Sjögren syndrome, or systemic lupus erythematosus.⁴⁰ Type II is the most common type, and most of these patients also have hepatitis C.^1,18,19

Clinical Presentation

Symptoms vary depending on the type of cryoglobulinemia present and the organs that are affected. Systemic signs that occur with Types II and III may include difficulty breathing, fatigue, glomerulonephritis, joint pain, and muscle pain. Integumentary signs may begin with purpura and Raynaud’s phenomenon (FIGURE 8-12). The Meltzer triad which is associated with Types II and III includes arthralgia, purpura, and weakness.⁴¹ See TABLE 8-8 for a list of cryoglobulinemia symptoms.

Differential Diagnosis (partial list)

• 
  

  Antiphospholipid syndrome

  
  
• 
  

  Chronic lymphocytic leukemia

  
  
• 
  

  Churg–Strauss syndrome

  
  
• 
  

  Cirrhosis

  
  
• 
  

  Giant cell arteritis

  
  
• 
  

  Systemic lupus erythematosus

  
  
• 
  

  Vasculitis

Medical Management

The goal of treating cryoglobulinemia is to treat the underlying cause (which will often treat or prevent cutaneous symptoms) and to limit the precipitant cryoglobulin and subsequent inflammatory effects. Simply avoiding cold temperatures can treat mild cases. Standard hepatitis C treatments usually work for patients who have hepatitis C and mild or moderate cryoglobulinemia. However, the condition can return when treatment stops. NSAIDs may be used to treat mild cases that involve arthralgia and myalgia. Severe cryoglobulinemia (involving vital organs or large areas of skin) is treated with corticosteroids, immunosuppressants, interferon, or cytotoxic medications. Plasmapheresis may be indicated if the complications are life threatening.^40–42

Wound Management

Wound care involves treatment of infection and pain management, especially in the early stages. Nonadherent dressings such as X-Cell (Medline, Mundelein, IL), hydrogel, Acticoat (Smith & Nephew, Largo, FL), and petrolatum gauze help minimize pain with dressing changes and promote autolytic debridement. A topical anesthetic is advised 10 to 15 minutes before initiating any sharp debridement; enzymatic debridement may also be beneficial but can cause stinging and burning upon application. Absorbent dressings are advised if there is wound drainage, and modified compression (eg, with short stretch bandages) helps reduce the edema that occurs with chronic inflammation, immobility, and lower extremity dependency. Compression bandages also help keep the extremities warm and facilitate vasodilation. If edema is not severe, warm hydrotherapy can help reduce precipitation of the cryoglobulins and relieve ischemic pain. Patient education regarding avoidance of cold or wearing warm clothing such as thermal socks is a crucial component of long-term management.

Pyoderma Gangrenosum

Pathophysiology

Pyoderma gangrenosum (PG) is an autoimmune disorder of unknown etiology that leads to painful skin necrosis. PG is commonly associated with other inflammatory diseases such as Crohn’s disease, inflammatory bowel syndrome, arthritis, and hematologic malignancy.⁴² Pathergy, the development of skin lesions in the area of trauma or the enlargement of initially small lesions, is commonly seen with PG, especially if debridement of necrotic tissue is attempted. Neutrophilic dermatosis occurs with altered neutrophilic chemotaxis and is thought to be part of the pathology.²²

Clinical Presentation

PG ulcers usually begin as small pustules or blisters (termed cat’s paw appearance⁴³) and become larger with a violaceous border and surrounding erythema. The first lesion may be at the site of minor trauma, but will progress and enlarge rapidly. Often the wound edge is undermined. They are painful, necrotic, and usually recurring. Sometimes PG will appear in groups of lesions at different stages of formation or healing. They do not respond to standard care if diagnosed as another wound type, and indeed may worsen if the standard TIMEO₂ care, particularly aggressive debridement, is administered (FIGURES 8-13 to 8-15). The following variants of PG have been identified:

• 
  

  Classic PG—commonly seen on the lower extremities; scars are often cribriform; patient complains of fever, malaise, arthralgia, and myalgia.

  
  
• 
  

  Peristomal PG—occurs close to abdominal stomas, usually in patients with IBD, ileostomies, or colostomies for malignancy; may have bridges of epithelium that traverse the ulcer base.

  
  
• 
  

  Pustular PG—commonly seen on the trunk and extremity extensor surfaces of patients with IBD; stalls at the pustular stage and may persist for months.

  
  
• 
  

  Bullous PG—commonly seen on upper limbs and face; associated with hematologic conditions with poor prognosis; presents as concentric bullous areas that spread rapidly.

  
  
• 
  

  Vegetative PG—less aggressive and more superficial; may respond well to local treatment.^19,43,44

Differential Diagnosis

As there is no diagnostic test to confirm PG and multiple other conditions that resemble PG, a correct diagnosis relies on clinical presentation and exclusion of other causes. TABLE 8-9 lists the systemic diseases most often associated with PG. Differential diagnosis includes infections, malignancy (squamous cell or cutaneous lymphoma), vascular lesions, and antiphospholipid syndrome.

Medical Management⁴⁵

Systemic management includes treatment of any underlying disease and long-term immunosuppression with high doses of corticosteroids or low doses of cyclosporin.^43,45 Other therapies that have been used in patients with PG include antibiotics (dapsone and minocycline), clofazimine, azathioprine, methotrexate, chlorambucil, cyclophosphamide, thalidomide, tacrolimus, mycophenolate, mofetil, IV immunoglobulin, plasmapheresis, and infliximab.^18,19,46

Wound Management

Topical steroids, topical tacrolimus, nicotine patches, and intralesional steroids have been used for mild or moderate disease. Debridement of adhered tissue is contraindicated and may cause pathergy; however, as the necrotic tissue loosens with re-epithelialization, it may be gently removed with sterile forceps. Keeping the lesions covered with a nonadherent mesh or silicone-backed wicking foam that will allow drainage to escape to a secondary dressing can help alleviate the pain associated with PD wound care. Maggot therapy has been successfully used in some cases. Split-thickness skin grafts, along with concurrent immunosuppressive therapy to reduce the risk of pathergy, have been reported. Alternative therapies include application of bioengineered skin and hyperbaric oxygen therapy.⁴⁷

Necrobiosis Lipoidica

Pathophysiology

Necrobiosis lipoidica (previously referred to as necrobiosis lipoidica diabeticorum) is a collagen disorder of unknown etiology that is usually seen in morbidly obese patients with a strong family history of diabetes; however, not all patients have diabetes, therefore the change in nomenclature.⁴⁸ Different pathological mechanisms have been proposed and include (1) diabetic microangiopathy as a result of glycoprotein deposition in the blood vessels, (2) abnormal collagen degeneration, (3) deposition of immunoglobulins in the blood vessel walls with enhanced platelet aggregation and coagulation, and (4) impaired neutrophil migration leading to an increased number of macrophages and subsequent granuloma formation.⁴⁹ Necrobiosis lipoidica also results in thickening of the blood vessel walls and fat deposition, making the integumentary symptoms similar to vasculitis. The disease tends to be chronic with recurrent lesions and scarring,⁴⁶ and carries an associated risk of the development of squamous cell carcinoma.⁵⁰

Clinical Presentation

Lesions usually are bilateral but asymmetric on the tibial surface of the lower leg, and begin as a rash or 1–3 mm slightly raised spots. They progress to irregular ovoid reddish-brown plaques with shiny yellow centers and violaceous indurated borders. The edges may be raised and purple, and the wound bed may have good granulation tissue but no epithelial migration. Pain and edema are also usually present. Remodeling is characterized by round patches of hyperpigmentation (FIGURE 8-16).^18,19,51 Direct immunofluorescence microscopy of necrobiosis lipoidica reveals IgM, IgA, C₃, and fibrinogen in the blood vessels which will cause vascular thickening.⁴⁹

Differential Diagnosis

• 
  

  Pyoderma gangrenosum

  
  
• 
  

  Calciphylaxis

  
  
• 
  

  Vasculitis

  
  
• 
  

  Diabetic wound with peripheral vascular disease

  
  
• 
  

  Granuloma annulare (Binkley’s spots)

  
  
• 
  

  Sarcoidosis

  
  
• 
  

  Necrobiotic xanthogranuloma

Medical Management

Systemic steroids or other immunotherapy can be given to patients with severe disease. Cutaneous blood enhancers such as pentoxifylline and aspirin may be helpful in facilitating cell migration to the damaged tissue and inhibiting platelet aggregation.⁴⁹ Cyclosporin,⁵² mycophenolate,⁵³ and infliximab⁵⁴ have also been reported to successfully treat necrobiosis lipoidica.

Wound Management

Topical and intralesional steroids can be beneficial in treating mild to moderate cases. Other reported treatments include 0.1% topical tacrolimus ointment,^48,51 collagen matrix dressings,⁵⁵ and phototherapy.⁵⁶ A combination of low-frequency noncontact ultrasound, topical steroid ointment, saline-impregnated cellulose dressings, and multilayer compression wraps, in conjunction with pentoxifylline, was a successful combination used by the author for a patient with chronic lesions of more than 1 year duration.

Varicella is a virus that presents in three different ways: herpes simplex Type 1 (oral or cold sores), herpes simplex Type 2 (genital herpes), and herpes zoster (chicken pox and shingles).

Pathophysiology

The herpes simplex virus (HSV) persists in an individual for a lifetime due to the presence of a latent pool of the virus in terminally differentiated neurons, usually the peripheral ganglion.⁵⁷ HSV is a DNA virus that invades the cell nucleus and replicates, thereby producing partial thickness wounds. Herpes simplex Type 1 activation is commonly referred to as “cold sores” that occur on the mouth and lips. (FIGURE 8-17). Herpes simplex Type 2 is recognized as a sexually transmitted disease that results in lesions on the genital skin. Both can be reactivated, and in immune-compromised individuals can lead to local infection, chronic herpetic ulcers, and mucous membrane damage, as well as systemic infections in the central and peripheral nervous systems, the gastrointestinal tract, and the ocular system.⁵⁸

Chicken pox is a childhood disorder caused by the varicella-zoster virus (VZV). The virus enters through the respiratory system and infects the tonsillar T cells. The infected T cells carry the virus to the reticuloendothelial system where the major replication occurs and to the skin where the rash appears (FIGURE 8-18).⁵⁹

The VZV can remain latent in the nerve ganglion and reactivate in later years, usually during a period of stress or immunosuppression, as herpes varicella-zoster or “shingles” (FIGURE 8-19A, B). Vesicles can involve the corium and dermis, with degenerative changes characterized by ballooning, multinucleated giant cells, and eosinophilic intranuclear inclusions. Infection may involve localized dermal blood vessels, resulting in necrosis and epidermal hemorrhage.¹⁸ Individuals who are immunosuppressed (eg, patients with HIV or transplants) can have more severe cases of herpes, with the incidence of herpes zoster more than 14 times higher in adults with HIV.

Clinical Presentation

Herpes simplex usually occurs initially in childhood and progresses through the stages of prodrome, erythema, papule, vesicle, ulcer, hard crust, and residual dry flaking and swelling. Lesions can become secondarily infected by Staphylococcus or Streptococcus. Individuals tend to have recurrent eruptions. Nonulcerative lesions tend to last 3 days; full-blown ulcerative lesions may last 7–10 days.

Chicken pox usually presents with prominent fever, malaise, and a pruritic rash that starts on the face, scalp, and trunk and spreads to the extremities. The rash is initially maculopapular and rapidly progresses to vesicles, then pustules that rupture, and then to crusts.