Chapter 107. Dermatologic Conditions

• In a patient with a dermatologic condition, observation and description of the lesions (morphology, distribution, and texture) are important for developing a differential diagnosis.
• Mucous membranes (oral, ocular, nasal, genital, and perianal) should be examined in all patients.
• The skin may provide clues to an underlying, life-threatening condition, such as endocarditis, graft-versus-host disease, bacterial sepsis, toxic shock syndrome, systemic vasculitis, or complications from the human immunodeficiency virus.
• Drug-related dermatoses are prevalent in the intensive care unit. Clues to diagnosis include a rapidly developing eruption; generalized, symmetrical, predominantly truncal distribution; maculopapular, urticarial, or acneiform morphology; and accompanying pruritus.
• Extensive skin disease can cause important fluid, electrolyte, and protein losses and predisposes the patient to life-threatening infections.

Application of Structure and Function to Dermatoses

The basic anatomy of the skin is described in Fig. 107-1. The skin is a complex organ whose major function is to provide a barrier against the environment. Other major functions include temperature regulation and sensation. The skin is divided into three major layers: epidermis, dermis, and subcutaneous tissue. The outermost layer of the epidermis, the stratum corneum, is composed of dead, anucleate keratinocytes and serves as the first and major physical barrier. The stratum granulosum and stratum spinosum lie below the stratum corneum and are composed of keratinocytes in the process of differentiation. They are derived from the bottom layer of the epidermis, the basal cell layer. The epidermis is connected to the dermis by a complex of proteins and adhesion molecules in the basement membrane zone. Nutrients and products of metabolism are exchanged in the superficial and deep vascular networks located in the dermis. The dermis also contains nerve endings and supporting structures such as sebaceous glands, eccrine sweat glands, and hair follicles.

Alteration of any layer or structure of the skin can result in primary dermatologic disease. Often the skin is secondarily affected in underlying comorbid conditions and may serve as a window to internal disease processes. The stratum corneum can be damaged in the intensive care setting by tape, electrocardiographic leads, defibrillator devices, dry environments, pressure, or adhesives. Alteration may impair barrier resistance to infectious agents or allow passage of antigens to deeper layers of the skin. Preparing the skin for invasive procedures with topical solutions exposes the patient to potential sensitizers. Metabolically active cells in the suprabasal layers are susceptible to inflammatory and cytotoxic reactions from medications and toxins. Disruption in cell adhesion clinically manifests as blisters and may result from medications, toxins, pressure, extremes in temperature, or autoimmune diseases. Infections and inflammatory processes can occur at any level or in any structure, leading to conditions such as impetigo, folliculitis, cellulitis, fasciitis, or vasculitis.

Basic Morphologic Approach and Descriptions

When approaching a patient with skin disease, careful observation, palpation, and description are critical for developing a differential diagnosis. The morphology, or type, of lesion may be flat (macule), elevated (papule, nodule, plaque, cyst, vesicle, bulla, pustule, or hyperkeratosis), or depressed (ulcer or atrophy; Table 107-1). Shape, margination (well or poorly defined borders), and arrangement of the lesions are important. Color may be white (leukoderma or hypomelanosis); red (erythema), pink, violaceous (purple), brown (hypermelanosis or hemosiderin), black, blue, gray, or yellow. Particular attention should be paid to the distribution of the eruption (e.g., localized, systemic, truncal, acral, unilateral, or intertriginous). Palpation will help determine consistency, temperature, mobility, tenderness, and depth of lesion. When various lesions are present, one should attempt to determine the primary lesion.

Clinical history is essential. Symptoms (fever, malaise, arthralgias, myalgias, etc.) must be questioned, especially cutaneous symptoms (pruritus, pain, tenderness, burning, or stinging). Time course of the skin lesions should be determined, with particular attention to medication history (prescription and nonprescription, oral, topical, and alternative). Common diagnostic aids in dermatology are skin biopsy for hematoxylin and eosin or other special staining, direct immunofluorescence (DIF), or culture; potassium hydroxide preparation (for dermatophytic infections); mineral oil mounts (for scabies); Gram stain (for bacterial infections); fluid cultures; and Tzanck smears (for herpes simplex and varicella zoster virus infections).

Epidemiology and Probability of Adverse Drug Reactions

The World Health Organization (WHO) defines an adverse drug reaction (ADR) as any noxious, unintended, and undesired effect of a drug that occurs at diagnostic, prophylactic, or therapeutic doses used in humans.1 This definition excludes untoward events due to noncompliance or errors in drug administration, therapeutic failures, intentional and accidental poisoning, and drug abuse. A meta-analysis of 39 prospective studies covering 32 years reported a 10.9% incidence of ADR in admitted hospital patients and a 4.7% incidence for patients admitted because of serious ADR.2 In addition, fatal ADR ranked “between the fourth and sixth" leading causes of death in the United States in 1994, exceeding deaths due to pneumonia and diabetes.2 The rate and severity of preventable ADRs in intensive care units (ICUs) is nearly twice that in non-ICUs,3 and ADRs are responsible for lengthening the stay in medical and surgical ICUs.4 It has been estimated that ADRs cost a 700-bed teaching hospital $5 million to $6 million a year5 and $1.56 billion to $4 billion for all hospitals in the United States.6,7

Cutaneous ADRs (CADRs) are the most common type of ADR and occur in 2% to 3% of hospitalized patients.8 One in 1000 patients has a serious CADR,9 representing approximately 3% of all disabling injuries in hospitalized patients.10

Many commonly used drugs have reaction rates exceeding 1%.11 The numbers of CADR may be higher in the ICU setting owing to the critical and compromised nature of the patient compounded by the multiplicity of drugs. Several factors influence the probability of a drug producing an adverse reaction: the size of the compound (larger compounds are more likely to act as haptens), drug-drug interactions (altered metabolism and protein displacement), the route of delivery (intravenous administration increases the incidence of reactions), and patient factors such as renal function, alcohol use, hepatic function, and severity of concomitant disease.12,13 However, a recent nested case-control study showed severity of illness and length of stay as the only relevant risk factors.14 A review of nine articles studying rates of CADR found that antibiotics (e.g., amoxicillin, penicillin, fluoroquinolones, sulfonamides, and cephalosporins), nonsteroidal anti-inflammatory agents (NSAIDs), and other analgesics were the leading culprits.11 Another study found that antiepileptics (e.g., phenytoin and carbamazepine) were also common causal agents. The following medications only rarely cause CADR: digoxin, acetaminophen, meperidine, aminophylline, diphenhydramine, bisacodyl, prochlorperazine, spironolactone, prednisone, thiamine, ferrous sulfate, atropine, morphine, insulin, and spironolactone.

An Approach to Cutaneous Adverse Drug Reactions

Cutaneous eruptions are the most frequent ADR in hospitalized patients, accounting for 97.5% of cases in a prospective study by Thong et al.15 Maculopapular or morbilliform exanthems (Fig. 107-2) and urticaria are responsible for 95% and 5% of CADRs, respectively.11 Onset of the exanthem is usually within 1 week of administration, with the notable exceptions of antibiotics and allopurinol. Clues to recognizing a CADR include a rapidly developing rash, with an onset temporally related to the administration of a drug. Medical history, physical examination, and laboratory findings may provide clues, although an extensive laboratory workup is usually unnecessary for diagnosis (Fig. 107-3). Identifying the causative agent in the ICU setting may be problematic due to the concurrent administration of multiple drugs and the inability of patients to recall important facts. Hence, all medical records and family members or close contacts should be questioned. Important information includes (1) time of onset and course of the reaction; (2) dosage and time of initiation and/or discontinuation of any medications (including over-the-counter and alternative products); (3) the patient's previous exposure to this or other related medications; (4) any previous history of ADR, its management, and any measures taken to prevent future ADRs; (5) the patient's medical problems; and (6) any physical and/or laboratory abnormalities present with the ADR, with special attention to organ system(s) involved. Clues to diagnosis include (1) an eruption that develops very rapidly; (2) a generalized, symmetrical, predominantly truncal distribution; (3) an exanthematous (maculopapular), urticarial, fixed drug, or acneiform morphology; and (4) accompanying pruritus. Other less common drug-associated morphologies are lichenoid, photosensitive, vasculitic, or lupus-like patterns. With all this information in hand and knowing the reaction rate of various medications, identification of the cause of an eruption becomes more likely.

Despite the benign nature of the overwhelming majority of CADRs, it important to evaluate for increasing liver or renal dysfunction and for signs suggesting progression to severe skin disease (Stevens-Johnson syndrome [SJS] or toxic epidermal necrolysis [TEN]). Signs indicative of serious skin problems include mucosal involvement, blistering lesions, and a positive Nikolsky sign (Table 107-2).

Classification of Cutaneous Adverse Drug Reactions

The classification of CADRs can be problematic, largely due to the lack of data on molecular mechanisms underlying these reactions. The most widely used classification scheme for ADR was devised by Rawlins and Thomson12 (Table 107-3): type A reactions are related to the pharmacologic effects of the drug, are consequently predictable, and occur with great frequency; type B reactions are unrelated to the pharmacologic actions of the drug and are therefore unpredictable and uncommon; type C reactions result from long-term use of a drug; and type D reactions relate to carcinogenicity and teratogenicity of a drug. Type A reactions are the most common (80%) and can occur at any dose. Type B reactions occur in susceptible individuals (6% to 10%) a few days after administration or with reexposure and are independent of dose. Type B comprises drug intolerance, idiosyncratic reactions, and allergic or hypersensitivity reactions (those having a well-defined immunologic mechanism). Allergic reactions can be categorized further into those that are mediated by drug-specific antibodies or drug-specific T lymphocytes. These include the four mechanisms identified in the Gell and Coombs classification: immediate, cytotoxic, immune complex, and delayed hypersensitivity.16 Allergic CADRs are characterized by occurrence in a subset of people who have had a previous exposure to the same or similar drug. The reactions often develop rapidly with reexposure and produce clinical syndromes that are commonly associated with immunologic reactions. These may include systemic manifestations such as hepatitis, fever, and eosinophilia, which have been found in 30% of hospitalized patients with drug reactions, particularly in those induced by allopurinol or anticonvulsants.

Anaphylaxis and urticaria are Gell-Coombs type I (immediate) hypersensitivity reactions. They usually occur within 1 hour of drug administration, although they may occur as late as 72 hours. These reactions are mediated by immunoglobulin (Ig) E antibodies specific to the causative drug, found on mast cells and peripheral blood basophils, and occur more frequently with parenteral administration. Urticaria may occur in the setting of the systemic manifestations of anaphylaxis, which comprise angioedema with laryngeal edema, bronchospasm, hypotension, diffuse erythema, hyperperistalsis, cardiac arrhythmias, and pruritus (see Chap. 106). Drug-induced anaphylaxis occurs in 1 of 2700 hospitalized patients and is most frequently induced by β-lactam antibiotics (including penicillin), radiocontrast medium, intravenous anesthetic drugs, aspirin, other NSAIDs, and opiates. In the United States, the most common cause of anaphylaxis is penicillin, accounting for 75% of 500 to 1000 anaphylactic deaths in 1 year.17 Urticarial lesions are pruritic, erythematous or white, nonpitting, round or oval edematous papules or plaques surrounded by a clear or red halo, usually at different stages of formation. Penicillins, sulfonamides, and NSAIDs are the most common causal medications.18 Angioedema refers to the same pathophysiologic process as urticaria with transudation of interstitial fluid into the dermis or hypodermis. Treatment of urticaria consists of discontinuation of the offending drug and the administration of oral antihistamine H1 blockers. These include diphenhydramine, hydroxyzine, and the nonsedating agents, loratadine, cetirizine, and fexofenadine. If anaphylaxis develops, emergency treatment is instituted with intramuscular or subcutaneous epinephrine, high-flow oxygen and airway management, intravenous diphenhydramine, steroids, fluids, vasopressors, and cardiopulmonary resuscitation, as needed. Skin testing with the offending agent is usually positive in IgE-mediated reactions.

Cytotoxic (type II) reactions are mediated by IgG and complement, usually occur longer than 72 hours after drug exposure, and manifest as increased clearance of red blood cells and platelets by the lymphoreticular system. Skin testing is not useful.

Type III reactions are serum sickness-like reactions, in which IgG and/or IgM immune complex deposition leads to diffuse tissue injury. Common clinical findings include fever, urticaria (often figurate or polycyclic), angioedema, malaise, arthralgias (particularly of the hands and feet with swelling), lymphadenopathy, and occasionally nephritis or endocarditis, usually starting after 1 to 3 weeks of drug administration. There is an associated eosinophilia. Heterologous antisera, xenogeneic antibodies, and drugs with a low molecular weight (e.g., penicillin) are common triggers. Systemic steroids are often used to treat this reaction, although largescale controlled clinical trials are lacking.

Allergic contact dermatitis is the most common type IV, delayed-type hypersensitivity reaction, usually caused by topically applied medications. Sensitization is required and usually occurs over 5 to 7 days, after which the reaction can be elicited by topical or systemic administration of the same or a structurally similar agent. This means that a previous exposure is necessary, although a reaction may appear de novo after several days of contact with the offending agent. A pruritic, erythematous, vesicular, scaly eruption occurs at the site of contact, which, with time, may become lichenified (thickened with accentuation of skin markings) related to rubbing or scratching.

Diagnostic tests for CADR may be useful to determine the causative agent, the type of reaction, and the prognosis. Skin testing may be performed by a prick or intradermal administration of the suspected drugs to determine the presence of drug-specific IgE antibodies (type I Gell-Coombs reactions). Penicillin, muscle relaxants, and barbiturates are amenable to this type of testing because their epitopes are known. In some institutions, allergists and immunologists are able to purify the offending epitopes from other drugs. Medicines that undergo significant metabolism and those with undefined epitopes cannot be tested. An in vitro test to study the presence of circulating drug-specific IgE antibodies is the radioallergosorbent test. Penicillin, insulin, thiopental, protamine, latex, chymopapain, and selected muscle relaxants can be tested by radioallergosorbent test, with variable consistency.

When ADRs are mediated by drug-specific T cells (type IV; e.g., contact dermatitis), patch testing is a useful adjunct. It is performed by applying predetermined dilutions of the compound on intact skin for different periods and assessing for erythema, edema, or vesiculation, all indicative of specific T-cell reactivity. A skin biopsy aids in clarifying the pathophysiology of a reaction, for example, by the demonstration of immune complexes, leukocytoclastic vasculitis, or tissue eosinophilia. However, the biopsy often does not help in establishing whether or not the cutaneous reaction is drug induced. Blood eosinophil counts have been regarded as an indicator of ADR; however, recent studies have shown that this criterion carries a low sensitivity (22% to 36%, depending on arbitrarily defined cutoff rates), making routine eosinophil testing unhelpful.19 Serum tryptase levels are useful in reactions caused by diffuse mast cell (anaphylactic or anaphylactoid) activation, especially when hemodynamic changes are present. Tryptase is a protease stored in the granules of mast cells and released with mast cell activation. Levels should be obtained within 2 hours of initiation of the episode. Serum tryptase concentrations are recommended over serum histamine concentrations due to the greater stability of tryptase.20

The clinical usefulness of in vitro diagnostic tests to detect the presence of drug-specific antibodies capable of eliciting basophil histamine release, lymphocyte blast transformation, or complement activation remains to be proven. These tests carry a low sensitivity, are currently used mainly as research tools, and therefore are not recommended for routine clinical use.

Despite the high prevalence of ADR to sulfonamides in the general population (3%) and those infected with the human immunodeficiency virus (HIV; 60%), there are no reliable diagnostic tests available for clinical use. If, however, there is certainty that a sulfa drug has caused a CADR, desensitization protocols have been developed for patients with the acquired immunodeficiency syndrome that allow for sulfonamide administration during treatment and prophylaxis of opportunistic infections.21

Despite the different proposed mechanisms, overlap is common, and one cannot infer the pathogenesis of an eruption by its morphology or causative drug alone. The diagnosis of a drug-related dermatosis encompasses a complex mental algorithm of probability, time and causality, alternative diagnoses, and plausibility.

Chemotherapy-Induced Dermatoses

Cancer patients may be affected by cutaneous reactions of diverse etiologies, including infections, paraneoplastic pemphigus, dermatomyositis, graft-versus-host disease (GVHD), nutritional deficiency, metastases, cutaneous neoplasms, radiation reactions, and administration of chemotherapeutic agents.

The most common CADR to chemotherapeutic agents is alopecia (hair loss), which may present as anagen (hair growth phase) or telogen (hair resting phase) effluvium.22 Anagen effluvium is usually caused by antineoplastic agents, which weaken the hair shaft, resulting in severe hair loss apparent 1 to 2 months after therapy. Telogen effluvium occurs secondary to acute physical or psychological stress, malnutrition, or drugs. Spontaneous regrowth with drug discontinuation is the norm for both types of alopecia. The most common causative agents include vincristine, cyclophosphamide, doxorubicin, daunorubicin, dactinomycin, and paclitaxel. Treatments are rarely successful. The effectiveness of 2% minoxidil has been inconsistent.23,24

Adverse effects in the oral mucosa occur in 40% of patients as a result of direct drug toxicity or indirectly via effects on the bone marrow. Stomatitis is a frequent complication leading to erythema, edema, ulceration, pain, burning, and xerostomia. It is particularly common in individuals who are younger than 20 years, who have prior oral disease, or who have hematologic malignancies. Common culprits include topotecan, methotrexate, fluorouracil, doxorubicin, docetaxel, daunorubicin, dactinomycin, and bleomycin. Healing occurs within 2 to 3 weeks. Treatment consists of adequate oral hygiene and the use of topical agents such as attapulgite, magnesium/aluminum hydroxide, diphenhydramine elixir, benzocaine, and viscous lidocaine.

Candidiasis, with its white, adherent velvety plaques, and varicella zoster virus may also affect the inside of the mouth. Herpes simplex usually affects the vermilion border of the lips, but in the immunosuppressed may cause indolent intraoral ulcers.

Intravenous administration of chemotherapeutic agents may result in extravasation into surrounding tissues. Severity depends on type, quantity, and concentration of drug,25 and disabling sequelae are uncommon. Agents may be irritants (e.g., bleomycin, carboplatin, cyclosphamide, doxorubicin, etoposide, fluorouracil, paclitaxel, or vinblastine), which cause sclerosis, hyperpigmentation, and tenderness along the vein, or vesicants (e.g., bleomycin, carmustine, cisplatin, doxorubicin, etoposide, fluorouracil, melphalan, mechlorethamine, mitomycin, paclitaxel, vinblastine, or vincristine), which cause burning, necrosis, and ulceration. Treatment consists of discontinuing the infusion, elevating the affected extremity, and applying local heat or cold. Heat should not be applied when extravasation of vinca alkaloids occurs because this may cause ulceration.26 Surgical debridement and skin grafting may be needed in persistent ulcers. Antidotes are also recommended (Table 107-4).

Localized or diffuse hyperpigmentation is a common CADR, as a result of melanin, carotene, hemoglobin, or other pigment. Characteristic gingival bands occur with cisplatin; horizontal hyperpigmented bands on blond hair (flag sign) with methotrexate; flagellate streaks of hyperpigmentation with bleomycin; pigmented nail bands with bleomycin, cytarabine, cyclophosphamide, daunorubicin, doxorubicin, fluorouracil, hydroxyurea, idarubicin, mitomycin, tegafur, or vinblastine; and mucosal hyperpigmentation with busulfan, fluorouracil, tegafur, doxorubicin, hydroxyurea, cisplatin, or cyclophosphamide.22

Another well-described ADR to chemotherapeutic agents is acral erythema, occurring in 6% to 24% of patients,27 mainly those treated with cytarabine, doxorubicin, and fluorouracil. This painful eruption consists of diffuse erythema and edema on the palms and soles. This resolves with exfoliation within 4 weeks of discontinuing the drug. It needs to be differentiated from acute GVHD in the appropriate clinical setting. Treatment is supportive, with elevation, cold compresses, analgesics, and pyridoxine 150 mg each day.28

Anticoagulant-Induced Dermatoses

Adverse reactions to anticoagulants can be localized or diffuse and mediated by various mechanisms. Unfractionated heparin, low-molecular-weight heparins, and vitamin K antagonists are drugs used routinely in the treatment and prophylaxis of thromboembolic disease. In addition to the well-known ADRs such as an increased bleeding tendency, these agents may cause CADR which necessitate institution of alternative therapies.

Heparin is a mucopolysaccharide that can induce various ADRs, including immediate reactions (e.g., urticaria, asthma and anaphylaxis), delayed-type reactions (e.g., erythematous plaques, skin necrosis, a generalized eruption, and thrombocytopenia).29 Delayed-type reactions manifest as erythematous, vesicular, or pruritic plaques at the injection site within 2 to 5 days of therapy, whereas heparin-induced skin necrosis develops between 5 and 10 days of therapy. Cutaneous reactions have also been described related to the use of low-molecular-weight heparins and heparinoids.30 In patients with skin necrosis, heparin must be discontinued due to the increased risk of developing heparin-induced thrombocytopenia II.31 These patients usually have significant concurrent illnesses but no coagulation abnormalities. Histology shows fibrin deposition in venules and capillaries in the dermis and hypodermis, with necrosis. Intracutaneous testing is useful for the diagnosis of delayed reactions (erythematous plaques at heparin injection sites) but is contraindicated in the presence of skin necrosis. A positive skin test has been associated with heparin-induced IgG antibodies. There may be cross-reactivity between unfractionated heparin and low-molecular-weight heparins and heparinoids. Rates of 50% and 30%, respectively, have been reported.32 Therefore, treatment consists of discontinuing heparin and administering one of the newly developed direct thrombin inhibitors (argatroban and lepirudin) to provide protection during warfarin initiation.

Warfarin, a racemic mixture of R and S enantiomers, inhibits the vitamin K–dependent clotting factors II, VII, IX, and X; it also inhibits the anticoagulant proteins C and S, thereby causing a transient hypercoagulable state.33 On rare occasions, skin necrosis, which is potentially fatal (15% of cases), occurs with initiation of therapy before full anticoagulation is achieved. Three to 10 days after starting therapy, pain precedes the appearance of ill-defined erythematous plaques, which progress into edematous, blue-black plaques with hemorrhagic bullae in the center. The lesions necrose, leaving central eschars. Necrosis commonly affects the breasts, abdomen, and thighs in females and the abdomen and thighs in males. Histopathology shows fibrin occluding dermal and hypodermal veins, with diffuse necrosis.34 This occurs more commonly in women. Other risk factors include a large loading dose, protein C deficiency, and the presence of the factor V Leiden mutation. Treatment consists of discontinuation of warfarin and administration of intravenous heparin. Some investigators have reported success with the use of protein C concentrate, prostacyclin, and factor VII.35 Lesions are treated as any other skin ulcer; however, when they are extensive, surgical debridement, grafting, or occasionally amputation may be necessary to prevent the development of infection and sepsis. In one review, surgical treatment was found to be necessary in more than 50% of cases.36

Adverse Reactions to Alternative Drugs

Botanical products are classified as dietary supplements. As such, they are exempt from the stringent evaluation and regulatory processes that drugs have to undergo to show efficacy, safety, and quality.37,38 Although not allowed to make specific health claims, the manufacturers of these remedies are permitted to state they maintain good health. Herbal remedies account for a $1.5 billion per year industry in the United States, and it is estimated that 33% of Americans use these remedies, especially women and people of high socioeconomic status.39 Eighty percent of the world population uses herbal remedies. In Taiwan, herbal remedies ranked third among culprits for ADR in a study of 2695 patients admitted to the medicine ward.40 In a Hong Kong study, 0.2% of all admissions were due to adverse reactions to Chinese herbal drugs.41 Another survey found that 8% of 400 users of complementary medicine experienced adverse herbal reactions (AHRs).42

It is not uncommon for patients admitted to the ICU to have been taking herbal medicines, or “supplements.” Contrary to popular belief, herbal products may result in clinically significant adverse reactions and herbal-drug interactions, which may alter diverse organ systems and drug metabolism (Table 107-5).

In addition to AHRs due to the major compounds present, contaminants are a significant source of adverse reactions. Contamination of herbal remedies is abundant, due in part to lack of regulation. Lead, arsenic, and other heavy metals have been found in numerous herbal remedies. Autoimmune thrombocytopenia has been reported in a patient receiving kelp tainted with arsenic. In addition, some remedies have been found to contain traditional drugs, such as aspirin, paracetamol, mefenamic acid, diazepam, and triamcinolone, with corresponding adverse reactions.

There are some herbal remedies not yet reported to cause adverse reactions: camomile (anti-inflammatory), garlic (cholesterol lowering, and antihypertensive, although it may cause a contact dermatitis when topically applied), Ginkgo biloba (increases blood flow), peppermint (analgesic), Sabal (anti-inflammatory), and saw palmetto (antiandrogenic, estrogenic, anti-edema). Underreporting is prevalent; therefore, it should not be assumed that these medicines are free of adverse reactions.

Similarly, interactions with traditional drugs are a significant cause of concern in individuals taking herbal remedies concurrently with traditional medicines43 (estimated at 18% of the population; Table 107-6). Components in herbal remedies such as St. John's Wort and Kava-Kava, used for depression and anxiety, respectively, have been shown to inhibit monoamine oxidase activity. Interactions with drugs affecting the metabolism of neuroactive amines, such as the selective serotonin-reuptake inhibitors, are a potential problem. Therefore, coffee, tea, and foods containing tyramine (aged cheese, soy sauce, smoked meats, bananas, and avocados) should be avoided.

Because many of the mechanisms underlying AHR are unclear, a careful history and evaluation is necessary. In addition, because the half-life of many of these components is not known, they should be discontinued immediately on admission to the hospital or the critical care unit.

Vasopressin-Induced Skin Necrosis

Vasopressin, a nonselective vasoconstrictor, is used in the treatment of vasodilatory septic shock, hypotension unresponsive to catecholamines,44 and variceal hemorrhage.45 Uncommon adverse reactions to large-dose (0.2 to 0.4 U/min), centrally administered vasopressin include cardiac arrhythmias, ischemia, infarction, and bowel ischemia.46 When peripheral intravenous administration is used, accidental extravasation of the drug may result in skin necrosis and gangrene. This CADR may occur even at small doses (0.04 U/min) or when small quantities that are undetectable by the occlusion pressure monitor infiltrate the tissue. Interestingly, this skin necrosis does not occur with large-dose subcutaneous administration, as performed for diabetes insipidus. Treatment consists of stopping the vasopressin infusion, surgically débriding the ischemic tissue, and applying wet dressings or grafting. Administration through a central venous catheter is encouraged, even for small doses, to minimize the occurrence of this adverse reaction.

Diffuse ischemic skin lesions, defined as new areas of mottled or livid skin, have been found to occur in approximately 30% of patients during infusion of arginine-vasopressin, an alternative powerful vasopressor agent that is increasingly used in catecholamine-resistant vasodilatory shock. Sepsis and arterial occlusive disease are predisposing factors. These lesions, often seen on the limbs and trunk but also on the tongue, may lead to gangrene, necessitating débridement and amputation.47

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

CADRs are classified by the WHO as severe when they are life-threatening, require hospitalization, or lead to permanent disability. Stevens-Johnson Syndrome (SJS) (Fig. 107-4) and toxic epidermal necrolysis (TEN) (Fig. 107-5) are rare, serious CADRs, with calculated incidences of 1 to 6 and 0.4 to 1.2 cases per million person-years, respectively.48 SJS and TEN are histopathologically identical diseases that are differentiated by the extent of epidermal detachment: less than 10% in SJS, 10% to 29% in transitional SJS/TEN, and greater than 30% in TEN. In addition to the hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms, SJS and TEN constitute the major groups of severe CADRs49 (Table 107-7).

Fever, sore throat, cough, and burning eyes may precede painful skin eruptions resembling burns for 1 to 3 days. Lesions usually appear within 3 weeks of drug administration and begin as irregularly defined, painful erythematous macules with purpuric centers that tend to coalesce. Within a few hours or days, blisters appear and epidermal detachment extends over the body. Lesions in the mucosae are characteristic, occasionally preceding skin lesions by several days. However, initial presentation of SJS and TEN may be very similar to less serious CADR, that is, a maculopapular rash. Involvement of the epithelium of the trachea, bronchi, or gastrointestinal tract increases morbidity rate.

TEN is the most severe form of drug eruption known, with a mortality rate of approximately 30%.50 Mortality is mainly a result of respiratory complications or sepsis. Prognosis is influenced by age (>60 years), the presence of comorbidities, sepsis, and extent of body surface area involved.9,50,51 TEN is caused almost exclusively by medications, although it may be a manifestation of severe acute GVHD.52 The implicated medication is usually started within 3 weeks of the eruption. An increased risk for SJS and TEN has been found with the use of the following drugs: anticonvulsants (phenytoin, valproic acid, phenobarbital, and carbamazepine), antibiotics (sulfonamides and aminopenicillins), NSAIDs (oxicam derivatives), chlormezanone, allopurinol, and, interestingly, corticosteroids.48 Drugs with long-half lives, known to be frequent culprits, have been associated with higher fatality rates.53 TEN occurs more frequently in HIV-infected individuals, especially those receiving sulfonamides and/or nevirapine. This may be related to the concurrence of the glutathione S-transferase M1 null and the slow acetylator genotypes.54 Precipitation of SJS and TEN by infectious agents is much less common. Infection with Mycoplasma pneumoniae is the best documented55 (Table 107-8).

The pathogenesis of SJS and TEN remains unclear. Humoral and cell-mediated cytotoxicities, drug metabolites, and apoptotic mechanisms have been implicated, with inconsistent data. Experimental data suggest that activation of Fas (CD95) through its ligand, FasL (CD95L), results in caspase-mediated keratinocyte apoptosis, possibly an important pathophysiologic mechanism in TEN.56 Fas (CD95) is a cell surface receptor expressed on keratinocytes and most cells and can be activated by FasL, which is expressed by natural killer cells and activated T lymphocytes.57 FasL can also exist in a soluble form (sFasL), capable of inducing apoptosis.58 Soluble FasL results from metalloproteinase-mediated cleavage of cell surface FasL and stimulation of peripheral blood mononuclear cells by an offending drug results in upregulated sFasL expression. Sera from SJS and TEN patients can induce Fas-FasL–mediated keratinocyte apoptosis in vitro and contain elevated concentrations of sFasL when compared with control patients.59

Initially, patients develop pain, tenderness, or a burning sensation in the skin. These symptoms often begin abruptly and are associated with fever and general malaise. Over the next 1 to 3 days, ill-defined erythematous macules or a diffuse erythema develop over the trunk and extremities. As the red areas enlarge, central dusky necrotic sites develop with subsequent bullae formation. Bullae result from edema occurring beneath the necrotic epidermis. As the disease progresses, sheets of full-thickness epidermis slough off, revealing dark red, moist dermis (resembling severe second-degree burns). The Nikolsky sign (separation of the skin with lateral traction) is positive and an important diagnostic clue.

Mucous membrane involvement occurs in 85% to 95% of patients and may be the presenting sign.60 The oropharynx and conjunctivae are most affected, resulting in severe erosions and pain. Keratitis, ocular erosions, and symblepharon may result in blindness. Dysuria is a sign of urethral involvement. Erosions in the lower respiratory tract and the intestine have also been described.61

Hematologic studies may show anemia, eosinophilia, neutropenia, lymphopenia, thrombocytopenia, and an elevated erythrocyte sedimentation rate. Lymphopenia is seen early in the course of disease in up to 90% of cases and is a result of depletion of CD4 T lymphocytes. Neutropenia is seen in up to 30% of cases and carries a poor prognosis.62 Serum chemistries show evidence of extensive fluid and protein loss, hypoalbuminemia, and hypocalcemia.63 Taking a small piece of tender erythematous skin for frozen section may help make a rapid diagnosis. This will show the level of the separation within the skin and, in TEN, reveals full-thickness necrosis of the epidermis, with an intact dermis with little or no inflammation. Alternatively, a skin biopsy in an area immediately adjacent to and overlapping a blister may be sent for routine histology. The irregular presence of necrotic keratinocytes along the dermal-epidermal junction is a hallmark of early lesions, whereas diffuse epidermal necrosis with subepidermal clefting is present in late lesions. There is minimal dermal inflammation. Immunofluorescence findings are nondescript, with no significant complement or antibody deposition, suggesting that cell-mediated cytotoxicity is an important mechanism.

The clinical differential diagnosis includes staphylococcal scalded skin syndrome, acute GVHD, scarlet fever, erythema multiforme, and pemphigus vulgaris. In all these cases, full-thickness epidermal necrosis is rare (except in GVHD, in which epidermal necrosis is accompanied by an abundant lymphocytic infiltrate).

Erythema multiforme (previously referred to as erythema multiforme minor), is an acute, self-limited reaction characterized by asymptomatic, annular erythematous, or urticarial plaques with central areas of blistering and necrosis, resulting in the so-called target lesions. Lesions usually develop on the extensor surfaces of the extremities and mucosae and cover less than 10% of the body surface area. Outbreaks last for 1 to 4 weeks. Relapses are frequent. It is associated with recurrent herpes simplex virus infections in the great majority of cases and with M. pneumoniae infection in a smaller subset.

Treatment for SJS and TEN includes pain management and prompt withdrawal of any agents that are not essential for the maintenance of life. This latter has been shown to decrease mortality rate in TEN by about 30% per day, despite some progression of the mucocutaneous involvement.64 Fluid resuscitation, treatment of infections, and meticulous skin and eye care are most appropriately managed in an isolation room in a burn unit, where the staff is trained in topical wound and skin care. Severe airway involvement may necessitate intubation and ventilation. An ophthalmologic consultation should be obtained to assess eye involvement, which is usually treated with topical antibiotics and lubricants. If symblepharon occurs, early lysis must be performed. Fluid and electrolyte imbalances are related to the percentage of body surface area involved; however, fluid loss tends to be less than in severe burn patients. Topical therapy includes gentle debridement of necrotic skin followed by the application of nonadherent dressings to the areas of skin erosion, a wrapping of a thin silver-impregnated dressing, and an outer linen covering to hold all in place. Antibiotic ointments are widely used, although their value is unproved. It is important to avoid the sulfonamide derivatives (silver sulfadiazine cream, topical mafenide acetate, and ophthalmic sodium sulfacetamide) because of potential significant absorption and the possibility of inducing SJS.65 A variety of other dressings may be used to decrease fluid loss and pain and promote wound healing, and may be useful adjuncts to therapy. These include porcine xenografts66 and synthetic dressings such as Omniderm, OpSite, Vigilon, Mepitel, and Biobrane. Systemic antibiotics should be used only when there is documented infection or neutropenia.

The use of corticosteroids and immunosuppressive agents in the treatment of TEN is controversial. The rationale for such an approach is based on the assumption that TEN is an immune-mediated event. There are no case-controlled studies supporting the use of corticosteroids; however, several case reports have advocated their use.67,68 In most cases in which steroids were found effective, they were started very early in the course of the disease. More recent literature has indicated a higher mortality rate, increased time to recovery, and increased length of hospital stay in patients treated with systemic corticosteroids.69,70 Patients undergoing long-term glucocorticoid therapy who develop TEN may have a delay in onset, but the severity of disease is unaffected.71 Based on this information, corticosteroids should not be used routinely in TEN and should only be considered in patients who present early in the course of disease. Intravenous immunoglobulin therapy in TEN aims to decrease Fas-mediated keratinocyte apoptosis by sequestering Fas available for binding to CD95. Four nonrandomized, uncontrolled studies have shown that large-dose intravenous immunoglobulin decreases mortality rate and progression of TEN,72–75 whereas one prospective study showed no benefit.49 Hence, there is no consensus, and controlled, randomized trials are needed. The use of plasmapheresis and immunosuppressive drugs remains controversial due to the lack of strong clinical data.

Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms

A severe hypersensitivity syndrome consisting of fever, rash, lymphadenopathy, and variable organ (usually liver) involvement may appear after several weeks of drug ingestion. When associated with eosinophilia and systemic symptoms, the term drug reaction with eosinophilia and systemic symptoms is used (see Table 107-7). The most common precipitants are the aromatic anticonvulsants (e.g., phenytoin, phenobarbital, and carbamazepine). Faulty metabolism of these drugs is thought to precipitate the disease process, which has also been associated with the initiation or reactivation of infection with human herpes virus type 6.76 There is a 75% incidence of cross-reactivity between these anticonvulsants; therefore, once one of these drugs has caused a reaction, further exposure to any of them should not be attempted. Other medications known to cause this syndrome include dapsone, sulfonamides, allopurinol and minocycline.77

The cutaneous component of this ADR varies from a maculopapular eruption to frank erythroderma. Discontinuation of the offending agent and the administration of moderate to large doses of systemic steroids are the treatments of choice and have shown benefit in multiple case reports. Supportive care, similar to that for SJS and TEN, in an ICU or burn unit, must be instituted when life-threatening visceral manifestations are present, whereas topical steroids alone may be sufficient for mild disease.

Pemphigus Vulgaris

Pemphigus vulgaris (PV) is an autoimmune, mucocutaneous, blistering disease characterized by an intraepidermal split that results in superficial flaccid bullae. Autoantibodies directed against intercellular adhering junction antigens lead to bullae formation. Circulating IgG directed toward intercellular desmogleins 3 and 1, which interact with plakoglobin in the dense plaque of the desmosome, can be detected in the serum and skin biopsies from perilesional skin.78,79 The stimulus for the circulating autoantibodies is unknown. PV has been described in association with autoimmune diseases, malignancy, and medications.80 The medications most often cited have thiol groups in their molecules, such as penicillamine and captopril.81 PV occurring in association with an underlying neoplasm is termed paraneoplastic pemphigus. Paraneoplastic PV is seen primarily with lymphomas. Patients develop flaccid bullae on normal or slightly erythematous skin. The bullae rupture easily, leaving superficial and crusted erosions (Fig. 107-6). The presence of Nikolsky's sign (lateral extension of an intraepidermal split with application of pressure to small intact bullae) is a characteristic feature. Blisters may occur anywhere on the body, with a predilection for the trunk, groin, scalp, and face. Mucous membrane involvement is characteristic. The oral mucosa is involved in more than 95% of patients and is the initial manifestation in up to 70%.82 Intact bullae are rarely seen due to their superficial location. PV occurs primarily in the middle and older age groups.

The diagnosis of PV is made using routine (hematoxylin and eosin) dermatopathologic analysis of a biopsy from the border of an active lesion in addition to direct immunofluorescence (DIF: patient's skin and anti-immunoglobulin) of a biopsy specimen from perilesional skin and indirect immunofluorescence (IIF) of a serum sample (patient's serum incubated with monkey esophagus and then with anti-immunoglobulin). Histologic examination shows loss of adhesion between keratinocytes (acantholysis) above the basal layer, resulting in an intraepidermal split. DIF reveals IgG and complement deposition between keratinocytes within the epidermis. IIF reveals intercellular IgG deposition on monkey esophagus. The IIF titer may be quantified and loosely reflects disease activity.

Before the advent of corticosteroids, PV carried a high mortality rate. At present, patients are typically started on doses of at least 1 to 2 mg/kg per day of prednisone to halt progression of the disease. Azathioprine may be started concurrently at a dose of 50 to 100 mg/day. The dose is calculated based on the red blood cell concentration of thiopurine methyltransferase, an enzyme involved in the metabolism of the thiopurine drugs, because low concentrations of this enzyme may lead to serious side effects, such as excessive myelosuppression, and high concentrations may lead to rapid metabolism of azathioprine and potential underdosing.83 Immunosuppressants should be initiated early in the course of the disease to allow time for their immunosuppressant actions to take effect as this may take up to 6 weeks. Current therapeutic regimens also include parenteral gold, dapsone, plasmapheresis, intravenous immune globulin, and other immunosuppressant agents, such as cyclosporine, cyclophosphamide, and mycophenolate mofetil.84,85

Bullous Pemphigoid

Bullous pemphigoid (BP) is a self-limited autoimmune blistering disease characterized by tense, subepidermal bullae (Fig. 107-7). Autoantibodies develop to portions of the hemidesmosome complex in the basement membrane zone. The resulting disruption in adhesion leads to a subepidermal split from the dermis. These antigens are identified by their molecular weights, 230 kDa (BPAGI) and 180 kDa (BPAG2). Table 107-9 lists the characteristics that distinguish BP from PV.

BP has an estimated incidence rate of 7 per million per year. It occurs equally in men and women usually between 60 and 80 years of age. Approximately 50% of treated patients will go into remission within 2.5 to 6 years of onset of disease; however, individuals may have active disease for as long as 10 years. There is a predilection for tense blisters on normal or erythematous skin to occur in the groin, axillae, and flexural areas. Nikolsky sign is negative. Mucous membranes are involved in approximately 20% of patients. In addition to the bullae, patients may have urticarial weals and serpiginous erythematous plaques. Lesions heal without scarring, although there may be significant pigmentary change.86

Histopathologic sections show a split between the epidermis and the dermis, with an infiltrate consisting predominantly of eosinophils. Lymphocytes and neutrophils may also be present in the superficial and deep dermis. DIF of perilesional skin shows a linear deposition of IgG and complement along the basement membrane zone. Although the titer does not reflect disease activity, indirect immunofluoresence (IIF) studies show circulating antibasement membrane zone IgG antibodies in 70% to 80%.87

Corticosteroids, at smaller doses (≤1 mg/kg per day) than those used for pemphigus vulgaris (PV), have been the mainstay of treatment for widespread disease. Localized or mild disease may respond to antibiotics at anti-inflammatory doses such as tetracycline 1 to 3 g/day or erythromycin 1 to 3 g/d with nicotinamide 1 g three times daily and/or high-potency topical steroids. Other therapies include dapsone and immunosuppressants such as azathioprine, cyclophosphamide, chlorambucil, mycophenolate mofetil, and methotrexate.88

Psoriasis

Psoriasis is a chronic, recurrent skin condition that affects 1% to 3% of the population. Both sexes are equally affected. Well-defined circular or oval plaques with adherent silver scale characterize the lesions. Lesions have a predilection for extensor surfaces, especially the knees, elbows, scalp, and the superior end of the gluteal fold. Psoriatic lesions often develop at sites of physical trauma such as scratched areas, surgical incisions, and tape removal. This finding is referred to as the Köbner phenomenon. Initial psoriatic episodes that may occur 2 to 3 weeks after a streptococcal infection sometimes appear as widespread, asymptomatic, small red papules with a silvery scale. This is called guttate psoriasis and usually resolves over 2 to 3 months with no specific treatment. Drugs may also precipitate or exacerbate preexisting psoriasis. Well-known culprits include the withdrawal of systemic or strong topical steroids or other immunosuppressive agents and the administration of β blockers, antimalarials, or lithium. Alcohol abuse and HIV infection are associated with extensive and resistant psoriasis.89

Many clinical variants of psoriasis exist. Generalized pustular psoriasis, also referred to as von Zumbusch psoriasis, is a rare but serious variant that is characterized by diffuse pustules on erythematous plaques. Erythematous skin rapidly develops crops of pustules that coalesce to form “lakes of pus.” Nails, palms, and soles are often affected. Fever, hypocalcemia, and leukocytosis may accompany the outbreak. The average age of onset is 50 years, with no sexual predilection. Precipitating factors include drugs, infection, pregnancy, exertion, and menstruation. The differential diagnosis in a patient with diffuse pustules and fever includes infection, drug reaction, acute generalized exanthematous pustulosis, pustular psoriasis, and subcorneal pustular dermatosis.90,91

Psoriasis may be treated initially with a variety of topical medications. These include corticosteroids, calcipotriene, tar, anthralin, and topical retinoids. These agents are used as monotherapy or in combination. Systemic drugs are reserved for extensive or disabling disease and include methotrexate, cyclosporine, and oral retinoids. Ultraviolet (UV) light therapy is often used in combination with topical and/or systemic agents. UV light therapy has been a mainstay of treatment for years. This includes natural sunshine, broadband UVB (280 to 320 nm), UVA (320 to 400nm), and a single-wavelength light narrowband UVB (311 nm). Psoralen, a photosensitizer, is used to potentiate the UVA effects in a regimen called PUVA. Acitretin, a systemic retinoid, may be used alone or in combination with phototherapy. Biologic therapy that targets specific cytokines and intercellular adhesion molecules has recently been introduced. At the time of writing three of these agents have been approved by the Food and Drug Administration for the treatment of psoriasis. Alefacept is a recombinant protein containing human leukocyte function-associated antigen 3 and human IgG1. IG binds to CD2 on memory-effector cells. Efalizumab is a humanized monoclonal antibody to CD11a, a subunit of LFA-1. IG inhibits trafficking of T-cells to the skin and T-cell reactivation in the skin. Etanercept is a soluble recombinant human tumor necrosis factor 2 receptor that binds the circulating inflammatory stimulator tumor necrosis factor 2. Each is administered parenterally using unique dosing regimens.92,93 The long-term affects of these therapies are not yet known. Acitretin, narrowband UVB, PUVA, methotrexate, and cyclosporine have been used effectively in the treatment of generalized pustular psoriasis.94

Erythroderma

Erythroderma or exfoliative dermatitis is a descriptive term for a clinical condition characterized by total body diffuse erythema and scaling (Fig. 107-8). The skin is initially red and warm. Scaling and exfoliation, often accompanied by fever, chills, and lymphadenopathy, follow. The percutaneous absorption barrier is lost and blood flow to the skin increases, which may lead to serious complications such as hypoalbuminemia, peripheral edema, loss of muscle mass, and high-output cardiac failure, with as much as 8% of the total cardiac output being directed at the inflamed cutaneous vasculature. Causes of exfoliative dermatitis include inflammatory conditions, drug eruptions, cutaneous T-cell lymphoma, and systemic neoplasms (Table 107-10).Common inflammatory conditions include psoriasis, atopic dermatitis, contact dermatitis, and pityriasis rubra pilaris. Antiepileptic medications (carbamazepine, phenobarbital, or phenytoin), antihypertensive medications (captopril or chlorothiazide), antibiotics (cephalosporins, dapsone, isoniazid, or minocycline), and calcium channel blockers have been associated with exfoliative erythroderma.95 Lymphomas and hematologic malignancies are common systemic neoplasms that may cause erythroderma.Sézary syndrome is the leukemic form of cutaneous T-cell lymphoma, which is characterized by circulating atypical lymphocytes with hyperconvoluted nuclei (Sézary cells). These atypical cells are identified on blood smear or in skin biopsies. Internal malignancies occasionally cause erythroderma.

The erythrodermic patient should be monitored with specific attention to fluid and electrolyte balance, temperature regulation, and nutritional status. Skin biopsy may help identify the underlying cause of the dermatosis and thus direct specific treatment. Initial management includes the use of medium potency topical steroid ointments covered with a bland ointment, such as zinc oxide ointment and wrapped with clean cloths, or topical steroids applied directly under a plastic sauna suit. It is important to avoid topical irritant agents, such as tar-containing ointments. Wet dressings may help weeping or crusted areas. Pruritus and anxiety typically respond to the sedating antihistamines. Alternatively, doxepin at doses of 25 to 50 may be given at bedtime.

Purpura

Purpura is a clinical term that represents the extravasation of blood into surrounding tissues.96 Purpura is a common skin condition that has many causes. An approach to the patient with purpura focusing on the dermatologic decision-making algorithm is discussed (Fig. 107-9). The type of lesion depends on the depth of the vascular plexus involved, the size of the vessel injury, precipitating factors, and coextravasated circulating substances. Visual and tactile assessments of a lesion are crucial. Lesions are placed into two main categories, palpable or nonpalpable (Fig. 107-10). The patient's underlying conditions, potential precipitating events, current and past laboratory values, and medication history are analyzed.

Nonpalpable (macular), nonblanching purpura arises from simple hemorrhage into tissue. The dermal vascular network consists of superficial and deep vascular plexuses. The superficial plexus possesses arteriovenous loops that ascend into the dermal papilla. Petechiae are lesions smaller than 0.2 cm in diameter that result from superficial vascular hemorrhage. Larger areas are termed ecchymoses. Nonpalpable purpura is most commonly attributed to fragility of the vascular tissue or defects in hemostasis. Examples include actinic or solar purpura (owing to the age-related loss of collagen in the basement membrane of blood vessels) and purpura secondary to systemic corticosteroids (related to inhibition of lysyl oxidase that is required for synthesis of type IV collagen, the principal collagen associated with blood vessel basement membrane integrity). Cutaneous amyloid, primary or secondary resulting from myeloma, may be deposited in endothelial cells.97 Deposition results in vascular fragility so that nonpalpable lesions representing common bruises, sometimes called pinch purpura, may occur after minor trauma. This occurs mainly on the face, especially periorbitally. Other common causes of flat purpura include platelet disorders (thrombocytopenia, thrombocytopathia, and thrombocytosis), disseminated intravascular coagulation (DIC), and warfarin-associated necrosis. If the diagnosis cannot be made on clinical grounds, a skin biopsy may be helpful. Flat purpura in neutropenic patients is approached as if it were palpable purpura, because these patients are unable to mount the appropriate immune response to cause dermal inflammation. In such patients, biopsy is important to assist with diagnosis.

Palpable purpura indicates underlying vasculitis (also called cutaneous necrotizing venulitis or leukocytoclastic vasculitis). For the first 24 to 48 hours, the lesions are a deep erythematous color that eventually becomes violaceous. The pathologic process results from segmental vascular inflammation, swelling and necrosis of endothelial cells, and neutrophilic infiltration of vessel walls with fragmentation of nuclei.

As outlined in Fig. 107-9, many factors may lead to vasculitic injury. Precipitating factors include infections, drugs, autoimmune diseases, and immunoglobulin-mediated complement activation. Common infectious agents include Staphylococcus aureus, hepatitis B, and hepatitis C. Drugs commonly associated with vasculitis include ampicillins, thiazides, phenytoin, sulfa-containing compounds, allopurinol, hydralazine, and propylthiouracil.

Workup includes identification of a potential primary cause and evaluation for systemic involvement. In addition to a biopsy, a complete blood count, chemistry panel, liver function tests, urinalysis, stool guaiac, hepatitis B and C viral serologies, cryoglobulins, and complement levels are evaluated. Antinuclear antibody titers are evaluated in patients with suspected connective tissue diseases. In patients with a fever and heart murmur, blood cultures and echocardiography should be performed.98

Retiform purpura is referred to as purpura fulminans, a pattern usually indicative of micro-occlusion. In contrast to inflammatory purpura, this type immediately manifests as violaceous purpura that may or may not be palpable. Lesions appear abruptly and display a retiform or jagged edge, sometimes blending into a livedo pattern at the periphery. The major causes of micro-occlusive disease include disseminated intravascular coagulation, meningococcemia, acquired protein C or S deficiency, warfarin-induced skin necrosis, antiphospholipid antibody syndrome, sepsis of various causes, cryoglobulinemia, cryofibrinogenemia, paroxysmal nocturnal hemoglobinuria, and cholesterol emboli.99

Graft‐versus-Host Disease (GVHD)

GVHD is a complex syndrome which occurs after allogeneic bone marrow transplantation. The skin is often the first and is the most frequent organ involved. Biopsy may help distinguish GVHD from other causes of erythema such as drug eruptions or viral exanthems. Acute GVHD usually occurs between days 10 and 30 after transplantation, but may appear at anytime.100

Skin changes consist of a generalized morbilliform eruption progressing to extensive redness, blistering, or skin necrosis. The earliest sign is pruritus and tenderness of the palms and soles, with reddening of the dorsal aspects of the fingers and periungual skin. Diffuse erythema of the hands and feet soon follows. In addition, the ears are commonly affected. Unusual clinical patterns may be seen due to the polymorphous nature of this disease. Confluence of lesions occurs on the trunk as the disease progresses. Blisters (with a positive Nikolsky sign) and generalized desquamation portend a poor prognosis. The palmar and plantar erythemas of acute GVHD need to be differentiated from those of palmar-plantar erythrodysesthesia due to chemotherapeutic agents. This syndrome may occur with GVHD or in similar clinical situations. The erythrodysesthesia begins as spotty erythema on the thenar and hypothenar eminences and progresses to severe pain and swelling.

The original grading system for GVHD was described in 1974 and is still in use today.101 Several features of GVHD are recognized: (1) 72% of transplanted patients develop clinically recognizable GVHD; (2) an increase in the serum aspartate aminotransferase concentration is related to the onset or worsening of the skin erruption; (3) cutaneous symptoms precede systemic involvement by 2 to 3 days; and (4) the severity of GVHD does not correlate with the underlying disease process, the conditioning regimen, or the day of onset after grafting. The initial management strategy when GVHD is suspected includes obtaining a skin biopsy to look for the characteristic changes. Unfortunately, the diagnostic yield of skin biopsies for GVHD is only 50% to 65%. When biopsies show nonspecific changes, additional biopsies are recommended in 24 to 48 hours. Tissue cultures to look for bacteria, mycobacteria, and fungi should be performed in febrile patients.

Factors associated with a high risk of developing GVHD include an HLA mismatch, an unrelated donor, older age of the recipient or donor, a sex mismatch, T-cell replete grafts, donor allosensitization, regimen toxicity, and compromised delivery of GVHD prophylaxis.102 splenectomy, bone marrow cell dose, and ABO match. Polymorphism of minor determinants such as the adhesion molecule CD31 may account for the risk of GVHD between HLA identical donor and transplant recipients.103 Future testing for minor and major determinants may help decrease the risk and severity of GVHD.

GVHD has also been described after autologous and syngeneic transplantation. This phenomenon has stimulated much interest because it indicates that factors other than donor reactivity against recipient antigens may be involved in allogenic GVHD. In autologous GVHD, only the skin is involved, and lesions typically resolve within 7 days. The combination of total body irradiation (which causes failure of the peripheral autoregulatory mechanisms) and cyclosporine (which blocks clonal deletion of autoreactive T cells that escape from the thymus) are believed to be important factors.104 Treatment for acute GVHD includes modifying the original immunosuppressive prophylactic regimen (cyclosporine, tacrolimus, or mycophenolate mofetil) and adding methylprednisolone at 2 mg/kg. Treatment protocols differ and may include anti-thymocyte globulin, intravenous immunoglobulin (IVIG), and monoclonal antibodies. Topical treatment is mainly supportive, with emollients and topical steroids. Erythrodermic and severe blistering patients deserve close monitoring and aggressive immunosuppression. Other therapies reported to be beneficial in the treatment of GVHD include ultraviolet light therapy (PUVA, broad band or narrow band UVB) extracorporeal photochemotherapy (photopheresis), pentoxifylline, and thalidomide.

Bacterial Infections

Infectious organisms can involve the skin via a primary or secondary route. Primary infections begin as a localized exogenous invasion that can spread superficially or invade to the deeper subcutaneous tissue, depending on host and virulence factors. Secondary infections occur by hematogenous dissemination of the organism or portions of the organism and may be accompanied by immune complex deposition.

Impetigo

Impetigo is a primary bacterial infection that occurs in two forms: impetigo contagiosa (caused by staphylococci and, less commonly, streptococci), and bullous impetigo (caused by a toxin released from S. aureus). Impetigo usually appears on exposed areas such as the face and extremities in children, the elderly, and the immunosuppressed. Impetigo begins as an erythematous plaque with scattered vesicles that subsequently rupture to form honey-colored crusts. The infection often begins after minor trauma allows bacterial invasion of the superficial epidermis. Constitutional symptoms are generally absent but regional lymphadenopathy is common. Bullous impetigo is characterized by large flaccid bullae that have a positive Nikolsky sign. Bullous impetigo is caused by a toxin-producing strain of phage group II S. aureus. Bullous impetigo may be considered a localized form of staphylococcal scalded skin syndrome.

The diagnosis of impetigo is made based on clinical findings. Culture and sensitivity may be useful to confirm the diagnosis or when resistant or nephritogenic strains are suspected. Anti-DNAase B and antihyaluronidase titers rise significantly after streptococcal skin infection, but there is no change in the antistreptolysin titer.105 Bullous impetigo is a toxin-mediated process and culture of blister fluid is often negative. Serious secondary infections related to pyoderma include osteomyelitis, septic arthritis, and pneumonia.

The prevalence of erythromycin-resistant streptococci and staphylococci has been increasing in recent years, so erythromycin is no longer a treatment of choice. Treatment includes room temperature tap water compresses in conjunction with topical mupirocin or a β-lactamase–resistant penicillin (dicloxacillin or cloxacillin) or a first-generation cephalosporin (cephalexin). Azithromycin may be given to penicillin-allergic patients. Up to 15% of individuals, usually children between the ages of 2 and 4 years, with impetigo caused by a group A streptococcal nephritogenic strain (usually M-49 serotype) develop acute poststreptococcal glomerulonephritis 1 to 5 weeks (median = 10 days) after infection. Occasionally, a group C streptococcus is involved.106 The overall incidence of nephritis related to impetigo is 2% to 5%. The use of antibiotics does not appear to decrease the incidence of poststreptococcal glomerulonephritis, despite prompt clinical and bacteriologic responses.107

Necrotizing Fasciitis

Necrotizing fasciitis (NF) is a rapidly progressive suppurative bacterial infection of the superficial and deep fascia that, if left unchecked, progresses to gangrene, sepsis, and death (see Chap. 55). Classically, this has been associated with group A streptococcus alone or with concomitant facultative and anaerobic bacteria (clostridium, bacteroides, Enterobacteriaceae, Vibrio species, and non–group A streptococci).108

NF occurs in adults of any age who may be otherwise healthy. Predisposing factors include any condition that may cause a break in the skin, such as varicella, cuts, burns, surgical procedures, and child birth. Diseases such as diabetes and cirrhosis, immunosuppression, and drugs such as infliximab may also increase the risk of infection.109 The patient's use of NSAIDS may delay diagnosis and allow for rapid progression of infection owing to attenuation of the early inflammatory host response and alteration of the humoral immune response.110

Patients present with skin erythema, edema, warmth, and tenderness often localized to one limb. Other areas such as the face are affected less often.111 Within 24 hours there is rapid spread proximally and distally along the limb, and there may be a bluish necrotic hue and bullae appearing within the affected area. The key features that distinguish NF from cellulitis are rapid spread and significant tenderness.

The diagnosis of NF is primarily clinical. Computed tomography or magnetic resonance imaging may help locate the site and extent of infection. In mixed anaerobic infections, plain radiographs may detect gas in the soft tissues. In evaluation of a swollen painful extremity, compartment pressure measurements may be useful. If pressures are elevated (>40 mm Hg), immediate fasciotomy is indicated. A superficial skin biopsy does not aid in the diagnosis. Tissue sampling that extends to the fascia is required.

Surgical debridement or incisional drainage is essential for treatment. Concomitant treatment with antibiotics should not delay surgical management. Antibiotics alone are ineffective owing to the amount of vascular occlusion in the affected area and to the slower growth rate of streptococci in large inocula.112 After debridement, tissue should be Gram stained and cultured for aerobes and anaerobes. Empiric antibiotic therapy includes penicillin and/or clindamycin.

Toxic Shock Syndrome

Toxic shock syndrome (TSS) is characterized by fever, shock, desquamating rash, and multiorgan system failure in association with toxins mediated from group A streptococcal or S. aureus infections. Streptococcal TSS (STSS) is seen most often in association with soft tissue infection, including necrotizing fasciitis (NF). The syndrome appears to be mediated by one or more of the streptococcal pyrogenic exotoxins (types A, B, or C). Type A exotoxin has the most potent inflammatory and cytotoxic properties and is most closely associated with STSS.113 These toxins may act as superantigens by directly linking the major histocompatibility complex of antigen presenting cells to the V-β portion of the T-cell receptor, thus bypassing the limiting step of antigen processing and resulting in massive T-cell activation.114 Up to 80% of patients with this syndrome present with soft tissue infections.115 Other access sites include the mucous membranes, such as the vagina, intravenous drug use, and burn wounds.116,117 In patients with no identifiable portal of entry, seeding of infection is thought to occur by a transient bacteremia originating in the pharynx. Symptomatic sore throat may occasionally precede STSS. Patients, who tend to be young and in good health, present with influenza-like symptoms (fever, myalgias, malaise, headache, nausea, vomiting, or diarrhea) often in conjunction with pain and erythema of an area such as an extremity. Approximately 20% of patients will develop a generalized blanching erythema that desquamates at days 7 to 14.118

The criteria for diagnosis of STSS are presented in Table 107-11. Laboratory data that support the diagnosis of STSS include a normal or moderately elevated white blood cell count with a profound left shift, azotemia, hypocalcemia, hypoalbuminemia, thrombocytopenia, hematuria, and an elevated creatine kinase. It is interesting to note that evidence of renal impairment precedes hypotension in approximately 50% of patients at the time of admission to the hospital and develops in all others within 4 to 8 hours after admission.

TSS caused by S. aureus begins with a scarlatiniform eruption. There may be flexural accentuation, erythema and edema of the palms and soles, hyperemia of the conjunctivae and mucous membranes, and a strawberry tongue.119 In contrast to STSS, which tends to present with a localized soft tissue infection, signs of infection are often absent in TSS mediated by S. aureus–producing toxin. Both syndromes tend to occur in young healthy adults, but TSS may be associated with staphylococcal overgrowth of occluded mucosal surfaces (e.g., superabsorbent tampons or nasal gauze packing).

Treatment of STSS and TSS consists of supportive care, vasopressors, and antibiotics. Adequate antimicrobial coverage for Staphylococcus and Streptococcus should be initiated with clindamycin alone or in combination with penicillin.120 Treatment with intravenous γ globulin may be considered in patients who present hypotensive and with a cellulitis.121 Hyperbaric O2 and plasmapheresis have also been used in STSS.41,122

Staphylococcal Scalded Skin Syndrome

Staphylococcal scalded skin syndrome (SSSS; Fig. 107-11) is a desquamative exanthem that occurs in conjunction with infection of toxin-producing S. aureus phage group II types 3A, 3C, 55, and 71.123 The desquamation is mediated by exfoliative toxins A and B.124 Most patients are younger than 5 years, and adults are only rarely affected. The major risk factors for developing SSSS in adults are renal failure (owing to decreased filtration of toxin), hematologic malignancies, and immunosuppression. The concurrent use of NSAIDs may predispose to SSSS.125

Several factors make SSSS an important consideration in the ICU setting. Nasal carriage of S. aureus is three times higher in hospital personnel and dialysis patients than in the general population. Approximately 6% of the coagulase-positive S. aureus strains randomly isolated from hospitalized patients are toxigenic. Patients in the ICU may be immunosuppressed and/or have renal failure, thereby increasing their risk for acquiring SSSS.

The disease process is similar to bullous impetigo but is generalized rather than localized. Patients may have a preceding upper respiratory infection with rhinorrhea, pharyngitis, and conjunctivitis. The exanthem begins abruptly with diffuse tender erythema and subsequent superficial desquamation. The erythematous skin has a rough sandpaper-like texture often accentuated in the flexural and periorificial area. Because the split occurs in the granular layer (superficial) of the epidermis), intact bullae are rarely seen although when present, the Nikolsky sign may be positive. The skin appears bright pink, moist, and eroded skin after desquamation. The clinical presentation sometimes may be difficult to separate from that of toxic epidermal neurolysis (TEN).

Cultures are taken from all orifices (eye, nose, throat, vagina, and rectum) and blood. The diagnosis of SSSS is supported by the isolation of S. aureus. Rapid distinction from TEN may be made by frozen section of the exfoliated skin and histopathologic examination to determine the level of cleavage. Biopsy at the border of a blister and normal skin should also be sent for routine processing. Cultures from blisters are negative owing to the toxin-mediated nature of the disease.

Treatment of SSSS requires appropriate antibiotics and vigilant monitoring of fluids and electrolytes. Antibiotic choice usually includes penicillinase-resistant semisynthetic penicillins (nafcillin, methicillin, or dicloxacillin) or a first-generation cephalosporin. Monotherapy is usually adequate because multiresistant strains of S. aureus are rarely encountered among the toxigenic strains. Adjunctive measures include the application of bland lubricants for the patient's comfort. Healing occurs in 7 to 10 days.

Pseudomonas Bacteremia

Different skin manifestations of pseudomonas bacteremia have been described. These have been divided into four categories.126 The first is ecthyma gangrenosum, which is characterized by a localized, erythematous, tender plaque or bulla that subsequently develops central necrosis leaving a gangrenous eschar with an erythematous annular border. The lesions can occur anywhere but are usually found in the anogenital region, buttocks, or axilla.127 Ecthyma gangrenosum occurs in approximately 5% of patients with pseudomonas bacteremia and has been described in association with localized pseudomonas infection without bacteremia. The second category includes vesicles or bullae that can occur anywhere and may occur singly or in clusters. These lesions frequently become hemorrhagic and take on the appearance of ecthyma gangrenosum lesions when ruptured. The third category is a cellulitis with a sharply demarcated border. This contrasts with cellulitis caused by staphylococcal or streptococcal infection, which tends to have ill-defined borders. The fourth category of lesion are small pink, round plaques or subcutaneous nodules that are concentrated on the trunk and proximal extremities. The nodules are considered a form of nodular cellulitis and, when incised and drained, grow Pseudomonas aeruginosa in culture. Pseudomonas aeruginosa bacteremia carries a high mortality rate and treatment should be initiated early. This requires dual therapy with an aminoglycoside in conjunction with ticarcillin, piperacillin, ceftazidime, or imipenem.

Vibrio Vulnificus Bacteremia

Vibrio vulnificus is a gram-negative rod that is found in salt water and in shellfish. The main portals of entry in humans are via ingestion (gastroenteritis) or direct inoculation into the skin (cellulitis). There may be an associated septicemia. The other Vibrio species (e.g., cholerae and parahaemolyticus) primarily cause gastroenteritis. Vibrio vulnificus infection is seen most commonly in association with underlying hepatic disease (cirrhosis or fatty liver), diabetes mellitus, chronic renal insufficiency, or underlying immune suppression. Most of the case reports in the United States involve patients with cirrhosis who injured themselves while in salt water or who ate raw oysters.128

A patient will present with an erythematous painful swollen limb with overlying hemorrhagic bullae and fever. Thirty-three percent of patients are in shock within 12 hours of presentation. The incubation period after ingestion is 4 to 96 hours. There may be a history of an abrasion occurring while in salt water or the recent ingestion of raw shellfish. The presence of hemorrhagic bullae overlying a cellulitis with the appropriate clinical history is highly suspicious for V. vulnificus septicemia. The clinical picture may be very similar to that of NF.

Aspiration of blister fluid for Gram stain and culture is essential, and biopsy for culture may be useful. Elevated creatine phosphokinase levels are often present in this condition and in STSS. This is in contrast to the normal creatine phosphokinase levels usually found in the less rapidly progressive conditions of cellulitis and erysipelas, and may be a helpful distinguishing feature.129 The laboratory should be alerted when Vibrio infection is suspected so that the material is set up for culture on thiosulfate-citrate-bile salt-sucrose agar. On thiosulfate-citrate-bile salt-sucrose agar, V. vulnificus yields large green colonies within 24 hours of aerobic incubation.130

Fortunately, V. vulnificus is sensitive to most antibiotics. Because of the high mortality and morbidity rates, effective treatment includes early search for and recognition of the infection, aggressive antibiotic therapy, supportive care, and, in cases of wound infections, débridement.131 Empiric therapy includes doxycycline or minocycline with an aminoglycoside or cephalosporin.

Meningococcemia

Acute infection with the gram-negative diplococcus Neisseria meningitidis is associated with characteristic cutaneous findings, which may aid in the early diagnosis of this rapidly fatal disease. Characteristic findings are petechiae, ecchymoses, or palpable purpura. Petechiae may be preceded by an urticarial, rubella-like, papular, or generalized scarlatiniform eruption for 2 days. Petechiae may have a smudged appearance and tend to be concentrated on the trunk, proximal extremities, and mucosal surfaces (Fig. 107-12). The number of petechiae correlates with the degree of thrombocytopenia and is indistinguishable from other causes of petechiae such as diffuse intravascular coagulation (DIC). A late finding may be hemorrhagic vesicles or bullae centrally located within a purpuric patch. Patients with deficiency of late-acting complement factors (C5 to C8) are at particular risk for severe or recurrent meningococcal infections.132

The purpura seen in meningococcemia is mediated by two events. The first is thrombosis precipitated by meningococcus, fibrin, and leukocytes with a corresponding leukocytoclastic vasculitis. Thrombi are concentrated in the lung, skin, spleen, heart, and liver. The second is DIC precipitated by meningococcal endotoxin.133 Fibrin thrombi within a vessel and a corresponding vasculitis are seen on histology.

The diagnosis is aided by a skin smear for Gram stain and biopsy for culture. Blood polymerase chain reaction is a sensitive test for confirming meningococcal disease.134 Mortality rates are high and fewer than 30% with septic shock survive. Mortality rate is higher with increasingly extensive skin hemorrhage (purpura fulminans). Prompt antibiotic treatment is essential to decrease mortality rate, and drotrecogin-alpha (recombinant human activated protein C) may be particularly valuable. High-dose penicillin is still the drug of choice despite evidence of some less susceptible strains of meningococcus.135 Cefotaxime and ceftriaxone have the advantages of being safe with a rapid onset of action and also being excellent antibiotics for Streptococcus pneumoniae and Haemophilus influenza, pending confirmatory diagnosis. Chloramphenicol is an acceptable alternative in penicillin-allergic patients.

The differential diagnosis of the purpuric lesions of meningococcemia includes gonococcemia, rickettsial infection, allergic vasculitis, bacterial endocarditis (with S. aureus or viridans streptococci), and DIC. Patients with gonococcemia usually have an associated arthritis and tenosynovitis with a very few scattered petechiae, each surmounted by a tiny pustule occurring in an acral distribution. Symmetric petechiae of the palms and soles are highly suggestive of Rocky Mountain spotted fever (infection with Rickettsia rickettsii).

Infective Endocarditis

The most common cutaneous finding in patients with infective endocarditis is petechiae. Petechiae are found in approximately 30% of patients and may be secondary to microemboli; however, bacteria are rarely cultured from skin specimens. Petechiae may appear on conjunctiva, buccal mucosa, palate, and retina (Roth spots). Petechiae on fingers or nail beds manifest as red to brown streaks termed splinter hemorrhages. Splinter hemorrhages are also seen in the elderly or related to trauma. The lesions are most suggestive of infective endocarditis when they occur on the proximal nail beds.

Petechiae occurring on the palms and soles with a nodular character are termed Janeway lesions (Fig. 107-13). Janeway lesions are characteristically nontender.136 The lesions result from septic emboli consisting of bacteria, neutrophilic infiltration, and subcutaneous hemorrhage. Janeway lesions persist for several days and occur commonly in staphylococcal endocarditis. Osler nodes are small (2 to 15 mm) painful nodules.137 The lesions are commonly found on the pads of the fingers, toes, or thenar eminences. They tend to occur in crops, are frequently multiple and evanescent, and disappear within hours to days. Osler nodes are seen in 5% to 15% of patients with streptococcally induced infective endocarditis but may also be seen in systemic lupus erythematosus, endocarditis due to fungal or gram-negative bacilli, typhoid fever, gonococcemia, and on the arms of patients with cannulated radial arteries. Microscopic examination shows microemboli in adjacent arterioles. Janeway lesions and Osler nodes resolve with appropriate antibiotic therapy. Clubbing of the digits is a nonspecific finding found in 10% to 20% of cases of infective endocarditis, especially when the disease is of long duration.

Herpes Simplex

Cutaneous herpes infection is associated with herpes simplex virus (HSV) types 1 and 2 that can occur on any cutaneous area. In general, HSV-1 causes orofacial infection and HSV-2 causes anogenital infection, although this distinction is changing with HSV-1 causing up to one-third of new genital infections. HSV-2 genital infection recurs six times more frequently than HSV-1 genital infection.138 Any stress on the immune system increases the likelihood of expression of HSV in a previously infected individual. The classic appearance of recurrent HSV infection is a cluster of vesicles or shallow erosions over the lips, genitals, and lumbosacral region (Fig. 107-14). It is not uncommon for the vesicles to go undetected, so the patient presents with punched-out erosions or shallow ulcerations. In the ICU, recurrent infections are extremely common and related to the stress of illness or the degree of immunosuppression. The patient may not have been aware of any previous outbreaks, but in the immunosuppressed, if early lesions go undetected, large, erosive areas of ulceration may occur. Chronic perianal HSV ulcers are easily mistaken for decubitus ulcers. Scalloped borders and small circular ulcerations at the periphery of the ulcer may be helpful distinguishing signs.

Rapid diagnosis in 30 minutes to 2 hours may be done by DIF on cells that have been smeared on a glass slide with saline and dried or by direct fluorescent antibody (DFA) testing with monoclonal antibodies on cultured specimens.139,140 This highly sensitive test distinguishes HSV-1 from HSV-2. Bedside diagnosis is aided by performing a Tzanck smear. The vesicle is unroofed, and the base of the lesion is scraped with a blade. The scraping is spread evenly on a glass slide and then allowed to air dry or is fixed with alcohol. The slide is then stained with Giemsa, Toluidine blue, or Diff-Quik stain and examined for multinucleated giant and/or balloon cells. If no vesicles are present, a scraping from a moist erosion may be helpful (crusted lesions generally will not yield a positive result). An early vesicle should be chosen for biopsy to avoid secondary changes that might obscure the characteristic features. These include an intraepidermal bulla with ballooning degeneration of keratinocytes at the base of the vesicle. Balloon cells develop intracellular edema and subsequently break their desmosomal attachment to adjacent cells and float up into the bulla cavity. These cells are often multi-nucleated (2 to 15 nuclei) and correspond to the multinucleated giant cells seen on the Tzanck smear. Culture of the vesicle fluid will allow identification of HSV or varicella zoster virus (VZV). HSV usually grows within 48 hours in tube cell cultures, whereas VZV may take 7 to 14 days to grow. Antibodies to HSV are found in 50% to 90% of adults. Testing is generally unhelpful for a diagnosis of a particular outbreak. The presence of IgM or a fourfold or greater rise in IgG titer reflects recent infection. The presence of IgG indicates prior exposure.

All HSV and VZV infections encountered in the ICU should be treated promptly with an antiviral agent such as acyclovir, famciclovir, or valacyclovir usually intravenously, although the medications are effective orally. These medications are converted to triphosphorylated purine analogues via viral thymidine kinase and host cell enzymes. Acyclovir triphosphate is an inhibitor and a substrate for viral DNA polymerase and becomes incorporated into the growing DNA chain. Acyclovir triphosphate lacks a hydroxyl group in the 3′ position and further chain synthesis is halted. In the setting of immunosuppression, strains of acyclovir-resistant HSV and VZV have developed. Resistance occurs when viral thymidine kinase no longer phosphorylates acyclovir (or famciclovir). Foscarnet is a second-line agent for treatment of HSV and VZV in cases where resistance occurs. Foscarnet attaches to the pyrophosphated binding sites of viral DNA and RNA polymerases, causing reversible inhibition of enzyme activity. Foscarnet does not require viral thymidine kinase for activation. Foscarnet is administered intravenously at a dose of 60 mg/kg twice daily or 40 mg/kg three times daily. HSV and VZV resistance to acyclovir can be determined in the laboratory.141

Local care consists of 0.5% silver nitrate or Burrow compresses applied for 20 minutes three to four times daily to alleviate swelling, inflammation, maceration, and crusting of extensive erosions. Topical acyclovir in general is not useful but may speed the healing of erosive HSV in immunosuppressed individuals. Topical penciclovir applied every 2 hours for 4 days has been shown to decrease clinical healing time by about 1 day in primary infections.

An important complication of HSV infection is eczema herpeticum. This is disseminated cutaneous HSV infection that occurs in patients with an underlying dermatitis such as atopic dermatitis, seborrheic dermatitis, contact dermatitis, or Darier disease. Patients present with diffuse crusting that may or may not be preceded by typical herpetic lesions. Intact vesicles are rarely seen. Diffuse eczema herpeticum is a severe and potentially life-threatening condition that may require therapy with intravenous acyclovir.142

Varicella Zoster

The varicella zoster virus belongs to the herpesvirus family (DNA-enveloped viruses). Varicella (chicken pox) is the primary disease, and zoster (shingles) is a recrudescence of the latent form. Primary infection occurs via aerosolized respiratory droplets (most common) or direct contact with vesicle fluid. After primary infection, the virus lies dormant in the dorsal root ganglion until reactivation occurs. Reactivation results in spread of the virus down the nerve root, causing pain, erythema, and vesicles in a dermatomal distribution.

The classic cutaneous finding in varicella is a generalized eruption of discrete vesicles, each on an erythematous base (“dew-drop on a rose petal”). These appear after an average incubation period of 14 days (range = 9–21 days) and are usually seen in association with prodromal symptoms of fever and malaise. The patient is contagious from 2 days before the eruption until all lesions have crusted. The vesicles first appear on the trunk and spread to the extremities. Lesions commonly occur in the mouth and vagina and tend to rupture rapidly, leaving small ulcers (aphthae). The cutaneous lesions progress from an erythematous papule to a vesicle to a hemorrhagic crust. There may be lesions at various stages of development at any one time. Varicella infection in adults and the immunosuppressed can be life-threatening. The most common complication is varicella pneumonia. Pneumonia generally appears 1 to 6 days after the onset of the rash. The symptoms may be out of proportion to chest radiographic findings. Encephalitis may be seen in patients with a persistent viremic state and appears to correspond to direct infection of the central nervous system. An immune complex vasculitis may lead to pancreatitis, myocarditis, arthritis, and palpable purpura.

Herpes zoster presents with a prodrome of intense pain affecting a dermatome before the onset of an erythematous, urticarial plaque in which the characteristic vesicles are seen. The eruption is generally unilateral, but spread across the midline and “spillover” into adjacent dermatomes may be seen. After several days the vesicles appear purulent or hemorrhagic. A crust subsequently forms. Occasionally, the only symptom is unilateral severe pain because the associated rash does not occur or goes undetected.

The most common dermatomes affected are in the thoracic (55%) and trigeminal (15% to 20%) distribution. Varicella zoster rarely occurs distal to the elbows or knees. Involvement of the eye is caused by infection of the ophthalmic branch of the trigeminal nerve. This may lead to conjunctivitis, keratitis, and iridocyclitis. The nasociliary branch innervates the tip and side of the nose. This branch also supplies the globe of the eye. Vesicles occurring in this area (Hutchinson sign) may be a clue to potential eye involvement. Ophthalmologic consultation is mandatory.

In patients who are immunosuppressed, disseminated herpes zoster may occur. The rash is initially limited to a few contiguous dermatomes and spreads to involve large areas of the body over several days. Patients should receive full doses of intravenous antiviral therapy.

Varicella zoster and HSV infection are diagnosed by Tzanck smear, histology, culture, DIF, and DFA. Tzanck smear and histology do not distinguish between VZ and HSV. Culture will identify the virus but may be delayed up to 14 days. DIF or DFA is recommended when rapid diagnosis is required.

Smallpox (Variola)

The WHO declared the world free of smallpox in 1980. The last case of naturally acquired smallpox occurred in Somalia in 1977 and the last case in the United States occurred in 1949. The threat of smallpox as a potential agent of terror has brought the disease back into focus (see Chap. 61). The cause is one of two Orthopoxviridae, variola major or variola minor. We have not seen the natural disease for more than 25 years, so the following description is based on old experience. The disease is spread through droplets during face-to-face contact by coughing or by contact with body fluids such as vesicle or conjunctival fluid, urine, or saliva. It enters the body through the respiratory tract.143 Infectiousness starts 1 day before the onset of the rash, peaks during the first week of the rash, and continues until the lesions are completely healed across. Incubation time is typically 7 to 17 days. Malaise, fever, and backache are followed by the exanthem in 2 to 4 days. Case fatality rate may be as high as 60% in an unvaccinated population with variola major and is due to pulmonary edema from heart failure.

The Center for Disease Control and Prevention (http://www.bt.cdc.gov/agent/smallpox/index.asp) has defined three major criteria for smallpox: (1) febrile prodrome occurring 1 to 4 days before rash onset, fever with a temperature higher than 101°F, and at least one of the following: prostration, headache, backache, chills, vomiting, or severe abdominal pain; (2) classic smallpox lesions consisting of deep-seated, firm, round, well-circumscribed vesicles or pustules that may become umbilicated or confluent; and (3) all lesions are in the same stage of development on any one part of the body, such as the face or the arm. Minor criteria include: (1) a centrifugal distribution of lesions with a predilection for the face and distal extremities; (2) lesions first appearing on the oral mucosa/palate, face, or forearms; (3) a toxic- or moribund-appearing patient; (4) slow evolution of lesions from macules to papules to pustules, with each stage lasting 24 to 48 hours; and (5) lesions on the palms and soles. The lesions scab at about 9 days and often leave pink, depressed pock marks that become permanent scars. The presence of many confluent or hemorrhagic lesions is correlated with the severity of the disease and portends a poor prognosis.

Varicella is the most likely condition to be confused with smallpox. The lesions of varicella are more superficial and are not preceded by a prodrome. They appear in crops, evolve rapidly, and have different stages of evolution, with papules, vesicles, and erosions appearing on any individual body segment at the same time. Other conditions to consider include disseminated herpes zoster, molluscum contagiosum, bullous impetigo, morbilliform drug eruptions, contact dermatitis, erythema multiforme, Stevens-Johnson syndrome, enteroviral infections, especially hand-foot-and-mouth disease, disseminated herpes simplex, scabies, and insect bites including flea bites.

No curative treatment is known for smallpox. Supportive care and treatment of secondary infections, often staphylococcal, are mainstays of therapy. Vaccination within 4 days of exposure may prevent or lessen the severity of the illness. Vaccinia immune globulin, which is in limited supply but can be obtained from the Centers fro Disease Control and Prevention, may be helpful if given early enough. There is no experience with antiviral agents.

Hepatitis C Virus

Infection with the hepatitis C virus (HCV) is associated with several dermatologic conditions. These include vasculitis (secondary to cryoglobulinemia), porphyria cutanea tarda, lichen planus, polyarteritis nodosa (rare), and generalized pruritus (common). Necrolytic acral erythema is associated with acute hepatitis C.

Two types of vasculitis have been associated with hepatitis C: leukocytoclastic vasculitis (which affects postcapillary venules) and necrotizing arteritis (which affects arteries in the subcutaneous tissue). The vasculitis is secondary to a mixed cryoglobulinemia. Palpable purpura, urticarial weals, or livedo reticularis (a mottled net-like pattern of blue-brown macules) characterize the vasculitis. The prevalence of mixed cryoglobulinemia in HCV-positive patients is 2% to 5% and is probably twice this in patients with hepatitis C–related chronic active hepatitis. Leukocytoclastic vasculitis may be the presenting sign of HCV infection. Rheumatoid factor is an extremely sensitive serologic marker for mixed cryoglobulinemia in HCV-infected patients.

Porphyria cutanea tarda (PCT) is a rare disease that is characterized by a defect in the enzyme uroporphyrinogen decarboxylase, which is essential to the production of protoporphyrin. Protoporphyrin is the precursor of heme, which is an important component of hemoglobin, myoglobin, cytochromes, peroxidases, and catalases. Two types of PCT exist: acquired and familial (autosomal dominant). Acquired PCT has been classically associated with liver disease. HCV may be the factor that links PCT and liver disease. The prevalence of HCV may be as high as 95% in patients with acquired PCT. The cutaneous manifestations of PCT include bullae and hyperpigmentation over sun-exposed areas of the body. Scarring, milia, and hypertrichosis, often seen on the sides of the face, develop as lesions resolve. The bullae of PCT are induced by visible light in the 400- to 410-nm wavelength (Soret band).144

A 24-hour collection of urine will show elevated levels of uroporphyrin and coproporphyrin. Quick screening for excess urinary porphyrins using a Woods lamp (blue light) on an acidified urine sample will demonstrate a characteristic coral-pink fluorescence.

Skin biopsy of a bulla shows characteristic histologic findings of a subepidermal separation of the epidermis from the dermis, with festooning of the dermal papillae into the base of the bulla related to the presence of hyaline-like material around the blood vessels and in the upper dermis. Laboratory data demonstrate excess total body iron stores.

The treatment of PCT is focused on decreasing the patient's iron load. Periodic phlebotomy to maintain a hemoglobin level of 10 g/dL or until the serum iron drops to 50 to 60 μg/dL. In cases in which phlebotomy is contraindicated or ineffective, small doses of chloroquine (125 mg twice weekly) may be effective. The response of PCT in patients treated with pegylated interferon α and ribavirin for hepatitis C has not been determined.

Lichen planus (LP) is an inflammatory cutaneous eruption characterized by purple-violaceous, polygonal, pruritic papules that have a predilection for the flexor surfaces of the forearms and wrists. Mucosal involvement manifests as a lacy white reticulate pattern on the buccal mucosa and gingiva. The prevalence of hepatitis C in patients with LP is variably estimated to be from 4% to 38%. LP also may occur secondary to medications such as thiazide diuretics, β blockers, gold, and antimalarials. Most cases are idiopathic.145,146

Other skin manifestations are a consequence of treatment with interferon α. These include erythema at injection sites, transient alopecia, excessive skin dryness, and sweating. Psoriasis may flare, and cutaneous necrosis has occurred due to the accidental injection of interferon α into an artery. There appears to be a high incidence of lichenoid cutaneous reactions with the combination of interferon α and ribavirin.

Human Immunodeficiency Virus

The cutaneous manifestations of HIV infection are protean. An acute nonspecific exanthem in association with influenza-like symptoms is seen in up to 66% of patients soon after initial infection. Subsequent cutaneous manifestations of HIV can be divided into three broad categories: inflammatory, infectious, and malignant.147

The most common inflammatory cutaneous manifestation of HIV-1 infection is seborrheic dermatitis. Seborrheic dermatitis is characterized by erythema and greasy scales over the scalp, eyebrows, nasolabial folds, chin, chest, and groin areas. The etiology of seborrheic dermatitis is unclear, but infection with the yeast Pityrosporum ovale has been proposed as the underlying cause. Psoriasis is also commonly seen in HIV-1 infection. Psoriasis is characterized by erythematous, welldemarcated plaques with a silvery scale that has a predilection for the extensor surfaces of the extremities, scalp, and trunk. Psoriasis may be seen alone or in association with Reiter syndrome (classic triad of conjunctivitis, urethritis, and arthritis). The rash associated with Reiter syndrome is also referred to as keratoderma blenorrhagicum (psoriasis of the soles) and balanitis circinata (psoriasis of the glans penis). The initial lesions are dull red macules that become papular and pseudovesicular. The roofs thicken to form hyperkeratotic plaques, and scaly collarettes may be seen. The mature lesions may stand out 1 cm or so from the skin. Reiter syndrome may be a reaction pattern seen in association with gastrointestinal infection (Salmonella, Shigella, or Yersinia) or Chlamydia infections.

The infections seen in patients with HIV-1 range from common conditions that take on a more aggressive and recalcitrant course (common warts, molluscum contagiosum, herpes simplex (HSV), varicella zoster, candidiasis, and dermatophyte infections) to rare conditions seen more commonly in the immunocompromised host (Mycobacterium tuberculosis, atypical mycobacteria, Mycobacterium avium intracellulare, Cryptococcus neoformans, and deep fungal infections). Infectious diseases may have atypical appearances. The classic flesh-colored papules with central umbilication seen in molluscum contagiosum closely resemble the cutaneous manifestations of C. neoformans and histoplasmosis. Chronic cutaneous ulceration may be the result of an underlying infection such as HSV, bacteria, fungus, mycobacteria, and atypical mycobacteria. Oral hairy leukoplakia (OHL; secondary to Epstein-Barr virus) and mucous membrane candidiasis are commonly seen. White plaques of OHL appear on the sides of the tongue, and the white patches due to colonization by Candida albicans may occur on any mucosal surface. Rubbing the white plaques removes candidal colonies, but OHL lesions are adherent.

The most common malignancies seen in association with HIV-1 infection are Kaposi's sarcoma (KS) and lymphomas. KS is almost always associated with human herpes virus 8 infection, although other factors, such as immunosuppression, may be necessary for its induction. HIV-associated KS is seen almost exclusively in homosexual males. It is rarely seen in patients who contracted the virus by nonsexual means. Cutaneous findings in KS vary from violaceous macules to plaques or nodules. Lesions may appear anywhere and at any time during the course of HIV infection. They tend to be symmetrically distributed, form oval patches along skin tension lines, and are often seen on the palate and tongue.148 Individuals with HIV have a 200-fold increased risk of nonHodgkin's lymphoma compared with the general population. Most of these lymphomas are of the B-cell variety and are associated with aggressive disease. The pathogenesis is not known but probably involves HIV, immune dysfunction, cytokine dysregulation, and other viral antigens (e.g., human herpes virus 8 and Epstein-Barr virus). Extranodal disease is the norm, and skin involvement is not unusual. Clinically, this includes variably distributed erythematous to flesh-colored papules or nodules.149

Superficial Fungal Infections

Fungi are ubiquitous. Geophilic fungi inhabit soil and are frequently isolated from the hair of small wild animals and birds. Zoophilic fungi are parasitic on animals, whereas anthropophilic fungi primarily live on human beings. Dermatophytes are specialized saprophytic fungi that use keratin and establish an equilibrium with the host, causing an ongoing toxic or allergic reaction. Yeasts are unicellular fungi. Dermatophytes (Epidermophyton, Microsporum, and Trichophyton) and yeasts (Candida species and Pityrosporum) cause superficial fungal infections. Dermatophyte infection may occur on any cutaneous surface including the hair and nails. Classic lesions are polycyclic, erythematous, scaling and have central clearing and a raised border. Pruritus is common. A raised, pustular, boggy inflammatory lesion is more likely to occur when a zoophilic fungus causes a human infection (e.g., a kerion in the scalp caused by Microsporum canis). Infections are named according to site of infection: tinea capitis (scalp and hair), tinea manuum (hand), tinea corporis (body), tinea cruris (groin), and tinea unguium (nail). All these conditions are common. For instance, tinea capitis occurs predominantly in prepubertal inner city children with a classroom prevalence rate 15% or higher in some areas, and toenail onychomycosis is variously estimated to have prevalence rates of 2% to 13% in the United States population, 15% to 20% in persons 40 to 60 years old, and higher than 50% in persons older than 70 years.

A bedside diagnosis can be made by demonstrating septate hyphae in potassium hydroxide mounts of scales or in material obtained from debris under an infected nail. The addition of chlorazol black E may enhance the visibility of the hyphae.150 Culture for accurate identification of a fungus may be done on Sabouraud dextrose agar with cycloheximide and chloramphenicol. The fungus may take 4 weeks to grow. For more rapid confirmation that a dermatophyte is present, dermatophyte test medium (turns red by 2 weeks when a dermatophyte is present) is often used. This test does not allow separation of one dermatophyte species from another.

Twice-daily topical treatment with allylamines (naftifine or terbinafine) or imidazoles (ketoconazole, econazole, or clotrimazole) is usually curative for skin infections. Despite a relative lack of sensitivity of trichophyton tonsurans, the common cause of tinea capitis, to oral griseofulvin, this agent is still in general use for scalp and hair infections. It is likely that one of the newer oral agents (e.g., terbinafine) will soon become the preferred treatment. Topical therapy has only limited success for nail involvement. A 3- or 4-month course of oral terbinafine or pulsed itraconazole is necessary to clear toenails. Fingernails require only 6 weeks of oral therapy. Other possible agents include fluconazole and ketoconazole.151,152 Primary cutaneous infection with C. albicans occurs in moist, warm environments such as intertriginous areas. Patients develop bright red, moist plaques with satellite pustules. The differential diagnosis includes dermatophyte infection, erythrasma (caused by Corynebacterium minutissimum), seborrheic dermatitis, and psoriasis. The diagnosis is supported by the typical pseudohyphae on potassium hydroxide mount or culture.

During the past two decades, the incidence of candidemia in patients in ICUs has soared from 1.5 to 60 infections per 10,000 adult ICU admissions and from 23 to 123 infections per 10,000 neonatal ICU admissions. Even with antifungal therapy, the mortality rate approaches 30%. Most cases occur in patients who have central venous lines placed. Candida species on the skin of the patient or caregivers can insinuate their way into these catheters, adhere to the inside of the tubing, and form biofilms.153 Disseminated candidiasis presents with the characteristic cutaneous finding of widespread papules and pustules. In neutropenic patients with candidiasis, the skin lesions may not develop until the white count begins to recover.154 Neutropenia and immunosuppression are the greatest risk factors for disseminated candidiasis. The differential diagnosis includes steroid-induced acne, which may develop in conjunction with chemotherapy. In steroid acne, the pustules arise from the hair follicle, are all in the same stage of development, and tend to concentrate on the face, shoulders, and upper trunk.

Diagnosis can be attempted by culturing the blood, the pustule contents, or tissue obtained from a skin biopsy, but the yield may be as low as 50%. Biopsy specimens may be stained with periodic acid-Schiff (PAS) or silver methenamine stain to visualize yeast forms. There is a need for better technology to identify disseminated candidiasis. Detection of anti-Candida antibodies, Candida metabolites, Candida DNA or the release of β glucan into the blood have not proved to be of general clinical use thus far.155

Colonization with Pityrosporum ovale or orbiculare may cause the very common tinea versicolor or it may lead to Pityrosporum folliculitis. Tinea versicolor presents with hypo- or hyperpigmented, regularly colored tan macules superimposed with a very fine scale, often on the upper trunk and limbs. It is seen in adolescents and young to middle-age adults. Typical hyphae and spores (“spaghetti and meatballs”) are seen on potassium hydroxide mounts. Treatment with topical antifungals, such as selenium sulfide or ketoconazole, is effective, but the pigmentary change may persist for some months. Recurrence is common.

Pityrosporum folliculitis presents with asymptomatic or slightly itchy follicular papules and pustules on the face, chest, and back of mainly young women. Predisposing factors include antibiotic ingestion, steroid treatment, diabetes, Hodgkin disease, and living in the tropics, where men and women are equally affected. The involvement of the periphery of the face, the nape of the neck, the lower trunk, buttocks, and thighs distinguishes this infection from acne vulgaris. Resolution follows the use of topical antifungals as for tinea versicolor or the use of oral ketoconazole and topical keratolytic agents.

Deep Fungal Infections

Deep cutaneous fungal infections are uncommon in the immunocompetent host. Opportunistic infections occur in patients who are immunocompromised by malignancies, systemic agents, or medical conditions, including the acquired immunodeficiency syndrome. Hematogenous seeding to the skin from the lung is the most common route for aspergillosis, histoplasmosis, blastomycosis, cryptococcosis, and zygomycosis (including the frequently fatal infections caused by Mucorales).156 Direct inoculation may occur but is less common. Lesions present as inflammatory plaques, ulcerations, nodules, and papules. Differentiation cannot be made on clinical grounds alone. Umbilicated papules resembling lesions of molluscum contagiosum are characteristically seen in disseminated cryptococcosis, but they have also been reported in disseminated aspergillosis and histoplasmosis. Biopsy and culture of the lesions is imperative. Under the microscope with the appropriate stains, rounded refractile spherical cells with broad-based buds are seen in blastomycosis (potassium hydroxide mounts of pus smears), macrophages containing tiny yeast-like spores in histoplasmosis (hematoxylin and eosin, Gram stain, or a Giemsa stain), round to ovoid spores usually with large capsules in cryptococcosis (India ink mounts of pus smears), branching septate hyphae in aspergillosis (hematoxylin and eosin, PAS or silver methenamine stains), and vascular invasion by very large, long, non-septate hyphae in mucormycosis (hematoxylin and eosin, PAS, or silver methenamine stains). Systemic treatment with itraconazole, fluconazole, amphotericin B, or caspofungin is required to control each of these diseases, as is extensive debridement of all necrotic tissue.157

Miliaria

Miliaria, sometimes referred to as heat rash, is caused by obstruction of the eccrine (sweat) ducts at a variety of levels causing sweat retention. Miliaria can be classified into three groups, based on the levels of ductal obstruction: miliaria crystalline, miliaria rubra, and miliaria profunda.157

Miliaria crystallina (also known as sudamina), presents as crops of 1 to 2 mm asymptomatic, clear fluid-filled vesicles (“dew drops”) on the skin, which develop after an episode of increased termperature (e.g., fever, increased ambient temperature), or after increased sweating (e.g., fever or drug-induced), increased ambient humidity (particularly in babies and the bedridden).

Miliaria rubra (also known as prickly heat) represents the same pathologic process o sweat duct obstruction and sweat retention, but in the stratum granulosum, resulting in 1–2 mm paroxysmally pruritic or stinging erythematous papules or macules. This type of miliaria is characteristic of hot and humid climates, affecting up to 30% of the population. Resolution of lesions is followed by variable periods of anhidrosis. The eruption often occurs on the trunk and neck, but it ca occur anywhere except the face and volar areas. Treatment consists of reducing the ambient temperature and humidity, and emollient application. When there is bacterial overgrowth, miliaria pustulosa may occur.158

Miliaria profunda (also known as mamillaria) is less frequent than the other types, and is characterized by asymptomatic 1 to 3 mm pink papules usually located on the trunk, that result from sweat duct obstruction at or below the dermalepidermal junction. This type of miliaria results from multiple episodes of miliaria rubra, as occurs in tropical climates. It may lead to extensive anhidrosis, predisposing the individual to malaise, dyspnea, tachycardia, hyperpyrexia, heat exhaustion, and in prolonged cases, to tropical anhidrotic asthenia.159

Dry Skin

Xerosis (dry skin, asteatosis) is one of the most common dermatologic conditions, and is characterized by a dry, scaly noncompliant, and rough appearance of the skin. Although most individuals will experience some degree of xerosis, prevalence increases with age (>75% of individuals over 64).160 Most commonly affected areas are the hands, the shins, the posterior upper arms, and the back.

In spite of its generally benign course, systemic causes must be taken into consideration, especially if the condition is severe and associated with inflammation: malignancies (usually lymphoproliferative), renal disease (uremic frost), obstructive biliary disease, hypothyroidism, drugs (lithium, isotretinoin), chronic diseases, and malnutrition leading to hypovitaminosis. Aggravating factors such as cold, dry, windy climates, air-conditioning, as well as organic solvents, harsh detergents, excessive bathing, or hot baths result in decreased water content in the stratum corneum and an increase in transepidermal water loss (TEWL). Erythema and pruritis are indicators of inflammation, present when the condition is sever. Rubbing and scratching can lead to dermatitis or thickened skin with accentuated markings (lichenification).

Treatment consists in restoring the epidermal water barrier, in order to minimize TEWL.162 This can be achieved by avoiding aggravating factors (see above), only using emollient soaps or soap substitutes, and lipid-based agents (e.g., emollients) that reduce water evaporation (petrolatum, mineral oil, dimethicone, cyclomethicone); humectant agents that attract water into the stratum corneum (glycerin, propylene glycol, urea, sodium lactate, sorbitol). In addition, skin roughness can be decreased with the use of the keratolytic alpha- or beta-hydroxy acids.

Pressure Ulcers

Continuous pressure over a bony site obstructs microcirculation, leading to tissue ischemia and necrosis. Pressure ulcers result, constituting a major problem in the ICU, with reported incidences of 1% to 56% and prevalences of 14% to 41%, which are two- to threefold higher than in other hospitalized patients.158,159 Altered circulation and ventilation and the use of vasoactive drugs may decrease peripheral oxygen delivery to tissues, thereby increasing the risk of pressure ulcers. The development of pressure ulcers leads to increased mortality rates, costs, and lengths of hospital stays.

A National Pressure Ulcer Advisory Panel in 1998 developed the most widely used staging system of pressure ulcers.160 It encompasses four grades.

Stage I

A stage I pressure ulcer is an observable pressure-related alteration of intact skin whose indicators, as compared with the adjacent or opposite area on the body, may include changes in one or more of the following: skin temperature (warmth or coolness), tissue consistency (firm or boggy feel), and/or sensation (pain, itching). The ulcer appears as a defined area of persistent redness in lightly pigmented skin, whereas the ulcer may appear with persistent red, blue, or purple hues in darker skin tones.

Stage II

A stage II ulcer is defined as partial-thickness skin loss involving epidermis, dermis, or both. The ulcer is superficial and presents clinically as an abrasion, blister, or shallow crater.

Stage III

Stage III ulcer is characterized by full-thickness skin loss involving damage to, or necrosis of, subcutaneous tissue that may extend down to, but not through, underlying fascia. The ulcer presents clinically as a deep crater with or without undermining of adjacent tissue.

Stage IV

This ulcer is characterized by full-thickness skin loss with extensive destruction, tissue necrosis, or damage to muscle, bone, or supporting structures (e.g., tendon, joint capsule). Undermining and sinus tracts also may be associated with stage IV pressure ulcers.

Given the right set of circumstances, pressure ulcers can develop within 2 to 6 hours. Many risk factors have been described in the literature, but the risk assessment scales have not been specific for the ICU.161 Notwithstanding the limitations of the studies, risk factors include the duration of previous surgeries and number of operations, preoperative protein and albumin concentrations, skin moisture, use of inotropic drugs, fecal incontinence or diarrhea, altered circulatory status, diabetes mellitus, decreased mobility, and a high score on the Acute Physiology and Chronic Health Evaluation II (APACHE II). Preventive strategies should be implemented from the moment of entry into the ICU. These include the use of risk assessment scales, repositioning the patient every 2 hours, provision of dynamic or static support surfaces that redistribute pressure, and proper nutrition.162 A critical aspect of the topical treatment is the maintenance of a moist environment. This can be achieved by the use of any one of many different dressings: transparent films, hydrocolloids, alginates, foams, hydrogels, or hydrofibers marketed for pressure ulcer care. These dressings require few changes, so they result in less need for nursing care, faster healing, and decreased infection. Gauze dressings, particularly wet to dry dressings, are to be avoided because they allow the wound to dry and, as such, slow healing.163 Surgery may be attempted for recalcitrant, full-thickness ulcers. However, recurrence rates are high.