| TABLE 142.2 Classification of Dermatologic Disorders in Intensive Care Medicine |
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| TABLE 142.3 Life-Threatening Dermatologic Disorders |
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FIGURE 142.1 Severe life-threatening pemphigus vulgaris. Extensive erosions caused acute skin failure.
Mucous Membrane Pemphigoid
Mucous membrane pemphigoid (MMP) includes a group of autoimmune bullous diseases characterized by subepithelial blistering, erosions, and scarring of mucous membranes and/or skin, which generally affects the elderly but can also affect young people and children. The natural course of the disease involves exacerbations and relapses, but it halts, even without treatment, in most patients after 5 years (19).
The typical lesions of MMP are tense blisters that can appear on normal or inflamed skin. The mucous membrane, particularly the oral and ocular mucous, is the most common area affected. The bullae are normally full of clear liquid and do not scar. Unlike pemphigus vulgaris, the lesions are pruritic and, after their rupture, are not painful. The Nikolsky sign is negative (20). The clinical characteristics of the lesions, along with the histopathologic and immunologic findings, are diagnostic. Histologic study of the lesion shows a subepidermal blister with fibrinoid material and inflammatory cell infiltration in its interior, with a predominance of eosinophils. Direct IF will show deposits of IgG and C3 in the dermoepidermal junction, whereas indirect IF shows autoantibodies circulating in the serum of the patient against proteins of the basal membrane.
FIGURE 142.2 Histopathology of pemphigus vulgaris. Intraepidermic blister containing acantholytic cells. 1. Stratum corneum. 2. Granular and spinous layers. 3. Suprabasilar blister. 4. Basal layer. 5. Dermis. Hematoxylin–eosin stain.
Systemic or topical corticosteroids are the mainstay of therapy for MMP. Localized MMP usually responds to topical corticoid treatment (21).
Acute Generalized Pustular Psoriasis
Acute generalized pustular psoriasis (von Zumbusch type) is an acute variant of the psoriasis that is characterized by widespread erythema and pustules. Precipitating factors have been detailed and include infection, pregnancy, hypocalcemia, lithium, and the withdrawal of steroids (22). The disorder is characterized by a high fever, followed by the sudden appearance of sterile pustules 2 to 3 mm in diameter. Skin pain and tenderness are also observed. These are initially noted in pre-existing psoriatic plaques but rapidly generalize to the trunk and extremities, including palms and soles, and are associated with generalized erythema (23).
The diagnosis is clinical, based on the previous history of psoriasis with the appearance of marked erythema and pinpoint pustules.
The recommended first-line therapy is acitretin, cyclosporine, and methotrexate. However, infliximab is a good alternative, especially in patients with extensive diseases. Topical therapy may be useful as an adjunct to systemic therapy. Triamcinolone ointment plus wet dressings reduces scaling, tenderness, pruritus, and discomfort, and helps to re-establish the barrier function of the skin (24).
Erythroderma
Erythroderma is defined as a cutaneous inflammation affecting more than 90% of the body surface area, with a loss of normal integumentary function. It is the clinical manifestation of diverse dermatologic or systemic diseases (Table 142.4). The most frequent causes are psoriasis, spongiotic dermatitis, drug reaction, and cutaneous T-cell lymphoma, although, on occasion, it is not possible to identify the underlying disease, and the disorder is classified as idiopathic erythroderma (25).
Laboratory findings are not particularly helpful in making the diagnosis of erythroderma. Clinical signs, together with a cutaneous biopsy, are what actually yield the data for the diagnosis.
The main objective is the control of systemic problems derived from the loss of cutaneous function. Parallel to this, it is necessary to investigate the disease responsible for erythroderma in order to establish a specific treatment regimen. In the case where the underlying disease is not known, we evaluate the use of corticosteroids and cyclosporine (26).
Severe Drug Eruptions
Toxic Epidermal Necrolysis
Toxic epidermal necrolysis (TEN), described by Lyell, is a dermatologic disease caused by an idiosyncratic reaction to drugs. Usually it starts with a nonspecific febrile picture, followed by mucocutaneous lesions, and later develops epidermal detachment, which affects more than 30% of the body’s surface area (27); the mortality rate ranges between 30% and 50%.
| TABLE 142.4 Principal Causes of Erythroderma |
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Certain medications, an altered immune response, and genetic susceptibility are predisposing factors to develop TEN. Sulfonamides are the drugs most frequently associated with TEN, followed by cephalosporins, quinolones, imidazoles, and anticonvulsants such as carbamazepine and phenytoin. Certain specific HLA genotypes have been implicated in TEN caused by carbamazepine and allopurinol, namely HLA-B1502. This association has been found mostly in the Han-Chinese, Thai, and Malaysian populations but not in Caucasian patients. Therefore, the FDA recommends genetic screening for patients of Asian ancestry before initiation of carbamazepine therapy (28).
The severity and prognosis of TEN is assessed based on the SCORTEN scale. This scoring system use seven independent factors: age, malignancy, heart rate, percentage of epidermal detachment, serum urea, serum glucose, and serum bicarbonate. However, a potential limitation is that SCORTEN may underestimate mortality in patients with respiratory involvement (29).
The lesions start as erythematous macules, followed by flaccid blisters that are easily ruptured, producing necrosis and weeping from the epidermis; the Nikolsky sign is positive. The eroded surface usually comprises between 30% and 80% of the cutaneous surface. In most cases, there is mucous membrane involvement with painful erosions.
TEN lesions are characterized by a massive apoptosis of the epidermis that induces epidermal necrosis with the development of subepidermal blisters, with an underlying sparse mononuclear cell infiltration (30).
After making the diagnosis, the first therapeutic response is the rapid withdrawal of potentially culpable medications from the patient, along with general supportive therapy; the latter therapy usually requires a burn or ICU. The major goal of supportive care is resuscitation and cardiovascular stabilization.
Although corticosteroids have been used extensively, they have not demonstrated obvious beneficial effects and, in some series, result in an increase in mortality. Notwithstanding this lack of positive effect of steroids, severe TEN may be treated with cyclosporine at a dose of 3 to 5 mg/kg/d; this regimen has resulted in promising results. Other therapies, such as zinc, plasmapheresis, and immunoglobulins, although promising, require more study (31,32).
Stevens–Johnson Syndrome
Stevens–Johnson syndrome (SJS) is a mucocutaneous disease caused by a drug-induced reaction, sharing etiologic, histologic, and therapeutic characteristics with TEN. Classically, SJS was considered a severe variant of erythema multiforme. Today, however, these are considered to be two different entities (33).
The clinical presentation of SJS is the same as that of TEN but usually involves less than 10% of the total body surface area. The range of epidermal loss between 10% and 30% is called SJS–TEN overlap. The mucous membranes are involved, and a disseminated cutaneous eruption with discrete, dark-red maculae—sometimes with a necrotic center—followed by epidermal necrosis, is seen.
Therapy involves withdrawal of causal drugs, supportive measures, and the avoidance of steroids (34,35).
Infectious Dermatologic Disorders
Staphylococcal Scalded Skin Syndrome
Staphylococcal scalded skin syndrome (SSSS) is a severe blistering disease caused by exfoliative exotoxin produced by Staphylococcus aureus. The exotoxin provokes subcorneal separation of the cornea stratum through interaction with desmoglein 1, essential for maintaining the integrity of the epidermis (36).
SSSS is produced in the context of staphylococcal septicemia. The primary infection is usually not found cutaneously, but in the nasopharyngeal mucous membrane, in the urinary tract, or at the conjunctival level. Flaccid bullae form predominantly in the folds of the skin and around natural orifices. The blisters grow and break easily, leaving a wet erythematous base that gives the appearance of scalded skin (Fig. 142.3). At resolution, there is no scarring, and very rarely are the mucous membranes involved. The Nikolsky sign is positive.
The diagnosis is initially based on the clinical picture, with the presence of erythroderma, desquamation, and bullae. Microbiologic study, with the isolation of an exotoxin producing S. aureus, confirms the diagnosis. Histologic study reveals a subcorneal separation in the granular layer due to intraepidermal acantholysis. As with the isolation of S. aureus, the histologic study—showing no epidermal necrosis—permits the exclusion of TEN, as these two entities can be indistinguishable clinically.
FIGURE 142.3 Widespread blistering and erosions over the limbs with staphylococcal scalded syndrome. (Courtesy of J.M. Casanova, MD, www.dermatoweb.net.)
The resolution of the cutaneous lesions is swift after the initiation of an adequate antibacterial regimen, often with beta-lactamase–resistant penicillin. Other therapies such as plasma exchange or intravenous immunoglobulin may be considered. As the cutaneous desquamation is superficial, usually there is no serious loss of fluids or electrolytes through the skin. If treatment is begun promptly, the mortality rate can be reduced in children, although in adults the prognosis is much worse (37,38).
SYSTEMIC DISEASES PRESENTING AS DERMATOLOGIC-LIKE DISORDERS
Some dermatologic alterations are not signs of a life-threatening cutaneous disorder. However, they are expressions of potentially serious systemic diseases. Sometimes these lesions are subtle and may pass unnoticed by the patient and/or his or her physician; however, their recognition may be the key to obtaining early diagnosis and treatment (Table 142.5).
Peripheral Vascular Disorder–Related Systemic Infection
In some infectious systemic diseases, an alteration to the blood vessels is produced, secondary to direct vascular damage or, on occasion, due to a hypersensitivity reaction whereby immune-complex deposits give rise to characteristic cutaneous lesions.
| TABLE 142.5 Dermatologic Disorders That Are Manifestations of a Systemic Disease |
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FIGURE 142.4 Necrotic purpuric rash in meningococcal septicemia.
Purpura Fulminans
Purpura fulminans is a severe skin manifestation of disseminated intravascular coagulation associated with acute systemic infection. Although various bacterial infections have been associated with purpura such as Haemophylus influenzae, S. aureus, or Streptococcus pneumoniae, these lesions are highly specific of meningococcemia. Neissseria meningitidis targets human endothelial cells and this interaction triggers the vascular damages that characterize purpura fulminans (39). Generally, early recognition of these lesions helps in the diagnosis of this severe systemic disease.
Petechiae and ecchymoses are the most common lesions, usually localized on the trunk and the extremities (Fig. 142.4), although, occasionally, they may affect mucous membranes as well. In the most serious cases, these ecchymotic areas become necrotic, requiring amputation if the patient survives.
Histologic study of the lesions reveals endothelial damage with areas of thrombosis and hemorrhage in the vascular wall, and containing nuclear “dust” and neutrophils in, and around, the vessels. The Gram stain and culture of the skin lesion biopsy may show meningococci.
When diagnosing a patient with fever and hemorrhagic eruption, especially in the presence of meningeal signs, meningococcemia should be suspected. Early diagnosis is crucial for establishing a cause and administering life-saving treatment for an illness with high mortality that affects mainly young people (40).
Ecthyma Gangrenosum
Ecthyma gangrenosum (EG) is an infectious vascular occlusive disease normally associated with Pseudomonas aeruginosa bacteremia.
Normally, EG is seen in immunologically compromised patients, such as those with diabetes mellitus, neutropenia, hematologic malignancies, organ transplantation, AIDS, or other severe chronic diseases in immunocompetent patients (41).
The lesions of EG are characterized by cutaneous macules or papules, with central vesicle, that progress into hemorrhagic bullae. These break, leaving ulcerations with a black necrotic center, surrounded by narrow, pink to violaceous halos. Perhaps most important, these lesions appear on the extremities and buttocks.
FIGURE 142.5 Multiple Janeway lesions on the fingers. (Courtesy of J.M. Casanova, MD, www.dermatoweb.net.)
Histologic studies always show invasion of the adventitial and medial layers of the small vessel walls by gram-negative bacilli, resulting in a necrotizing and hemorrhagic vasculitis. Cultures of blood and of the vesicular contents usually show P. aeruginosa as well.
Early treatment with intravenously administered antipseudomonal antibiotics is essential since EG manifests as a necrotizing soft-tissue lesion, which often requires surgical debridement (42).
Septic Microemboli
Septic microemboli result in the eponymic Janeway lesions and Osler nodules, often associated with bacterial endocarditis.
Janeway lesions are painless, irregular, and hemorrhagic macules that are found on the palms and soles (Fig. 142.5). Histologically, they show dermal neutrophilic microabscesses and vessel thrombosis without evidence of vasculitis. Gram stain of the tissue is usually positive for organisms (43).
Osler nodes are small, painful erythematous nodules—normally found in the pads of fingers or toes—that resolve without ulceration. Histologic evaluation shows endothelial swelling, inflammation, and thrombosis, with obliteration of the superficial arteriolar lumina. Only very few biopsies of Osler’s node have obtained positive cultures for the pathogenic organism.
Peripheral stigmata provide an excellent clue for the diagnosis of infective endocarditis (44).
Connective Tissue Disorders
Connective tissue diseases—such as scleroderma, lupus erythematosus, and dermatomyositis—are autoimmune disorders of unknown origin, which can affect various organs and show characteristic skin damage that can assist in making the diagnosis. These three diseases sometimes require admission to ICU, either because of their impact on vital organs or due to the secondary infectious complications related to the immunosuppressive treatment.
Scleroderma, a disorder characterized by widespread disruption of the microcirculation with intense fibrosis of the blood vessels, manifests with integumentary lesions with symmetrical fibrosis that usually affects the distal extremities and is often limited to the fingers and face, although a widespread form may affect the distal and proximal extremities and, often, the trunk and face (45).
Systemic lupus erythematosus (SLE) affects the skin, kidneys, lungs, central nervous system, and joints. The skin is a target organ that is affected by the disease in a variety of ways. About 80% of the patients have some cutaneous manifestation in the course of the SLE. In the skin, a characteristic “butterfly” blush (erythema over the malar eminences of the face and bridge of the nose) is seen. When especially severe, acute cutaneous lupus erythematous produces vesiculobullous skin lesions (46).
Dermatomyositis is an inflammatory, degenerative myopathy of striated muscle with characteristic cutaneous manifestations. The integument presents a heliotropic rash, which may or may not be accompanied by periorbital edema and violet Gottron papules on the extensor surfaces of the joints; these are pathognomonic of the disease (47).
Cutaneous Vasculitis
Vasculitis includes a varied group of diseases with different degrees of systemic manifestations, and common characteristic of inflammation and necrosis of the blood vessels.
The skin and subcutaneous tissues are frequently affected and often show the initial manifestation of vasculitis. Although the impact of the systemic vasculitis on the integument does not result in great risk, per se, its importance lies in the fact that it is suggestive of the type of vasculitis with which the patient is presenting and may assist in the generation of an appropriate differential diagnoses list.
Cutaneous manifestations of vasculitis include urticaria, purpura, papules, ulcer, livido reticularis, nodules, and digital gangrene. Vasculitis affecting small vessels is noted as palpable purpura, above all on the lower extremities (Fig. 142.6). On the other hand, nodules are typical lesions of vasculitis affecting the larger blood vessels. They are usually hot, inflamed, red, and surrounded by a halo of livido reticularis (48). The classification of primitive vasculitis, which was originally based on the size of the vessel affected, currently also involves immunologic markers from the 2012 Chapell Hill Consensus Conference Nomenclature of Vasculitides (49).
FIGURE 142.6 Palpable purpura affecting the lower legs in leukocytoclastic angiitis. (Courtesy of J.M. Casanova, MD, www.dermatoweb.net.)
The systemic vasculitis presenting as skin lesions that most often require ICU admission are polyarteritis nodosa, microscopic polyangiitis, granulomatosis with polyangiitis (Wegener’s), and eosinophilic granulomatosis with polyangiitis (Churg–Strauss).
Dermatologic Disorders during ICU Stay
ICUs are characterized by the use of invasive monitoring techniques and therapeutic procedures that, sometimes, represent an assault on the anatomic barrier of the patient. The critically ill patient’s skin is also affected by a series of local factors such as immobility, humidity, and maceration, as well as more general factors such as diabetes mellitus and the use of corticosteroids that may compound dermatologic problems. The skin is in continuous contact with pathogens, and the alteration of its protective function and characteristics allows bacterial, viral, and fungal agents to more easily penetrate this barrier. On the other hand, ICU patients often receive many drugs that may result in cutaneous drug reactions.
The most common dermatologic problems in the ICU as a result of polypharmacy and a patient’s prolonged length of stay are noted in Table 142.6. Although these dermatopathies do not usually increase patient mortality, they may require specific treatment.
Cutaneous Infection
Bacterial Infection
Superficial bacterial infections are usually produced by S. aureus and Streptococci pyogenes. The most frequent form of infection is impetigo (Fig. 142.7). This is an infection of the superficial layers of the epidermis that exists in two clinical varieties, bullous impetigo—caused exclusively by S. aureus, a producer of an exotoxin—and impetigo contagiosa. Impetigo contagiosa or nonbullous impetigo is the most common form and can be caused by both streptococci and staphylococci.
It is characterized by discrete thin-walled vesicles that rapidly become pustular and then rupture. The exudates dry to form loosely stratified golden yellow crusts, which usually appear on exposed areas of the body such as the face, nose, and extremities (50). In ICU patients, these lesions usually appear on areas of skin damaged by pressure, wounds, or trauma. For bacteriologic diagnosis, a culture of the lesion is required, as the exanthem resultant from S. aureus and group A streptococci are clinically indistinguishable. In the last two decades, S. aureus has eclipsed S. pyogenes as being the most common cause of nonbullous impetigo.
| TABLE 142.6 Dermatologic Disorders Developed during ICU Stay |
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