The Acutely Ill Patient With 57 and Jonathan J. Juliano, Myron S. Cohen, and David J. Weber

SHORT VIEW SUMMARY

Definition bioweapon (e.g., anthrax, smallpox, , lesions are suggestive of mycobacterial or } Skin lesions are frequently present in acutely viral hemorrhagic ). fungal . Diffuse suggests , TSS, Kawasaki disease, or ill patients with serious infectious diseases and Microbiology may provide important clues that aid in early Stevens-Johnson syndrome/toxic epidermal } Serious bacterial infections with skin lesions diagnosis and treatment. necrolysis. Bullous lesions suggest include Staphylococcus aureuss (toxic shock streptococcal with necrotizing Epidemiology syndrome [TSS], scalded skin syndrome), fasciitis, gangrenosum, and Vibrio Acutely ill patients with a potential infectious pyogeness (TSS), Salmonella } infections. Petechial eruptions suggest disease and skin lesions (or rash) should have entericaa serovar Typhi, Neisseria meningitidis, gram-negative , invasive N. meningitidis a history obtained that elicits the following: and Rickettsia rickettsii. , rickettsial infections, and viral recent drug ingestion; travel outside the local } Potentially serious viral infections with skin hemorrhagic fever. area; potential occupational exposures; recent lesions include measles, rubella, Epstein-Barr } Consideration should be given to biopsy of immunizations; risk factors for sexually virus infection, cytomegalovirus, human skin lesions, if present, in acutely ill transmitted infections, including human herpesvirus 6, and viral hemorrhagic fevers immunocompromised patients for appropriate immunodeficiency virus infection; factors (e.g., dengue hemorrhagic fever, Ebola, stains (e.g., , fungal stain) and affecting host resistance or Marburg, Lassa). cultures and for pathologic study. immunocompromising conditions; prior } Life-threatening drug reactions may result allergies to ; recent exposures to from therapy for disorders such as Therapy febrile or ill persons; exposure to rural Stevens-Johnson syndrome/toxic epidermolysis } Empirical therapy should often be initiated in habitats, insects, arthropods, and wild animals; necrosis and from drug reaction with acutely ill patients with skin lesions based on and exposure to pets or animals. eosinophilia and systemic symptoms (DRESS). the clinical diagnosis. Most acutely ill patients with skin lesions will } Patients with skin lesions or consistent Diagnosis } with a communicable infectious disease (e.g., require systemic therapy. } Key aspects of skin lesions that aid in a proper invasive meningococcal infection) should be diagnosis include (1) primary type(s) of skin Prevention immediately placed on appropriate isolation lesions, (2) distribution of the lesions, (3) } Standard vaccines should be provided to precautions (i.e., contact, droplet, airborne, or pattern of progression of the rash, and (4) children and adults because many special precautions for highly communicable timing of onset of the rash relative to the vaccine-preventable diseases produce rashes diseases, such as Lassa and Ebola virus onset of fever and other systemic signs. (e.g., measles, rubella, varicella). infections). } The appearance of skin lesions may be very } Underlying noninfectious diseases that lead to Infectious disease physicians should be } useful in the diagnosis of specific infectious disruption of skin should be treated because familiar with the skin lesions (or rash) that diseases. Maculopapular rashes are usually the damaged skin serves as a risk factor for might accompany a patient with disease that seen in viral illnesses, drug eruptions, and infection. could be the result of the intentional use of a immune complex–mediated diseases. Nodular

A recognizable rash can lead to immediate diagnosis and appropriate immediate institution of isolation precautions. Isolation is required therapy. Material isolated from involved skin, when properly handled, primarily for patients whose illnesses allow droplet or airborne spread can confirm a specific diagnosis. Unfortunately, rashes often present a of the pathogen, including both viral (e.g., possible viral hemorrhagic bewildering array of diagnostic possibilities. Dermatologists, who are fever) and bacterial diseases (e.g., possible invasive meningococcal generally more comfortable with evaluation of the skin, are not always infection). Isolation precautions should be adhered to scrupulously. available for immediate consultation. Furthermore, dermatologists and Health care personnel should exercise caution in all interactions with infectious disease specialists frequently differ in their approach to the patients with undiagnosed infectious diseases, and they should use patient with a rash. standard precautions, including the avoidance of direct contact with all A framework is provided in this chapter for investigation of the excretions and secretions with the exception of sweat.1–4 Although the cause of rash, with emphasis on the following: (1) a diagnostic approach vast majority of skin eruptions are noninfectious, gloves should always to patients with fever and rash, (2) categories of skin lesions, and (3) be worn during the examination of the skin whenever an infectious brief descriptions of the most important febrile illnesses characterized cause is being considered because some infections (e.g., , herpes by a rash. simplex virus [HSV]) may be acquired via direct skin contact. In the event of potential exposure to a pathogen, health care personnel should APPROACH TO THE PATIENT be evaluated by their occupational health service for postexposure pro- In the iniinitialtial evaluationevaluation of a patientpatient withwith feverfever and rash, four concerns phylaxis or the need for work restrictions or both.4–7 The third concern must be addressed immediately. The first is if the patient is well enough to is if skin lesions suggest a life-threatening infection, such as bacterial provide further history or whether cardiorespiratory support is required. sepsis, staphylococcal or streptococcal toxic shock, Kawasaki disease, The second is whether the nature and presentation of the rash demands , toxic epidermal necrolysis, or Rocky Mountain 801 802 spotted fever (RMSF).8–11 Early diagnosis is important because prompt 3. Signs of toxicity initiation of appropriate therapy may improve survival.12,13 If skin lesions 4. Presence and location of adenopathy are consistent with (see later discussion), the 5. Presence and morphology of genital, mucosal, or conjunctival s immediate institution of antibacterial therapy is crucial.14,15–17 Finally, lesions consideration must be given to the possibility that the patient has an 6. Detection of hepatosplenomegaly exotic disease acquired as a result of travel or the intentional release of 7. Presence of arthritis

ndrome 18 y an agent of bioterrorism. Bioterrorist agents that may be acquired via 8. Signs of nuchal rigidity, meningismus, or neurologic dysfunction person-to-person transmission and characteristically cause a general- Key ingredients in arriving at a correct diagnosis, or at least a useful, ized rash include smallpox1,19 and the viral hemorrhagic fevers (i.e., limited, “working” list of likely diagnoses, include determination of (1) Ebola, Lassa, Marburg, Crimean-Congo, Bolivian, and Argentinean).1,20 the primary type(s) of skin lesions present, (2) the location and distribu- Patients with plague1,21 and anthrax1,22 may present with localized tion of the eruption, (3) the number and size of the lesions, (4) the or Clinical S j skin lesions. pattern of progression of the rash, and (5) the timing of the onset of The history obtained from the patient should elicit the following the rash relative to the onset of fever and other signs of systemic Ma 23–31 I information: illness. It is important for physicians who observe a rash to carefully 1. Drug ingestion within the past 60 days document the characteristics or take images of the skin lesions in the art I 2. Travel outside the local area medical record to aid other providers in the later care of the patient. P 3. Occupational exposure Although histologic findings from lesional skin biopsies may help to 4. Sun exposure confirm some diagnoses,29 the patterns observed are frequently not 5. Immunizations specific for a single organism, the presence of infectious agents may 6. Sexually transmitted disease exposure, including risk factors for not always be detectable, and laboratory studies often require at least infection with human immunodeficiency virus (HIV) 24 hours to complete. Thus the clinician must attempt to use other 7. Factors affecting immunologic status, including chemotherapy, diagnostic skills during the early evaluation of a patient with fever and corticosteroid use, use of immune modulators, hematologic rash. As discussed elsewhere, specific types of primary skin lesions malignancy, solid-organ or stem cell transplantation, and frequently suggest different infectious disorders in patients with fever functional or anatomic asplenia and rash. For example, palpable purpura, the hallmark feature of 8. Valvular heart disease, including heart valve replacement leukocytoclastic vasculitis, is the prototypic early finding in meningococ- 9. Prior illnesses, including a history of drug or antibiotic allergies cemia and RMSF, whereas rapidly enlarging but asymptomatic red dermal 10. Exposure to febrile or ill persons within the recent past nodules instead suggest candidemia in the appropriate host. Skin nodules 11. Exposure to wild or rural habitats, insects, arthropods, and wild noted on very deep palpation are probably located within the subcutane- animals ous fat, suggesting one of several types of panniculitis, including erythema 12. Exposure to outdoor water sources such as lakes, streams, or nodosum, a disorder caused by many different types of inflammatory oceans or infectious processes, and , which is a classic 13. Pets, animal exposures, and habits tuberculoid reaction. The clinician should pay particular attention to the season of the Examples of differences in the types of primary skin lesions present year, which dramatically affects the epidemiology of febrile rashes of in the setting of underlying systemic infectious diseases are summarized infectious origin. in Table 57.1, although it should be clear that such a classification, Physical examination should focus on the following: by itself, rarely ever suggests only a single diagnosis. On the other 1. Vital signs hand, the presence of other more specific lesions, most notably “target” 2. General appearance or “iris” lesions (as in [EM]), may suggest a

TABLE 57.1 Systemic Infections With Prominent Cutaneous Manifestations ORGANISM/DISEASE MACULES, PAPULES VESICLES, BULLAE PETECHIAE, PURPURA Viruses Human immunodeficiency virus type 1 X Echoviruses X X X Coxsackieviruses X X X Rubeola (measles) X Atypical measles X X Adenovirus X X Lymphocytic choriomeningitis X Dengue X X Zika virus X West Nile virus X Viral hemorrhagic fevers X Rubella (German measles) X X Colorado tick fever X Yellow fever X Varicella-zoster (disseminated) X Herpes simplex (disseminated) X Varicella () X Vaccinia X 803

TABLE 57.1 Systemic Infections With Prominent Cutaneous Manifestations—cont’d ORGANISM/DISEASE MACULES, PAPULES VESICLES, BULLAE PETECHIAE, PURPURA Cha Variola X X p

Cytomegalovirus X ter 5 Congenital cytomegalovirus X 7

Epstein-Barr virus X X The Acutely Ill Patient With Fever and Rash Hepatitis B virus X X (as palpable purpura) Monkeypox X Parvovirus B19 (erythema infectiosum) X Human herpesvirus 6 X Human herpesvirus 7 X psittaci X X pneumoniae X Ehrlichia spp. X Rickettsia rickettsii (RMSF) X X Rickettsia akari () X X Rickettsia prowazekii (epidemic/louse-borne typhus) X X Rickettsia typhi (endemic/) X Rickettsia tsutsugamushi () X Bartonella henselae X Bartonella quintana X Salmonella enterica serovar Typhi X Francisella tularensis X Streptobacillus moniliformiss (rat-bite fever) X X Treponema pallidum (secondary syphilis) X Mycobacterium haemophilum X Neisseria gonorrhoeae X X Neisseria meningitidis X Leptospira spp. X Listeria monocytogenes X (rare) Bartonella bacilliformis X Borrelia spp. (relapsing fever) X X Borrelia burgdorferii () X (annular) X Spirillum minus (rat-bite fever) X X X X Streptococci—group A (scarlet fever) X Capnocytophaga canimorsus X Vibrio vulnificus X Fungi (Disseminated Infection) Candida spp. X Cryptococcus neoformans X Histoplasma capsulatum X Blastomyces dermatitidis X Coccidioides immitis X Fusarium spp. (agents of ) X Protozoa Plasmodium falciparum (malaria) X 804 single diagnosis, implicating a limited group of underlying infectious eruptions that begin as generalized exanthems are the “rashes” that diseases as possible causes. Similarly, the presence of some lesions in constitute the focus of the discussion in this chapter. the setting of fever may immediately exclude an infectious disorder An exanthem is a cutaneous eruption due to the systemic effects of s as the cause of rash. For example, high fever accompanying a paucity a microorganism infecting the skin. An enanthem is an eruption caused of tender, red to violaceous, peripherally mammillated plaques sug- in similar fashion but involving the mucous membranes. Microorganisms gests Sweet syndrome (acute febrile neutrophilic dermatosis), a rare may produce eruptions through (1) multiplication in the skin (e.g., ndrome y hypersensitivity reaction frequently associated with selected underlying HSV); (2) release of toxins that act on skin structures (e.g., in scarlet malignancies,32 or neutrophilic eccrine hidradenitis, a rare neutrophilic fever, infections due to Pseudomonas aeruginosa, dermatosis most commonly found in patients treated with chemotherapy [TSS], staphylococcal scalded skin syndrome [SSSS]); (3) inflammatory for malignancies.33 response involving phagocytes and lymphocytes, in which the Distribution or direction of spread of an eruption may be highly microbicidal/tumoricidal metabolism of host defense cells is directed or Clinical S j informative. The rash of RMSF and acute meningococcal infection, for at the skin; and (4) effects on vasculature, including vasoocclusion and example, most often begins on the lower extremities and then spreads necrosis or vasodilation with edema and hyperemia. Obviously, for Ma

I centrally (i.e., centripetally), whereas most drug- and viral-infection– many eruptions, several concurrent mechanisms can play a role. associated eruptions (with the exception of those caused by echoviruses art I and coxsackieviruses) begin on the face or trunk and spread outward DIFFERENTIAL DIAGNOSIS IN RASH P (centrifugally). “Streaky” facial involvement, usually without other skin ThereThere a raree two two ways ways to to app approachroach t hthee in investigationvestigation ofof i ninfectious rash: findings, is characteristic of infection due to parvovirus B19 (fifth disease, either by the type of lesion visualized or by knowledge of individual erythema infectiosum). pathogens and the rashes they produce (Table 57.2). Unfortunately, The number of lesions can also provide useful insight. For example, neither system alone serves both to generate a complete list of diagnostic “rose spots” (see later discussion), the hallmark cutaneous feature of possibilities to rule out disorders as appropriate. In accordance, both Salmonella infection, are characteristically present in much greater approaches should be incorporated into evaluation of the patient with numbers in patients who have paratyphoid fever than in those who rash and fever. have typhoid fever. In contrast, may be associated with only one or a few clinically subtle skin lesions, as seen in a fixed-drug Characteristics of the Lesion eruption. Morphologic types of primary skin lesions include macules, papules, Finally, timing of the rash may be particularly helpful in allowing nodules, vesicles, bullae, pustules, and plaques. Macules are flat, non- the clinician to exclude reactions due to certain drugs as the underlying palpable lesions in the plane of the skin. Papuless are small, solid, palpable cause. With the exception of urticarial eruptions, which usually occur lesions elevated above the plane of the skin. Masses that are located within a few minutes to a few hours of the administration of a systemic deeper within or below the skin are referred to as nodules. Vesicles and agent, the more typical generalized maculopapular or morbilliform drug bullae are small and large , respectively, and pustules are usually eruption typically occurs within the first 7 to 14 days of the first dose small, palpable lesions filled with pus. Plaques are large, flat lesions, of the offending agent, suggesting the need for a very careful drug usually greater than 1 cm in diameter, that are palpable. In addition to history (including start and stop dates for all medications taken within morphology, lesions are characterized by their color and, particularly 30 days of the onset of eruption). in the setting of a systemically ill–appearing patient, by the presence It must be emphasized that noninfectious processes often include or absence of hemorrhage, with hemorrhagic lesions being termed rash and fever and should be among the diagnostic considerations in purpura or petechiae. Lesions may be skin colored, hyperpigmented, the initial evaluation.34 As noted previously, the presence of some highly or hypopigmented or any of several other colors, of which red is the specific morphologic types or patterns of skin lesions may quickly suggest most common; the presence of such reddening is termed erythema. a noninfectious cause to the astute clinician, thereby obviating the need Blanching erythematous lesions are those in which erythema is due to to pursue a more extensive clinical and laboratory evaluation. vasodilation, whereas nonblanching erythema may be due to extravasation Between 5% and 15% of all patients to whom a drug is administered of blood. For purposes of the following discussion, it is useful to divide experience an adverse reaction.35–37 Adverse cutaneous reactions to drugs eruptions into those that are maculopapular (characterized by both flat are frequent, affecting 2% to 3% of all hospitalized patients,38–44 20% of and elevated lesions), nodular, vesiculobullous, erythematous, and emergency department visits,44 and 0% to 8% of all patients placed on purpuric. Enanthums and neutrophilic dermatoses are also important medications.41 Fortunately, only about 2% of adverse cutaneous reactions in the differential diagnosis of fever and rash. are severe and very few fatal.36 The rate of cutaneous reactions to drugs is highest for antibiotics (1%–8% depending on the class of antibiotic), Maculopapular Rash mainly penicillins and .42,44 Exanthems (75%–95%) and Maculopapular rashes (see Table 57.1) (Fig. 57.1) are usually seen in a urticaria (5%–6%) account for most drug reactions. Because of their range of illnesses, including those due to viruses, bacteria, fungi, drug frequency, a drug reaction must be considered in any patient with a eruptions, and immune complex–mediated syndromes. Descriptions generalized maculopapular rash, especially if associated with palmoplantar of some of the specific pathogens are included later in the chapter or involvement. Severe cutaneous reactions often induced yb drugs include are included in other chapters. Physicians, in particular, should be Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN),11,38,45 familiar with maculopapular rashes associated with EM and SJS/TEN. hypersensitivity syndromes (urticaria, angioedema, anaphylaxis),38,46 EM and its variants may be considered a special category of macu- small vessel vasculitis,38,39 serum sickness,11,38 and drug reaction with lopapular rash. EM is an uncommon acute, immune-mediated, self- eosinophilia and systemic symptoms (DRESS).11,39,47,48 As with other limited, usually mild mucocutaneous syndrome that is often relapsing.71,72,73 rashes, a morphologic approach to drug eruptions should be used in The disease is usually related to an acute infection, most commonly a evaluating the patient.35,40,43 recurrent HSV infection. It is uncommonly related to drug ingestion Rashes and skin infections associated with occupational exposures,49–53 (i.e., <10%). athletics,54–61 animal exposures,62 international travel,63,64–69 and working The following classification of EM is based on that provided by in a clinical or research laboratoryy70 have been reviewed in other chapters Bastuji-Garin and colleagues.73,74 Subtypes of EM include (1) EM major: in this textbook. skin lesions with involvement of mucous membranes, (2) EM minor: skin lesions without involvement of mucous membranes, (3) herpes- PATHOGENESIS OF RASH associated EM, and (4) mucosal EM (Fuchs syndrome): mucous Rash wwithith fevefeverr cacann rresultesult ffromrom a local ininfectiousf process due to virtually membrane lesions without cutaneous involvement. Until recently, EM any class of microbe that has been allowed to penetrate the stratum was considered as a variant of the same pathophysiologic process as corneum and multiply locally. A typical example is streptococcal . SJS and TEN. However, currently evidence suggests that EM with mucous In rare cases such localized inoculations result in more generalized membrane involvement and SJS are different diseases with distinct eruptions, and the diagnosis is then relatively straightforward. However, causes.75 Further, the epidemiology of EM differs from SJS/TEN because 805

TABLE 57.2 Skin Lesions and Systemic Infections SMEARS POSITIVE TIME TO APPEARANCE LESION COMMON PATHOGENS HISTOLOGIC FINDINGS FOR PATHOGENS (AFTER ONSET OF ILLNESS) Cha p

Symmetrical peripheral Noninfectious or gram-negative Bleeding in the skin, vascular No 12–36 h ter 5 , purpura bacteria, Capnocytophaga thrombosis, perivascular fulminans, acrocyanosis canimorsus infiltration 7 a b Multiple purpuric lesions Neisseria meningitidis, Vascular thrombosis, Yes 12–36 h T in severely ill patients Capnocytophaga canimorsus, perivascular hemorrhage he Acutely Ill Patient With Fever and Ras Rickettsia spp., other gram-negative bacteria , Pseudomonas, gram-negative Veins, mainly involved, intima Yes Several days other bullous lesions bacteria, Vibrio vulnificus spared, inflammatory reaction Macronodular lesions Candida, Cryptococcus Hyphae, mononuclear No Several days neoformans, Histoplasma perivascular reaction capsulatum, Fusarium Delayed-onset rash with Neisseria gonorrhoeae, N. Perivascular mononuclear Occasionally (few 3–10 days nonsymmetrical, meningitidis (chronic) infiltrate, immune complex bacteria only) scattered maculopapular or vesicular lesions Rose spots Salmonella spp. Perivascular mononuclear No 5–10 days

infiltrate, or leukocytoclastic h vasculitis “Toxic erythema” Staphylococcus aureus (SSSS) Dilation and perivascular No At presentation edema aExcept for Rocky Mountain spotted fever, in which therapy, biopsy, and immunofluorescent staining may aid early diagnosis. bIn Rocky Mountain spotted fever, 1–7 days. SSSS, Staphylococcal scalded skin syndrome. Modified from Kingston ME, Mackey D. Skin clues in the diagnosis of life-threatening infections. Rev Infect Dis. 1986;8:1–11.

involvement usually accompanies the cutaneous lesions, although patients may present only with mucous membrane involvement.77 Although many factors (e.g., infections, medications, malignancy, autoimmune disease, immunizations, sarcoidosis, and radiation) have been linked to EM, infections account for approximately 90% of cases. HSV has been the infection most commonly linked to EM (≈80% of infectious cases),78,79 but Mycoplasma pneumoniae is an important cause of EM (≈5%–10% of infectious cases), especially in children.80 The differential diagnosis of target-appearing skin lesions has been reviewed and includes EM, SJS, TEN, ecthyma gangrenosum, syphilis, fixed-drug eruption, contact dermatitis, vasculitis, acute connective tissue diseases, and autoimmune blistering diseases.81 SJS and TEN are acute, life-threatening mucocutaneous reactions characterized by extensive necrosis and detachment of the epidermis.82–87 Although TEN is rare, with an incidence of approximately two cases per million population per year, it is a devastating disease with a mortality rate of 30% to 50%. Owing to the similarity in clinical and histologic FIG. 57.1 Maculopapular rash. The maculopapular rash of measles findings, risk factors, drug causality, and mechanisms, these two syn- showing coalescence of lesions (From Ferri FF. Ferri’s Clinical Advisor. 1st dromes are considered severity variants of an identical process that ed. St. Louis: Elsevier; 2019.) differs only in the final extent of body surface involved.87 TEN involves sloughing of greater than 30% of the body surface, whereas SJS involves less than 10% of the total body surface; total body surface area involve- patients with EM are younger, are more often male, have frequent ment between 10% and 30% is known as SJS-TEN overlap. SJS and recurrences, have less fever, have milder mucosal lesions, and lack TEN typically have a prodrome of fever and flulike symptoms beginning association with collagen vascular diseases, HIV infection, or cancer.76 1 to 3 days before the development of skin lesions. These may be Target lesions are the hallmark of EM. The skin eruption generally accompanied by skin tenderness and photophobia. Both SJS and TEN arises abruptly; most commonly all lesions appear within 3 to 5 days are characterized by rapidly expanding, often irregular macules (“atypical and resolve in approximately 2 weeks. Initially, lesions may begin as target lesions”) and involvement of more than one mucosal site (oral, round erythematous papules that evolve into classic target lesions. Typical conjunctival, and anogenital). If untreated, TEN rapidly progresses to target lesions consist of three components: a dusky central area or , widespread full-thickness necrosis of the epidermis, resulting in separa- a dark red inflammatory zone surrounded by a pale ring of edema, and tion of large sheets of epidermis from the underlying dermis either an erythematous halo on the extreme edge of the lesion. Although there spontaneously or after the application of minimal lateral traction or are often a limited number of lesions, in some cases hundreds may pressure to the skin. The Nikolsky sign (i.e., ability to extend the area form. Most lesions occur in a symmetrical, acral distribution on the of superficial sloughing by gentle lateral pressure on the surface of the extensor surfaces of the extremities (hands and feet, elbows, and knees), skin at an apparently uninvolved site) may be positive. Constitutional face and neck, and, less commonly, thighs, buttocks, and trunk. They symptoms and internal organ involvement occur often and may be often appear acrally and then spread in a centripetal manner. Although severe. the lesions are usually asymptomatic, patients occasionally report burning A majority of cases in adults are drug induced; medications cause or itching. Mucous membrane (≈70% oral, ≈25% genital, ≈15% ocular) 30% to 50% of cases of SJS and up to 80% of cases of TEN. Although 806 infections may be an occasional trigger of SJS in adults, they uncommonly cause TEN. Rare precipitating causes include vaccinations, systemic diseases, chemical exposures, and foods. In contrast, in children, although s medications are the leading cause of both SJS and TEN, infections such as M. pneumoniae and herpesviruses are more common causes of SJS and TEN. Although most of the highest-risk medications are

ndrome 82 y not antiinfective agents, nevirapine is a confirmed high-risk drug. Antiinfective agents most commonly associated with SJS and TEN include amoxicillin, sulfadiazine, and trimethoprim-sulfamethoxazole (TMP-SMX); less common antiinfective agents include cephalosporins, macrolides, tetracyclines, rifampin, thiabendazole, ethambutol, and or Clinical S > j fluoroquinolones (sulfonamides Ԡ penicillins cephalosporins). Patients infected with HIV have been reported to be at threefold increased risk for Ma

I SJS/TEN, with a 40-fold increased risk for SJS/TEN due to TMP-SMX. Unfortunately, there is no laboratory test to support the diagnosis of SJS art I or TEN. The following diseases must always be excluded before making a P diagnosis of SJS or TEN: varicella, EM major, SSSS, staphylococcal TSS, skin necrosis from disseminated intravascular coagulation or purpura fulminans, and chemical toxicity.87 Treatment should always include appropriate fluid and wound care (for extensive disease the patient should be managed in a burn center), strict aseptic care to prevent infections, and consideration for topical antibiotic therapy (avoid silver sulfadiazine).82,86,88 Adjunctive therapies that are based on extensive use but have not been studied in clinical trials include intravenous (IV) gamma globulin and glucocorticoids.82,88–90 Plasmapheresis, cyclosporine, and tumor necrosis factor (TNF) antagonists (infliximab, etanercept) have been reported to be of benefit based on small case series.82,86,88–90 Thalidomide increased mortality in a double-blind randomized 91 FIG. 57.2 Nodular rash. Multiple erythematous skin nodules of Myco- placebo-controlled trial. bacterium abscessus (From Su S, Chen Y-H, Tsai T-Y, et al. Catheter-related Last, in several life-threatening infections, the presenting manifesta- Mycobacterium abscessus bacteremia manifested with skin nodules, tions may include blanching erythematous maculopapular lesions that pneumonia, and mediastinal . Kaohsiung J Med Sci. later evolve into petechiae, making initial diagnosis difficult on the 2013;29:50–54.) basis of lesion morphology alone. These infections include acute meningococcemia, RMSF, and viral hemorrhagic fevers such as dengue. Although a diagnostic feature of rheumatic fever is an annular or a polycyclic, migrating (or expanding) erythema known as erythema marginatum, this disease may also be associated with the presence of a maculopapular eruption and subcutaneous nodules. Patients with enteric fever due to Salmonella may develop “rose spots,” a transient scattering of rose-colored macules over the abdomen. Typically, the rose spots of typhoid fever are pale pink, oval or circular, completely blanchable, few in number, moderately sized (up to 0.5–1.0 cm in diameter), and usually present on the abdomen or trunk.92 In contrast, rose spots of paratyphoid fever are typically smaller and more numerous.93 Nodular Lesions A nodule is a palpable, solid, round or ellipsoidal lesion, usually resulting from disease in the dermis and/or subcutis (Fig. 57.2). Nodules may contain various inflammatory cells (as part of a hypersensitivity phe- nomenon), organisms (most notably fungi, as in septic emboli), or tumor cells (from metastatic cancer, lymphoma, or leukemia cutis). In the appropriate clinical setting, sudden development of dermal nodules may suggest candidal sepsis (see later discussion), but other fungal diseases, including blastomycosis, histoplasmosis, coccidioidomycosis, and sporotrichosis, may produce skin nodules. Bacteria such as Nocardia and nontuberculous mycobacteria94–96 (especially Mycobacterium marinum)97 may also cause nodular lesions that typically later ulcerate. Leishmaniasis can cause nodules. Lesions consistent with ecthyma gangrenosum, typified by the presence of deep, “punched-out” ulcerations FIG. 57.3 Erythema nodosum. Erythematous nodules which are ill with overlying black eschar and peripheral erythema, suggest Pseudo- defined without epidermal changes on the lower leg. (From Brinster NK, monass sepsis. A skin biopsy specimen with appropriate stains and cultures Liu V, Diwan H, McKee PH. Erythema nodosum. Brinster NK, Liu V, Diwan defines the diagnosis. H, McKee PH, eds. Dermatopathology: High-Yield Pathology. Philadelphia: Saunders; 2011:170–171.) Subcutaneous nodules pose a real diagnostic challenge because they may reflect the presence of a variety of underlying disorders, including hypersensitivity reactions to systemic infection. The lesions of erythema They typically do not suppurate. These lesions often develop in crops nodosum are characterized by tender, erythematous nodules that range and usually heal in days to a few weeks without scarring. Infectious in diameter from less than a centimeter to several centimeters (Fig. agents are a prominent cause of this lesion (Table 57.3). In contrast, 57.3).98–100 They are usually multiple and located on the anterior portions erythema induratum, a known tuberculoid reaction, typically presents of the legs but may be solitary and occur on other parts of the body. as painful, red, subcutaneous nodules over the posterior lower legs and 807

TABLE 57.3 Known Noninfectious and Infectious Causes of Erythema Nodosum Cha Noninfectious p

Systemic erythematosus ter 5 Sarcoidosis Ulcerative colitis Crohn disease 7 T

Malignancies (Hodgkin and non-Hodgkin lymphoma, leukemia, renal cell he Acutely Ill Patient With Fever and Ras carcinoma) Behçet syndrome Drugs (especially oral contraceptives, sulfonamides) Pregnancy Infectious Viral Hepatitis B virus Hepatitis C virus Herpes simplex virus Human immunodeficiency virus FIG. 57.4 Diffuse erythema. Diffuse erythema associated with toxic Epstein-Barr virus Measles shock syndrome. (Courtesy Centers for Disease Control and Prevention Parvovirus B19 Public Health Image Library.) Varicella h Bacterial Bartonella henselae (cat-scratch disease) Brucella spp. (brucellosis) Campylobacter spp. (campylobacteriosis) Chlamydia trachomatis () Chlamydia psittacii (psittacosis) diphtheriae (diphtheria) Coxiella burnetii () Francisella tularensis () Haemophilus ducreyii () Mycoplasma pneumoniae Mycobacterium tuberculosis (tuberculosis) Mycobacterium leprae () Mycobacterium marinum (atypical mycobacteriosis) Neisseria gonorrhoeae () Neisseria meningitidis (meningitis) Salmonella spp. () Shigella spp. () (respiratory tract infection) Treponema pallidum (syphilis) Yersinia spp. (gastroenteritis) Fungal FIG. 57.5 Vesicular rash. Vesicles associated with varicella infection. Aspergillus spp. (aspergillosis) (From Goering RV, Dockrell HM, Zuckerman M, et al. Infections of the skin, Cryptococcus neoformans (cryptococcosis) soft tissue, muscle and associated systems. In: Goering RV, Dockrell HM, Blastomyces dermatitidis (blastomycosis) Zuckerman M, et al, eds. Mim’s Medical Microbiology. 5th ed. St. Louis: Histoplasma capsulatum (histoplasmosis) Elsevier; 2013.) Coccidioides immitis (coccidioidomycosis) Sporothrix schenckii (sporotrichosis) Protozoal/Helminths Ascaris lumbricoides (ascariasis) Giardia lamblia (giardiasis) the clinical course should not be considered a reason for excluding any Toxoplasma gondiii (toxoplasmosis) disease process. Most of these disorders can be easily diagnosed on the Wuchereria bancroftii (filariasis) basis of the patient’s history and appropriate tests. Vesiculobullous Eruptions A vesicle is a circumscribed, elevated lesion containing free fluid (Fig. ankles. These lesions tend to suppurate, distinguishing them morphologi- 57.5). A vesicular lesion larger than 0.5 cm is termed a bulla. Most cally from erythema nodosum and most other types of panniculitis. vesiculobullous eruptions are immunologic in origin; few are associated Furthermore, erythema induratum can usually be easily differentiated with infectious systemic infections. Infectious diseases to be considered from erythema nodosum on histologic examination of a wedge biopsy include varicella, disseminated herpes simplex, eczema herpeticum specimen. can be seen within subcutaneous fat lobules (HSV superinfection of atopic eczema), and infections due to echoviruses in the former, rather than within septal connective tissue as classically and coxsackieviruses (including coxsackievirus A16, a cause of hand- seen in erythema nodosum. Acid-fast bacilli are rarely visible within foot-and-mouth disease). In addition, other poxvirus infections, such the lesions of erythema induratum because this condition typically as monkeypox, smallpox, and generalized vaccinia, need to be considered represents reactivation of long-standing infection with, or hypersensitivity (see later). HSV infection, the most common of these infections causing to, the tuberculosis bacilli that are present at distant sites. vesiculobullous lesions, is characterized by a grouped clustering of vesicles on an erythematous base that progresses to mucocutaneous Diffuse Erythema ulceration.101–103 HSV can be detected by a viral culture of a scraping Diffuse erythema, especially if desquamation or peeling is present, should from a blister but more commonly is now accomplished by polymerase lead to consideration of scarlet fever, TSS, mucocutaneous lymph node chain reaction assay. In addition, the demonstration of multinucleated syndrome (Kawasaki disease), SSSS, SJS, and TEN (Fig. 57.4). Desquama- giant cells in a scraping (Tzanck preparation) of the base of a vesicle tion may occur late in all of these syndromes, and its absence early in indicates infection with HSV or varicella-zoster virus (VZV). Older 808 vesicles can be easily confused with pustules. A pustule is an elevation of the skin enclosing a purulent exudate. Vesicular lesions may at times become pustules, as can occur with HSV or VZV lesions. Diffuse pustular s diseases usually represent a noninfectious dermatologic illness (e.g., pustular psoriasis) or a cutaneous infection (e.g., pustular Pseudomonas lesions developing after the use of contaminated hot tubs or staphylococ- ndrome y cal ). Pustular skin lesions associated with arthralgias should lead to a consideration of , Moraxella bacteremia, chronic meningococcemia, subacute bacterial endocarditis, coxsackievirus infection, and Behçet syndrome. Bullous skin lesions with sepsis are suggestive of the following or Clinical S j infections: group A streptococcal erysipelas with necrotizing fasciitis (gangrenous erysipelas), ecthyma gangrenosum (due to Pseudomonas Ma

I aeruginosa or Aeromonas spp.), Vibrio infections (especially those due to ) (Fig. 57.6), staphylococcal cellulitis or , art I and streptococcal cellulitis. Rarely, in immunocompromised patients P the initial manifestation of gram-negative sepsis may be the appear- ance of a solitary hemorrhagic blister. V. v ulnificus infection should be strongly considered in patients with preexisting liver disease, or other immunocompromising states, who have recently ingested raw seafood, especially oysters.104,105 V. v ulnificus sepsis may also occur in persons with open wounds exposed to a marine environment.106 Aeromonas hydrophila skin and tissue infections, which may be acquired from exposure to fresh or brackish water, may also present as cellulitis with bulla formation.107 Vesicopustular eruptions in the neonate may be due to both noninfectious and infectious causes. Potential infectious causes include congenital and neonatal candidiasis, staphylococcal infections, streptococcal infections, Listeria monocytogenes infection, infection with HSV, neonatal varicella, and bacterial sepsis (due to various organisms).108 Petechial and Purpuric Eruptions Petechiaee are lesions less than 3 mm in diameter that contain extravasated red blood cells or hemoglobin (Fig. 57.7). Larger lesions are termed ecchymoses or purpura. Diffuse petechial lesions should always prompt urgent investigation. In critically ill patients these lesions are often associated with symmetrical peripheral gangrene (purpura fulminans), consumptive coagulopathy, and shock. The most common infectious agents include gram-negative organisms, especially Neisseria meningitidis, and rickettsiae. Less commonly, L. monocytogenes or staphylococci may be associated with a similar clinical picture. Physicians must also consider a hemorrhagic fever if the patient has a history of recent travel to an area experiencing an epidemic or there is a potential household contact with such a traveler. Asplenic patients are at an increased risk for overwhelming sepsis (lifetime risk of ≈5%), which may be accompanied by symmetrical peripheral gangrene.109–112 The lifetime risk for sepsis in asplenic hosts has been reported to range from 3% to 5%. Streptococcus pneumoniae is responsible for 50% to 90% of infections in the asplenic patients and has a mortality rate of approximately 50%. Other important pathogens include Haemophilus influenzae, N. meningitidis, and Capnocytophaga canimorsus. Additional occasional pathogens include Staphylococcus aureus, group B streptococci, Enterococcus, and other Enterobacteriaceae, Salmonella, Campylobacter, Bacteroides, Bordetella holmesii, Pseudomonas, and Babesia spp. The risks from many of these diseases can be significantly reduced by vaccination of asplenic patients using Centers for Disease Control and Prevention (CDC)/ Advisory Committee on Immunization Practices (ACIP) guidelines.113 Children should also receive H. influenzae type b vaccine. Immuniza- tions with pneumococcal vaccines (i.e., PCV13 and PPSV23 as CDC/ ACIP recommended) significantly reduces the risk for pneumococcal 112 FIG. 57.6 Vibrio vulnificus. Bullae caused by infection with Vibrio sepsis. vulnificus. (A) Prior to amputation. (B) and (C) Predébridement. (D) Post- Viral illnesses associated with petechial rashes include infections débridement. (From Ralph A, Currie BJ. Vibrio vulnificus and V. parahae- due to coxsackievirus A9, echovirus 9, Epstein-Barr virus (EBV), or molyticus necrotising fasciitis in fishermen visiting an estuarine tropical cytomegalovirus (CMV); atypical measles; and the viral hemorrhagic northern Australian location. J Infect. 2007;54: e111–e114.) fevers. Although children with coxsackievirus and echovirus infections are usually nontoxic in appearance, some may appear very ill. In these patients differential diagnosis from acute meningococcemia is difficult. However, in a series of children presenting with fever and petechiae, only 8% had meningococcal infections and 4% had bacterial sepsis secondary to other disorders.114,115 809 NEUTROPHILIC DERMATOSES, INCLUDING SWEET SYNDROME The neutrophilicneutrophilic dermatoses dermatoses are area heterogeneous a heterogeneous ggroup of diseases that Cha can occur with localized, generalized, and systemic skin involvement

and include Sweet syndrome, gangrenosum, Behçet disease, p and neutrophilic urticaria. Sweet syndrome, also known as acute febrile ter 5 neutrophilic dermatosis, is characterized by a constellation of clinical 7

symptoms, physical features, and pathologic findings that include fever, T neutrophilia, tender erythematous skin lesions (papules, nodules, and he Acutely Ill Patient With Fever and Ras plaques), and a diffuse infiltrate consisting predominantly of mature neutrophils that are typically located in the upper dermis.121–124 Sweet syndrome occurs in a variety of clinical settings: idiopathic (or classic), malignancy associated, immunodeficiency associated, and drug induced. The classic syndrome is more frequent in women between the ages of 30 and 50 years, is often preceded by symptoms of an upper respiratory tract infection, and may be associated with inflammatory bowel disease and pregnancy. The skin demonstrates one or more tender, red, edema- FIG. 57.7 Petichial rash. Diffuse petechial associated with meningococ- tous, urticarial plaques or large papules. Often the border of each plaque cemia. (From Connolly AJ, Finkbeiner WE, Ursell PC, Davis RL. Atlas of is studded with papules (or, infrequently, with vesicles or pustules), gross autopsy pathology. In: Connolly AJ, Finkbeiner WE, Ursell PC, Davis giving an irregularly contoured, mammillated appearance reminiscent RL, eds. 3rd ed. Autopsy Pathology: A Manual and Atlas. St. Louis: Elsevier; of that of the areolae of the breast. If solitary and large, such lesions 2016:186–319.) may be confused with those caused by a variety of infectious processes, h including primary HSV infection or streptococcal cellulitis. When solitary and present on the dorsum of the hand, a lesion of Sweet syndrome may mimic or a severe reaction to an arthropod bite. On occasion, these plaques become dusky in color and frankly hemorrhagic, A diffuse rash is often a prominent characteristic of the tick-borne suggesting instead EM or leukocytoclastic vasculitis. Some lesions may diseases found in the United States (i.e., infections caused by Rickettsia, also become bullous, suggesting bullous EM or fixed drug eruption. Ehrlichia, Anaplasma, Borrelia, and Coxiella), with the exception of Rare bullous lesions may erode or ulcerate, mimicking pyoderma tularemia.116,117,118 The frequency of a diffuse rash has been reported as gangrenosum. Mucosal surfaces may rarely be involved. Characteristically, follows: RMSF, 99%; Ehrlichia chaffeensiss (ehrlichiosis), 36%; Anaplasma patients with Sweet syndrome have associated fever; other findings may phagocytophila (anaplasmosis), 2% to 11%; Borrelia spp. (relapsing fever), include leukocytosis, malaise, arthralgias, myalgias, conjunctivitis, and 28%; and Coxiella burnetii (Q fever), 5% to 21%.116 Although Lyme episcleritis. arthritis is characterized by EM, a diffuse rash may occur at the time The diagnosis of Sweet syndrome is one of exclusion and includes of disseminated infection. Lesions caused by rickettsiae are usually infectious and inflammatory disorders, neoplastic conditions, reac- generalized and symmetrical. An eschar (tache noire) characteristically tive , systemic diseases, and vasculitis. Sweet syndrome develops at the site of inoculation in the following rickettsial infections responds rapidly to high-dose systemic corticosteroids, but relapse is (infecting species): (R. africae), Mediterranean frequent if tapering is too rapid. Second-line systemic agents include spotted fever (R. conorii), (R. sibirica), colchicine, dapsone, potassium iodide, TNF-α antagonists, and (R. australis), rickettsialpox (due to R. akari), cyclosporine.124 and scrub- or chigger-borne typhus (R. tsutsugamushi). New rickettsioses continue to be recognized worldwide that are characterized by generalized PATHOGENS OR INFECTIOUS skin lesions, often with tache noire lesions, such as Japanese or Oriental CONDITIONS STRONGLY spotted fever (R. japonica), Flinders Island spotted fever (R. honei), and ASSOCIATED WITH RASH Astrakhan fever (R. conorii Astrakhan).116 AsAs nnotedoted ppreviously,reviously, the ininvestigationvestigation oof infectious rash requires con- In patients with an appropriate travel history, infection with Plas- sideration of not only the characteristics of the skin lesions but also the modium falciparum must be considered.119 In addition, clinicians should pathogens and infectious processes strongly associated with rash. The be aware that malaria may occasionally be acquired in the United States.120 following discussion reviews the various skin manifestations of these Rash with petechiae secondary to thrombocytopenia is present in about pathologic processes. 5% of affected patients heavily parasitized. The most important causes of noninfectious petechiae are throm- Sepsis bocytopenia, large and small vessel necrotizing vasculitis (usually present- Sepsis is a clinical syndrome that complicates severe infection and is ing as palpable purpura), and the pigmented purpuric eruptions (which characterized by inflammation, including vasodilation, increased usually represent capillaritis). microvascular permeability, and end-organ dysfunction. The inflam- matory response has been divided into the systemic inflammatory Enanthems response syndrome (SIRS), sepsis, severe sepsis, and septic shock,125 In attempting to classify the enanthem, it is essential that a thorough and the pathophysiology has been reviewed.126 Although SIRS may search of the mucous membranes (including the mouth, conjunc- result from infection or from noninfectious causes (e.g., autoimmune tiva, and, on occasion, also the vagina, rectum, and glans penis) be disorder, pancreatitis, vasculitis, thromboembolism, burns, surgery, heat made for the presence of enanthems. In many allergic reactions the shock), sepsis results from a dysregulated inflammatory response to mucous membranes are frequently involved. Koplik spots, diagnostic an infection. of rubeola, are tiny, white or blue-gray specks superimposed on an Kingston and Mackeyy29 classified the skin lesions associated with sepsis erythematous base, located on the buccal mucosa, most prominently into five pathogenic processes (major categories of infectious causes): (1) on that adjacent to the molars. A “strawberry tongue” suggests the disseminated intravascular coagulation (DIC) and coagulopathy (due to possibility of Kawasaki disease, TSS, or scarlet fever. Petechiae of the N. meningitidis, streptococci, enteric gram-negative bacilli), (2) direct palate are common in scarlet fever and some vasculitides and with vascular invasion and occlusion by bacteria and fungi (N. meningitidis, thrombocytopenia. In infectious mononucleosis, petechiae of both the P. aeruginosa, Aspergilluss spp., agents of mucormycosis, Rickettsia spp.), hard palate and soft palate are common. Oral ulcers occur in a variety (3) immune vasculitis and immune complex formation (associated with of noninfectious immunologic diseases and also with coxsackievirus infection due to N. meningitidis, Neisseria gonorrhoeae, Salmonella A16 infection. enterica serovar Typhi), (4) formation of emboli in endocarditis (due 810 to S. aureus, streptococci), and (5) vascular effects of toxins (in SSSS, superimposed vesicles or pustules centrally. Small, irregularly round, TSS, scarlet fever). Various systemic bacterial infections may spread to subcutaneous hemorrhages with a bluish gray center containing pus the skin, generally producing discrete lesions from which the organisms cells are a distinctive lesion of this syndrome. Ecchymotic areas or s can be isolated or recognized on biopsy with special stains. The most hemorrhagic, tender nodules that are located deep in the dermis may characteristic finding in DIC is noninflammatory purpura with extensive also occur. Lesions associated with chronic meningococcemia tend to microvascular occlusion referred to as purpura fulminans.127–130 Other appear in showers in association with the onset of fever. In contrast to ndrome y manifestations include diffuse bleeding, hemorrhagic necrosis of tissue, the lesions associated with fulminant meningococcemia, those of chronic and skin necrosis. Although DIC may result from sepsis, it may also meningococcemia rarely include organisms demonstrable on Gram- be caused by trauma, malignancy, obstetric calamities, severe hepatic stained smear or biopsy specimen. In addition, purpura fulminans is failure, and severe toxic or immunologic reactions. Purpura fulminans, a not a typical finding in chronic meningococcemia. A number of diseases severe skin disorder that is typically associated with DIC, occurs in three with periodic fever, skin lesions, and joint involvement may resemble or Clinical S j clinical settings: (1) as a consequence of severe sepsis, (2) after infec- chronic meningococcemia, including subacute bacterial endocarditis, tion, and (3) in neonates (usually seen in association with homozygous acute rheumatic fever, Henoch-Schönlein purpura, rat-bite fever, EM, Ma

I protein C deficiency). N. meningitidis is the organism most commonly and chronic gonococcemia. responsible for symmetrical peripheral gangrene (i.e., ischemic necrosis art I simultaneously involving the distal portion of two or more extremities Pseudomonas Infection P without arterial obstruction), but this disorder may also be due to S. Pseudomonas spp. are ubiquitous environmental organisms that are pneumoniae and other streptococcal species, H. influenzae, S. aureus, important pathogens in the hospital and in patients with certain underly- E. coli, Klebsiella spp., Proteus spp., A. hydrophila, other gram-negative ing host defense abnormalities (e.g., cystic fibrosis). They may also organisms, and Aspergillus. Symmetrical peripheral gangrene is preceded cause infection in normal hosts, especially when the skin has been by bleeding into the skin, ecchymosis, purpura, and acrocyanosis (a moistened. P. aeruginosa can cause folliculitis (“hot tub” folliculitis), grayish cyanosis that does not blanch on pressure and occurs on the lips, which is characterized by follicular, macular, papular, vesicular, or pustular legs, nose, ear lobes, and genitalia). Subsequently, the ecchymotic lesions lesions on any part of the body that has been immersed in contaminated become confluent, blister, undergo necrosis and ulceration, and develop water and has followed bathing in contaminated whirlpools, hot tubs, overlying eschars. Histologic examination reveals a Schwartzman-like and swimming pools.139 Exposure to contaminated water may also result reaction in the skin characterized by diffuse and extensive hemorrhages, in nodular lesions on the palms and soles (“hot foot” syndrome).140,141 perivascular cuffing, and intravascular thrombosis. Bacteria are usually Of importance, 96% of P. ae r uginosa isolates from swimming and hot absent from smears of the lesions. Shock rather than DIC appears to be tubs have been reported to be multidrug resistant.142 the major factor in the pathogenesis of symmetrical peripheral gangrene. Skin lesions have been reported to accompany P. aeruginosa sepsis As noted earlier, purpura fulminans may follow a benign infection, in 13% to 39% of patients.143–145 The dermatologic manifestations of P. especially in children. Common preceding illnesses include scarlet aeruginosa sepsis consist of four types of lesions. First, vesicles and fever, streptococcal pharyngitis, staphylococcal bacteremia, varicella, bullae may occur singly or in clusters and frequently are spread in and measles. random fashion over the skin. They may become hemorrhagic as they evolve. Second, gangrenous cellulitis may occur as a sharply demarcated, Neisseria meningitidis Infection superficial, painless, necrotic lesion. It may also begin abruptly as an With the widespread use of the H. influenzae vaccine, N. meningitidis acute infection with local pain, swelling, and erythema and involve is now the second-most common cause of bacterial meningitis after S. deep tissue and fascia. Third, macular or papular nodular lesions are pneumoniae and has a similar incidence as gram-negative and staphy- located predominantly over the trunk; the lesions are small, oval, and lococcal meningitis.131 Skin hemorrhages are the hallmark of invasive painless. These lesions may resemble the rose spots of typhoid fever. meningococcal disease.132–134 N. meningitidis has been cultured from Finally, ecthyma gangrenosum is a lesion characteristic but not pathog- 0.5% to 27.5% of children presenting with fever and petechiae, but nomonic of P. ae r uginosa sepsis. Ecthyma gangrenosum has generally many of these studies were conducted before the availability of menin- been reported to occur in 1.3% to 2.8% of septic patients,143,146,147 but gococcal vaccines. Hemorrhagic skin lesions have been present in 28% one report noted ecthyma gangrenosum in 28% of patients with to 77% of patients with invasive meningococcal disease.135 The lesions Pseudomonas bacteremia.145 characteristically are petechial but may be noted to blanch with pressure Ecthyma gangrenosum lesions begin as painless, round, erythematous early in the course of infection, thus resembling a viral exanthem. The macules, with or without adherent vesicles, that soon become indurated petechiae are irregular and small and are often accompanied yb palpable and progress to hemorrhagic bluish bullae. Later, the lesion sloughs to purpuric lesions, some of which may have pale centers. Coalescing form a deep gangrenous ulcer with a gray-black eschar and a surrounding lesions, often macular, may have a characteristic gun-metal gray color erythematous halo. The process evolves rapidly over 12 to 24 hours. centrally, consistent with epidermal necrosis. Lesions most commonly Lesions may be discrete or multiple and are usually found in the groin, occur on the extremities and trunk but may also be found on the head, axillary, or perianal areas but may occur anywhere on the body. Although palms and soles, and mucous membranes. Symmetrical peripheral most commonly associated with P. ae r uginosa sepsis, ecthyma gangrene may rapidly develop, often in association with DIC. Histologic gangrenosum–like lesions have also been reported in sepsis associated examination reveals diffuse endothelial damage, fibrin thrombi, necrosis with other pseudomonal species, S. pyogenes, S. aureus, A. hydrophila, of the vessel walls, and perivascular hemorrhage in the involved skin. K. pneumoniae, Serratia marcescens, Stenotrophomonas maltophilia, Gram staining of aspirates of the involved areas frequently reveals the , E. coli, , N. gonorrhoeae, Yersinia presence of organisms.136 In addition to the direct involvement of skin pestis, Chromobacterium violaceum, Candida spp., Aspergilluss spp., Mucor vessels by meningococci, excessive activation of the coagulation system spp., and HSV.148 These lesions may also occur with vasculitis or malignant and concomitant downregulation of the fibrinolytic system caused by infiltration.149 Rarely, ecthyma gangrenosum due to P. ae r uginosa may high concentrations of endotoxin in the blood may lead to cutaneous be found in the absence of sepsis.150–152 hemorrhagic lesions. Histologically, ecthyma gangrenosum is characterized by three Chronic meningococcemia is a rare disease. The classic clinical features: bacterial invasion of the media and adventitia of vein walls constellation of symptoms includes intermittent or sustained fevers; deep in the dermis, sparing of the intima and lumen, and minimal recurring maculopapular, nodular, pustular, or petechial eruptions; and inflammation.149 Bacterial invasion results in marked fibrin exudation migratory arthritis or arthralgias with little systemic toxicity.137 In one and frank hemorrhage, followed by bulla formation. Finally, necrosis large series comprising 148 patients, skin lesions were noted in 93%.138 of the dermis occurs. Bacteria are readily visible in biopsy samples and A variety of skin lesions may occur in chronic meningococcemia, the can be demonstrated in Gram-stained material scraped from the base most frequently reported being pale to pink macules and papules, seen of the lesion. in greater than 40% of cases. Nodular lesions may occur, mostly on Subcutaneous nodules may also result from P. aeruginosa bacteremia. the lower extremities. Petechiae of variable size may be seen, with Characteristically, the nodules are erythematous and warm, may be 811 either fluctuant or nonfluctuant, and may be tender. Despite prolonged enterotoxin A and LukE-LukD), and community-associated S. aureus antibiotic therapy, these lesions may contain viable bacteria weeks after skin and soft tissue infections( α-toxins, phenol-soluble modulins, the blood has been cleared of infection. The absence of fluctuance may leukocidins).176,177 Cha be due to either the lack of pus in neutropenic patients or the deep Community-associated methicillin-resistant S. aureus (CA-MRSA) location of the , or both. Although successful treatment may strains are now the predominant cause of community staphylococcal p require incision and drainage,153,154 prolonged antibiotic therapy without skin infections.178–185 In the United States most CA-MRSA strains carry ter 5 drainage may result in a cure.155,156 the staphylococcal cassette chromosome (SCC) mec types IV or V, are 7

typed as USA clones 300 or 400, and carry the gene for Panton-Valentine T Bacterial Endocarditis leukocidin. Groups at higher risk for CA-MRSA infections include he Acutely Ill Patient With Fever and Ras Skin lesions have been reported to accompany bacterial endocarditis athletes, HIV-infected persons, homeless persons, household members in 4% to 50% of cases.157–162 The cutaneous manifestations of bacterial of infected people, injection drug users, military personnel, prisoners endocarditis are important clues to the diagnosis, although they occur in correctional facilities, tattoo recipients, and urban dwellers who have less frequently than in the preantibiotic era.163 Cutaneous lesions are lower socioeconomic status and live in crowded conditions. CA-MRSA also less frequent in older patients (i.e., ≥65 years of age).164 Skin lesions strains are more likely to cause skin and soft tissue infections than include Osler nodes, Janeway lesions, subungual splinter hemorrhages, methicillin-susceptible strains. Skin lesions may occur as tender red cutaneous purpura and petechiae, and conjunctival petechiae (Roth that are commonly misinterpreted as “spider bites” by the spots). The prevalence of embolic and hypersensitivity lesions in skin patient. CA-MRSA strains may manifest as furuncles, , erythematous and mucous membranes (50%) in heroin-associated infective endocarditis patches and nodules, erythematous pustules (folliculitis), crusted plaques is similar to that described in patients with non–heroin-associated (impetigo), or any combination of these. Other soft tissue infections infective endocarditis.165 described include chronic external otitis, , cellulitis, necrotizing Petechiae are the most common skin and mucous membrane lesions fasciitis, and necrotizing myositis. However, the clinical picture is not observed in endocarditis, occurring in 20% to 40% of patients. The sufficiently distinct to allow a diagnosis of CA-MRSA based on clinical h lesions are small, flat, and reddish brown and do not blanch on pressure. features. The petechiae may be observed on the skin, especially on the heels, shoulders, and legs. Mucous membrane (oral and conjunctiva) involve- Staphylococcal Scalded Skin Syndrome ment is common. Petechiae frequently occur in small crops. Lesions SSSS (Ritter disease) describes a spectrum of superficial blistering skin usually are transient. disorders caused by the exfoliative toxins (also known as epidermolytic In the preantibiotic era, Osler nodes were present in 10% to 90% of toxins, epidermolysins, and exfoliatins) of S. aureus.186 Its severity varies patients with bacterial endocarditis.166 In the 1980s they were seen in from localized blisters to generalized exfoliation affecting the entire 10% to 20% of cases. Recent series suggests that they are now present body surface. Although mortality in appropriately treated children is in less than 10% of patients with endocarditis because endocarditis is less than 4%, in adults it can reach almost 60%. Approximately 5% of now diagnosed more rapidly before the development of Osler nodes. all S. aureus strains produce exfoliative toxins; two serotypes have been These lesions are tender, indurated, erythematous nodules, with a identified as affecting humans, ETA and ETB. pale center that is 1.0 to 1.5 mm in diameter.166–168 Osler nodes most , a disorder usually confined to children that results commonly occur on the pads of the fingers or toes but may also occur from toxin-producing strains of S. aureus, is characterized by discrete, on the thenar and hypothenar eminences and over the arms. Pain flaccid bullae containing clear or cloudy yellow fluid. Lesions are fre- may be elicited by palpating the tips of the digits. Osler nodes tend quently localized to the umbilicus, groin, or axillae. The surrounding to occur in crops, are rarely numerous, and tend to be transient. The skin may appear normal or mildly erythematous. The bullae rapidly lesions usually resolve without necrosis or suppuration 1 to 3 days rupture, leaving raw, denuded erosions that reepithelialize in 5 to 7 after antibiotic therapy is initiated. Histologically, Osler nodes show days. Affected infants are usually afebrile and lack constitutional signs. microabscesses with microemboli in adjacent arterioles. Osler nodes SSSS usually occurs in neonates or young children (<5 years of are most commonly associated with subacute bacterial endocarditis age) but may affect older children or, rarely, adults. Most cases in due to infection with streptococci but may occur in endocarditis due adults occur in association with renal impairment, lymphoma, or to infection with fungi or gram-negative bacilli or in systemic lupus immunosuppression. A well-characterized animal model exists for erythematosus, typhoid fever, and gonococcemia. Osler nodes probably SSSS, demonstrating that decreased renal clearance of the causative represent the sequelae of vascular occlusion by microemboli leading to toxin results in the clinical presentation. Unlike bullous impetigo, in localized vasculitis.169 which the produces skin lesions at the site of Janeway lesions consist of small erythematous macules or, less infection, in SSSS the infection produces a toxin (ETA or ETB) that commonly, small nodular hemorrhages in the palms and soles. Although disseminates, causing a diffuse, blanchable erythema in association they may be seen in subacute bacterial endocarditis, they are more with marked skin tenderness, fever, and irritability. Light stroking of common in acute endocarditis, especially that due to S. aureus. Unlike involved skin causes rupture and separation of the upper portion of the Osler nodes, Janeway lesions are painless. Histologically, they show epidermis (Nikolsky sign). Generalized desquamation usually occurs, microabscesses with neutrophil infiltration of capillaries. especially in intertriginous areas. Unless secondary infection intervenes, the skin heals within 10 to 14 days. A skin biopsy specimen (or a frozen Infections Due to Staphylococcus aureus section of an induced peel for more rapid diagnosis) may be studied and Streptococcus pyogenes to distinguish between SSSS and TEN. In SSSS the cleavage plane of Most commonly, S. aureus and Streptococcus pyogenes cause local skin the early intraepidermal bulla is just beneath the granular cell layer, infections, including impetigo; folliculitis; furuncles and ; whereas in TEN the bulla is subepidermal and associated with full- hidradenitis suppurativa (follicular infection of intertriginous regions); thickness necrosis of the epidermis. In addition, mucous membranes are and erysipelas, mastitis, and cellulitis.170 Both pathogens may produce relatively spared in SSSS in contrast to TEN. Early distinction between serious local infection, including abscesses, myositis, and fasciitis. S. these two diseases is important because the therapy for SSSS includes aureus is responsible for a variety of infectious syndromes that may antistaphylococcal antibiotics, whereas in TEN the discontinuation of produce local or diffuse skin lesions.171–172 Skin lesions arise from (1) treatment with the offending drug and initiation of aggressive burn production of toxins,173–175 (2) septic shock, and (3) vascular inva- unit intervention may be lifesaving. SSSS due to MRSA has been sion, often in association with endocarditis.S. aureus strains may reported.186,187 produce more than 30 different extracellular proteins.144 Staphylo- A mild form of SSSS is characterized by a generalized scarlatiniform coccal disease syndromes linked to toxins include toxic shock (TSS eruption with exfoliation (“staphylococcal scarlet fever”). The skin has toxin 1 [TSST-1]), SSSS (mediated by exfoliative toxins, primarily a sandpaper roughness, and Pastia lines are present, as in streptococcal exfoliative toxin A and exfoliative toxin B [ETA and ETB]), staphy- scarlet fever, but the strawberry tongue and palatal enanthem of lococcal food poisoning (due to staphylococcal exotoxins, principally streptococcal scarlet fever are absent. 812 Staphylococcal Toxic Shock Syndrome about pressure points (e.g., buttocks). The rash often exhibits a linear TSS is an acute febrile illness characterized by a generalized erythematous petechial character in the antecubital fossae and axillary folds (Pastia eruption that is due to in vivo production of a toxin at the site of lines). The rash of scarlet fever may be confused with rashes due to s localized, often relatively asymptomatic or unnoticed infection by S. erythema infectiosum (fifth disease), rubella, rubeola, EBV, hepatitis aureus strains capable of toxin production.188–192 The multisystem effects B, HIV, enteroviruses, and Streptobacillus moniliformis (rat-bite fever). observed in TSS patients are induced by TSST-1 and, to a lesser extent, The cutaneous eruptions of TSS and secondary syphilis may also appear ndrome y other staphylococcal enterotoxins. The toxins act as superantigens binding similar to that of scarlet fever, but vasomotor instability in the former directly to the Vβ chain of the T-cell receptor and to the major histo- and positive serology in the latter should suffice to differentiate them compatibility complex molecule, which triggers clonal expansion of the from scarlet fever. Noninfectious syndromes that should be considered T cells and an unregulated outpouring of proinflammatory cytokines.175,193 include Kawasaki disease, acute systemic lupus erythematosus, and Although staphylococcal TSS has been most commonly linked to S. juvenile rheumatoid arthritis. or Clinical S j aureus, TSST-1–producing coagulase-negative staphylococci have also In the later part of the 1990s an increased incidence of severe group been described.194 A streptococcal infections was reported.197 Invasive group A streptococcal Ma

I Although in the early 1980s most cases of TSS occurred in menstruat- infections are life threatening, especially when associated with streptococ- ing females, often in association with tampon use, nonmenstrual cal TSS. Similar to staphylococcal TSS, this syndrome is due to the 191 art I staphylococcal TSS is now more common. Nonmenstrual TSS has production of highly potent exoproteins that act as superantigens. The P been associated with a variety of infections, including postoperative term streptococcal toxic shock syndrome is now used for those patients wounds, cutaneous infections, burn wounds, postpartum complications, with hypotension and organ dysfunction as a result of toxin-mediated and S. aureus respiratory infections, often after viral influenza.195 Recur- streptococcal disease (Table 57.4).191,198,200 Many, but not all, patients rent nonmenstrual toxic shock has been described.196 have a rash at the time of presentation. Skin manifestations include TSS may range in severity from a relatively mild disease, often generalized erythroderma with desquamation and localized cellulitis misdiagnosed as a viral syndrome, to a severe life-threatening illness. with vesiculation or bulla formation. The differential diagnosis of a The most common symptoms include a temperature greater than 40°C desquamative rash includes Kawasaki disease, EM, toxic epidermal (104°F), hypotension, and diffuse erythroderma with desquamation 1 necrolysis, , and RMSF. Unlike staphylococcal TSS, a focus to 2 weeks after the onset of illness. Additional early features include of pyogenic inflammation is usually present, and a large proportion of conjunctival, oropharyngeal, and vaginal hyperemia; vomiting and the patients have documented bacteremia. Commonly, the local focus diarrhea; and myalgias. Most patients have abnormalities in three or of infection results in necrotizing fasciitis manifest by diffuse swelling more organ systems: (1) muscular: rhabdomyolysis, (2) central nervous and tenderness, a peau d’orange appearance, and erythema with sub- system: toxic encephalopathy, (3) renal: azotemia, (4) liver: abnormal sequent formation of bullae. Later the skin color changes from red to aminotransferase levels, and (5) hematologic: thrombocytopenia. The purple or black as the skin becomes necrotic. However, initially the rash of TSS is almost always noted within the first 24 hours of illness. clinical symptom of the local site of infection often is only severe pain, Desquamation occurs after 7 to 10 days, most prominently on the hands with tenderness and other physical findings appearing later. Rarely, and feet. Histologically, the epidermis exhibits cleavage in the basilar group B201 and group G202 streptococci have been reported to cause layers, which differentiates TSS from SSSS and from viral and drug myositis with TSS. eruptions. S. aureus septicemia may be associated with erythematous, petechial, or pustular lesions. In addition, lesions associated with Rickettsial Infections endocarditis, such as Osler nodes, Janeway lesions, and splinter hemor- Rickettsiae comprise several important pathogens transmitted by ticks rhages, may occur. Such skin lesions have been reported in 10% to 64% in the United States. Cutaneous manifestations often provide important of patients with staphylococcal septicemia. Purpuric lesions may in and early clues in the diagnosis of tick-borne diseases.203–206 Rickettsiae some cases be so extensive as to suggest meningococcemia or RMSF. are obligate intracellular parasites whose primary target in humans Gram-stained smears of the material in these lesions usually demonstrate appears to be the endothelial cell. After parasitization of the endothelial gram-positive cocci. cell, necrosis of the media and intima results in thrombosis, formation of microinfarcts, and extravasation of blood. The end result is increased Streptococcal Infections vascular permeability and vasculitis. The group A streptococci (S. pyogenes) cause a wide variety of local (e.g., impetigo, erysipelas, cellulitis, ) and invasive syndromes (e.g., bacteremia, necrotizing soft tissue infections, streptococcal TSS) associated with cutaneous manifestations.197,198 These manifestations of streptococcal infection occur via three distinct mechanisms199: (1) direct infection of the skin, (2) immunologically mediated disease, and (3) TABLE 57.4 Staphylococcal Versus Streptococcal toxin-mediated disease. Rheumatic fever affects up to 3% of people Toxic Shock Syndrome with untreated group A hemolytic streptococcal infections of the FEATURE STAPHYLOCOCCAL STREPTOCOCCAL nasopharynx. Cutaneous manifestations include erythema marginatum (occurring in 10%–20% of cases), subcutaneous nodules (in up to 30%), Age Primarily 15–35 yr Primarily 20–50 yr and erythema papulatum (rare). Gender Higher frequency in Men and women Scarlet fever is a diffuse erythematous eruption that results from women equally affected the production of pyrogenic exotoxin (erythrogenic toxin) produced Severe pain Rare Common by S. pyogenes, most commonly in the setting of pharyngitis. There Hypotension 100% 100% appear to be three distinct exotoxins (types A, B, and C) produced by approximately 90% of group A strains. The rash of scarlet fever requires Erythroderma rash Very common Less common both the presence of pyrogenic exotoxin and the existence of delayed-type Renal failure Common Common skin reactivity to streptococcal products. The latter requires prior exposure Bacteremia Low frequency 60% to organism. The pharynx is usually beefy red with edema involving the tonsillar area extending anteriorly to the soft palate and uvula. The Tissue necrosis Rare Common rash of scarlet fever usually starts on the head and neck and then rapidly Predisposing factors Tampons, surgery Cuts, burns, varicella expands to cover the trunk and finally the extremities. The palms and soles are usually spared. The rash is a diffuse erythema, blanching on Thrombocytopenia Common Common pressure, with numerous small (1–2 mm) papular elevations, giving a Mortality rare <3% 30%–70% “sandpaper” quality to the skin. The rash is most marked in the skin Data from Stevens DL. The toxic shock syndromes. Infect Dis Clin North Am. folds of the inguinal, axillary, antecubital, and abdominal areas and 1996;10:727–746. 813 Rash is a hallmark of RMSF,207,208 the most common serious rickettsial fever, headache, malaise, and myalgia. Rash occurs in approximately disease in the United States. Initially, a maculopapular rash develops. 60% of children but in less than 30% of adults. The rashp attern varies Subsequently, the rash becomes more petechial. Characteristically, the from petechial to maculopapular to diffuse erythema and typically occurs Cha rash appears between the second and sixth days of illness (average, 4 late in the course of the disease (median, 5 days after onset). The rash days). However, the rash may be absent in 5% to 17% of patients, and pattern might involve the extremities, trunk, face, or rarely, the palms p in up to 50% it may not appear within the first 3 days of illness.209–211 and soles. A newly recognized human pathogen, Ehrlichia ewingii, also ter 5 Failure to initiate proper therapy within 5 days of onset of symptoms212 may cause rash, but it is uncommon. 7 213 and failure to use a tetracycline have been associated with an increased Anaplasmosis is caused by Anaplasma phagocytophilum (human T mortality rate. Independent predictors of failure by the physician to granulocytotropic anaplasmosis). In the United States it is most common he Acutely Ill Patient With Fever and Ras initiate therapy the first time a patient was seen include absence of a in New England and the north-central and Pacific coastal states. Common rash, presentation between August 1 and April 30, and presentation signs and symptoms include fever, headache, malaise, myalgia, and within 3 days of illness.213 Most commonly, the rash begins on the vomiting. Rash is reported in less than 10% of cases. The clinical and extremities, often around the wrists and ankles, and spreads centripetally epidemiologic features of anaplasmosis and ehrlichiosis overlap with to the trunk, with relative sparing of the face. However, the rash may those of RMSF. Rash is less common with ehrlichiosis and anaplasmosis begin on the trunk (10%) and spread centrifugally or may have a diffuse than with RMSF, but it is important to remember that at presentation distribution at the time of onset (10%). Characteristically, the rash less than 50% of patients with RMSF will have a rash, and 15% will involves the palms or soles or both in the later stages of infection (Fig. never demonstrate a rash (i.e., so-called Rocky Mountain spotless fever). 57.8). Over time the rash, which begins as maculopapular lesions, may As with RMSF, the rash of these other tick-borne diseases may resemble progress to become petechial or ecchymotic. Rarely, gangrene or skin that of mononucleosis, thrombotic thrombocytopenic purpura, hepatitis necrosis that requires amputation occurs.214 The rash may rarely be A, and drug eruptions. urticarial or pruritic. Because the mortality rate for infection may be decreased from 15% to 3% with appropriate treatment, institution of Borrelia burgdorferii Infection h antibiotic therapy should never be delayed in the absence of rash. Signs Lyme disease is a tick-borne borreliosis with broad distribution and and symptoms similar to those of RMSF may occur with ehrlichiosis myriad manifestations.221–224 In early localized or disseminated Lyme and anaplasmosis (see later discussion). The rash of rickettsialpox yt pically disease, fever is present in approximately 15% of patients, although it begins as maculopapular and in its early phase may be confused with is usually low grade. Skin lesions are prominent clinical manifestations that of RMSF, but it quickly becomes papulovesicular, which is not of all stages of Lyme disease.225–228 Clinically, the disease is divided characteristic of the RMSF eruption. The rash of RMSF may also be into three stages of illness: early localized disease, early disseminated confused with measles, mononucleosis, viral hepatitis, streptococcal disease, and persisting late disease. The most common manifestation infection, primary HIV infection, secondary syphilis, parvovirus infection of early localized Lyme disease is EM, which usually appears at the (fifth disease), Kawasaki disease, and roseola. If a penicillin or cepha- site of the tick bite within 7 to 10 days (range, 3–30 days). Seventy losporin is administered before the appearance of the rash, the subsequent percent to 80% of infected patients will demonstrate EM.203 Most patients rash may be incorrectly diagnosed as a drug eruption rather than the (75%–80%) who exhibit EM in the United States have only a single rash of RMSF. (primary) lesion. EM initially begins as a red macule or papule that is usually homogeneous in its redness and may remain so until it heals. Ehrlichia and Anaplasma Species More commonly, the lesion partly or totally clears centrally, leaving Important tick-borne diseases that occur in the United States include an annular erythema that spreads centrifugally. The EM skin lesions RMSF, Lyme disease, tick-borne viral encephalitis, babesiosis, and are typically 5 cm or more in their largest diameter. EM may develop tularemia (see Chapter 296). Recently, Ehrlichia spp. and Anaplasma anywhere but is most frequently located around the knees, in the axillae, spp. have emerged as important and potentially life-threatening and in the groin. Although the lesion may last from a few days to about pathogens.215–220 1 year, it usually disappears within a few weeks to months. In about In the United States ehrlichiosis caused by Ehrlichia chaffeensiss (human half of the patients, itching, dysesthesia/hyperesthesia, or sensations of monocytotropic ehrlichiosis) is most common in the southern and heat may develop at the site of erythema. Many patients who develop mid-Atlantic, and north- and south-central states and in isolated areas early disseminated disease exhibit EM-like lesions. The disseminated of New England. Common early signs and symptoms of infection include lesions are usually smaller than the primary lesion and often multiple. These lesions may be ring shaped but are often homogeneous and nonmigrating. Syphilis Physicians should be familiar with the cutaneous manifestations of syphilis because primary and secondary syphilis and congenital syphilis continue to occur in the United States, especially in the southern states. The primary skin lesion () typically develops about 21 days after exposure. The differential diagnosis of patients with a genital ulcer in addition to syphilis includes genital herpes and chancroid. Secondary syphilis (Fig. 57.9) is often accompanied yb a rash with highly variable morphology. Lesions may be macular, papular, maculopapular, papu- losquamous, or pustular. On occasion, all types of lesions may be present in the same patient. A characteristic presentation of secondary syphilis is that of a pityriasis rosea–like eruption appearing as numerous, tan to reddish brown, scaly macules, usually distributed along skin tension lines on the trunk and, to a lesser extent, other body sites. Typically, no herald patch (a hallmark feature of pityriasis rosea) is present when this eruption is caused by syphilis, and usually the patient with secondary syphilis lacks associated pruritus and may have concurrent “copper penny” macules or plaques on the palms or soles. The differential diagnosis for secondary syphilis skin manifestations includes RMSF, FIG. 57.8 Rocky Mountain spotted fever. An example of late stage pityriasis rosea, psoriasis, lichen planus, and exanthematous drug/viral rash in an RMSF patient. (From Lin L, Decker CF. Rocky Mountain spotted eruptions. Condylomata lata, which are grayish, raised, broad, flat- fever. Dis Mon. 2012;58:361–369.) appearing papular lesions, may occur in skin folds or apposed skin in 814 of fever (as high as 105°F) and malaise; cough, coryza, and conjunctivitis (the three “C”s); and a pathognomonic enanthem (Koplik spots, tiny white spots that appear inside the mouth), followed by a maculopapular s rash. The classic morbilliform rash associated with measles typically occurs at the end of the prodromal phase of disease (see Fig. 57.1). The rash typically develops on the face and then proceeds to spread down ndrome y the body to involve extremities, including the palms and soles. The rash usually lasts 5 days and will become confluent, especially on the face. During the healing phase, the rash may desquamate and typically clears first from the regions initially involved. Typically, measles patients are most ill during the first 1 to 2 days of the rash. or Clinical S j Measles also presents in an atypical form, usually associated with inactivated measles vaccination.239,240 The atypical measles syndrome is Ma

I characterized by pneumonia, often with lobular infiltrates, hilar lymphadenopathy, and pleural effusion. The pulmonary syndrome is art I associated with a maculopapular rash that progresses to vesicular petechial P FIG. 57.9 Secondary syphilis. Rash of secondary syphilis on patient’s sole. (From Miller AC, Rashid RM, Khachemoune A. Secondary syphilis. J or purpuric lesions. Despite appearing ill, spontaneous recovery is Emerg Med. 2008;35:83–85.) expected with atypical measles syndrome. NEW AND EMERGING INFECTIOUS DISEASES moist areas, such as the anus, vulva, and scrotum. Condylomata lata The InInstitutestitute ofof MMedicineedicine definesdefines newn and emerging diseases as “new, need to be distinguished from condylomata acuminata (genital warts), reemerging or drug-resistant infections whose incidence in humans has squamous cell carcinoma, molluscum contagiosum, and micropapil- increased within the past two decades or whose incidence threatens lomatosis of the vulva. to increase in the near future.”241 Many would also include infections whose geographic range is increasing. The factors leading to the Candidiasis development of new and emerging diseases have been reviewed in The incidence and relative frequency of health care–associated infections the literature.241–244 Approximately 75% of emerging or reemerging due to Candida has risen dramatically in the recent past, and this increase diseases are known to be zoonotic.245 It is important for infectious has been accompanied by a shift in the infecting pathogen away from disease clinicians to realize that international travel has dramatically Candida albicans to non–C. albicans spp.229–231 The most recent data increased; in accordance, patients may present with diseases only from the CDC (2011–14) reported that non-glabrata, non-albicans rarely seen in the United States. Many of these diseases may be associ- Candida spp. accounted for 4.9%, C. glabrata for 3.4%, and C. albicans ated with either local or generalized skin lesions, including dengue for 6% of central line–associated .232 Predisposing fever, yellow fever, viral hemorrhagic fevers, Zika virus, malaria, and factors for disseminated or invasive infection are mucosal colonization leptospirosis. with Candida; malignancy with cytotoxic therapy; ; anti- microbial therapy, especially with broad-spectrum agents; parenteral Dengue, Chikungunya, and Zika Viruses hyperalimentation; severe burn injuries; very low birth weight; use of The etiologic agents of dengue fever are four serologically related RNA IV catheters; systemic administration of adrenocortical corticosteroids; viruses belonging to the family Flaviviridae.246–248 Dengue is widely acute renal failure; prolonged care in an intensive care unit; and distributed with endemic transmission in Africa, Asia, and South and complicated intraabdominal surgery.229–231 Central America. Most cases in the continental United States have An older study reported that 13% of patients with disseminated involved travelers, but transmission has been reported in Hawaii and candidiasis have skin lesions,233 whereas a more recent study reported Texas. Classic dengue fever begins after an incubation period of 3 to 35.8%.234 Typical skin lesions are 5 to 10 mm, erythematous or purpuric, 15 days (average, 5–8 days) with an abrupt onset of fever that may nontender, firm, deep dermal papules that characteristically do not be accompanied by chills, headache, and general malaise. The fever develop a central eschar or necrosis.234,235 The lesions may have the usually lasts 3 to 7 days and may be biphasic. Dermatologic findings appearance of papules, nodules, or plaques. In about half of the cases, do not occur in all patients with classical dengue. When they occur, they show characteristic central pale vesicular or pustular centers. erythema may appear shortly before the onset of fever, concurrently Uncommonly, they may have necrotic centers. Usually the lesions are with fever onset or 24 to 48 hours later. This rash may be noted as a diffuse, involving the trunk and proximal extremities, but they may be flushing or erythematous mottling beginning on the trunk and spreading localized to a small area. The face is usually spared. The diagnosis of centrifugally to the face, neck, and extremities. Flushing may disap- systemic candidiasis may be confirmed yb punch biopsy for touch pear after 1 or 2 days or may blend into an erythematous macular or preparation, histology, and culture in approximately 70% of patients.234,236 maculopapular rash that develops at any time during the course of illness. Congenital candidiasis is a rare disease with fewer than 100 cases reported Pruritus and desquamation, especially on the palms and soles, may follow that result from acquisition of infection in utero.237 It is characterized termination of the eruption. Dengue hemorrhagic fever/dengue shock by a diffuse erythematous skin eruption with or without vesicles and syndrome, a more severe disease, has more pronounced dermatologic pustules. Systemic infection, including pneumonia, may occur with or findings, including petechiae, purpura, ecchymoses, epistaxis, and without skin lesions. gum bleeding. Many other fungi produce nodular lesions identical to those caused Chikungunya virus is an arbovirus (genus Alphavirus, family by Candida and must be considered as possible pathogens in immuno- Togaviridae) that is prevalent in Africa and Asia, especially in India compromised patients. In patients with acquired immunodeficiency and islands in the Indian Ocean and has recently spread to the syndrome (AIDS), cryptococci may cause umbilicated nodules that Caribbean and South America.249 Disease has been reported in the mimic the lesions of molluscum contagiosum. United States in travelers returning from endemic areas, with local transmission in Puerto Rico and Florida.250 After an incubation period Measles of 2 to 4 days, patients have an abrupt onset of high fever, headache, Measles remains endemic in multiple regions of the world. However, back pain, myalgia, and arthralgia that may be intense. Skin involve- in recent years we have seen increases in the numbers of cases in countries ment is present in 20% to 50% of cases and consists of a pruriginous where there have been decreases in the frequency of measles vaccina- maculopapular rash mostly located on the face, trunk, and extremities. tion.238 Thus physicians need to become reacquainted with the skin The rash is transient. Facial edema and pruritus may accompany the manifestations of the disease. Measles is characterized by a prodrome rash. In children a bullous rash with pronounced sloughing may occur. 815 Hemorrhagic fever has been reported in Chikungunya-infected patients Infection with B. henselae results in disease syndromes of variable from Thailand. severity, ranging from lymphadenopathy to systemic disease. Cat- The rash from Zika virus is morphologically very similar to that of scratch disease occurs primarily in children and young adults and is Cha dengue virus, with the majority of Zika virus infections presenting with generally a benign self-limited disease. Cat-scratch disease typically 251–253 276–278 a morbilliform rash with islands of sparing. The rash can be begins with a cutaneous lesion at the site of inoculation. The p pruritic254–255, descending,256 and/or blanching.257–258 The rash typically lesion that develops 3 to 10 days after introduction of the organism ter 5 occurs after the initial 3 to 4 days of symptoms, with reports of the rash evolves through erythematous, vesicular, and papular crusted stages. 7

occurring as early as the first day of illness or even preceding other Less commonly, it can be pustular or nodular. Approximately 2 weeks T symptoms.259–261 The rash typically lasts for an average of 6 days (range, after inoculation, regional adenopathy develops proximal to the skin he Acutely Ill Patient With Fever and Ras 2–14 days) and can spread to any part of the body, including the torso, lesion. The nodes are usually tender, often have overlying erythema, extremities, palms, soles, and face.259,262 Fever tends to be less prominent and may suppurate. Low-grade fever and malaise occur in about 30% than with dengue virus infection, often occurring in less than 50% of of children. Uncommon cutaneous manifestations include a transient individuals.256 maculopapular rash, EM, erythema nodosum, and purpura. The diff- ferential diagnosis includes other diseases associated with regional Viral Hemorrhagic Fever lymphadenopathy and cutaneous inoculation lesions (e.g., nontuberculous Hemorrhagic fever may be caused by viruses belonging to several families, mycobacteria, Nocardia, Y. pestis, Bacillus anthracis, Francisella tularensis, including the Arenaviridae (e.g., New World arenaviruses, such as Erysipelothrix rhusiopathiae), pyogenic infections due to streptococci and Argentine hemorrhagic fever, Bolivian hemorrhagic fever, Venezuelan staphylococci, viral-associated lymphadenopathy (e.g., CMV, HIV, EBV), hemorrhagic fever; Lassa fever), Bunyaviridae (hantaviruses, Crimean- and lymphoma. Congo fever, Rift Valley fever), Filoviridae (Ebola, Marburg), and B. henselaee and B. quintana are capable of causing a variety of diseases Flaviviridae (yellow fever, dengue hemorrhagic fever, Omsk hemorrhagic in immunocompromised patients, principally patients with late-stage fever).263–265 HIV-1 infection, including , bacillary peliosis, h Hantaviruses are RNA viruses that belong to the family Bunyaviridae splenitis, osteomyelitis, and bacteremia. On occasion, bacillary angio- and include Hantaan, Seoul, Puumala, Dobrava, Sin Nombre, Bayou, matosis has been reported in immunocompetent individuals.279 Skin Black Creek Canal, and New York viruses.266–268 Hemorrhagic fever lesions are the most frequent clinical manifestation of bacillary angio- with renal syndrome (HFRS) may be caused by seven hantaviruses matosis, with a prevalence of 55% to 90%. The typical lesion is solitary (e.g., Hantaan, Seoul, Dobrava, Saaremaa, Amur, Puumala, and Far or disperses all over the body. The reddish purple papules may be difficult East).267 Severe forms of HFRS have characteristic phases that may to distinguish clinically from Kaposi sarcoma and pyogenic granuloma. not be seen with milder disease. After an incubation period of 2 to 3 The lesions of bacillary angiomatosis may appear as smooth, warty, and weeks, patients present with abrupt onset of fever in association with pedunculated papules; subcutaneous nodules; and hyperkeratotic plaques. malaise, headache, myalgias, back pain, abdominal pain, nausea, and They rarely ulcerate or bleed. vomiting. Conjunctival injection or hemorrhage with palatal and upper torso petechiae is commonly seen on physical examination. During this Orthopoxviruses phase, a characteristic erythematous flush that blanches with pressure The genus Orthopoxvirus contains multiple species that infect humans, may be observed, usually affecting the face, neck, and upper torso. including variola, monkeypox, vaccinia (includes buffalopox), and After the 3- to 7-day febrile phase, a period of hypotension and severe cowpox.280 Variola and monkeypox are often life-threatening diseases, shock ensues that is characterized by hemorrhagic manifestations. whereas vaccinia and cowpox generally are associated with local lesions. Overall, about 20% of the patients manifest severe disease, with death The eradication of smallpox represents one of the greatest public health from shock and renal failure in 5% to 10% of cases. The hantavirus achievements of the 20th century. After the successful eradication of pulmonary syndrome may be caused by multiple hantaviruses, including smallpox, the routine use of vaccinia vaccine was discontinued. However, Sin Nombre virus.267 Some forms of hantavirus pulmonary syndrome the threat of bioterrorism raises the prospect for an intentional use of (e.g., Andes) can present as conjunctivitis, facial flushing, and variable smallpox.281–283 Given the threat of bioterrorism, all health care personnel numbers of fine petechiae on the trunk, axillary folds, soft palate, should be familiar with the skin manifestations of the category A bioter- or neck. rorist agents (i.e., anthrax, plague, tularemia, Ebola, Marburg, Lassa, Filoviruses include the agents that cause Marburg and Ebola hemor- Machupo).284 Multiple outbreaks of monkeypox in humans have been rhagic fever.269–272 Ebola virus is more virulent than Marburg virus and reported,285,286 including a 2003 outbreak in the United States traced causes more severe clinical disease, with an accelerated course and high back to a consignment of rodents (giant Gambian rats) from Ghana. morbidity and mortality rates. Patients present with an acute onset of Thus the clinician is now confronted with having to distinguish the fever, severe frontal headache, anorexia, malaise, and myalgias. These skin lesions of several possible poxvirus infections, including smallpox, signs and symptoms are followed 2 to 3 days later by clinical deterioration complications of vaccinia (i.e., generalized or progressive vaccinia, heralded by pharyngitis, conjunctivitis, severe nausea and vomiting, eczema vaccinatum), and monkeypox. These lesions must be distinguished abdominal pain, and watery diarrhea. Five days later, patients develop from varicella, disseminated herpes simplex, and other disorders a maculopapular rash on the trunk and back that is followed by the characterized by a similar eruption, including meningococcal septicemia, appearance of petechiae, ecchymoses, subconjunctival hemorrhages, coagulation disorders, and typhus. epistaxis, hemoptysis, hematemesis, and melena. Hemorrhagic shock After a 12- to 14-day incubation period (range, 7–17 days), the may progress to death. Patients with Marburg virus infection may develop patient with smallpox typically develops high fever, malaise, and prostra- a scarlatiniform rash rather than a maculopapular rash. Considerations tion with headache and backache. A maculopapular rash then appears in the differential diagnosis of African hemorrhagic fevers also include on the mucosa of the mouth and pharynx, face, and forearms and yellow fever and Lassa fever, but these illnesses are not accompanied spreads to the trunk and legs. Within 1 to 2 days, the rash becomes by a rash. vesicular and later pustular. The pustules are characteristically round, firm, and deeply embedded in the skin. Crusts begin to form after 7 to Bacterial Diseases Due to Bartonella 9 days; the eschars later separate, leaving pits and scars. Bacterial Species superinfection of skin lesions may complicate smallpox. The rash of Bartonella are small, fastidious, intracellular gram-negative bacteria.273–275 variola differs from that of varicella in several ways. First, the lesions The genus now includes more than 20 distinct species, several of which of variola appear during a 1- to 2-day period and evolve at the same are capable of causing human disease. Most of our current knowledge time, whereas the lesions of varicella demonstrate different stages of on Bartonella infections is restricted to B. henselae, B. quintana, and B. maturation and generally appear in crops every few days. Second, the tribocorum. Bartonella spp. that cause human disease are generally lesions of variola tend to involve the extremities and face, whereas the associated with well-defined reservoirs, usually domestic and wild lesions of varicella have a centripetal predilection with a greater con- animals. centration of lesions on the trunk than on the face and extremities. 816 Also, varicella lesions are almost never found on the palms and soles. Skin Lesions in Finally, the lesions of variola are much more deeply embedded than Immunocompromised Patients the rash of varicella, where the lesions are more superficial. The rash The diagnosis of skin lesions in the immunocompromised patient is s of smallpox may be confused with SJS, measles, and coxsackievirus complex because of the wide range of potential microbial pathogens infections. that may cause disease in patients with abnormal immune responses Vaccinia vaccine is still being provided to members of the US military. (Table 57.5).289–297 In addition, in immunocompromised persons, common ndrome y Recognition and management of the complications of vaccinia vaccination infections may have unusual manifestations, and such patients often have been summarized.287,288 Vaccinia vaccination leads to the local have an insufficient response to conventional therapy. Johnson289 recom- lesion at the site of immunization. Local complications include satellite mends the following approach to cutaneous lesions suspected to be lesions, lymphangitis, secondary bacterial infections, lesions from infectious. First, the most rapid and sensitive methods for detecting inadvertent remote inoculation, and progressive vaccinia at the site of or Clinical S j the vaccination most commonly in immunosuppressed persons. Dis- seminated lesions include generalized vaccinia and eczema vaccinatum. Ma

I Generalized vaccinia refers to a relatively benign generalized eruption in which each lesion is identical to its primary smallpox vaccination. art I The incidence has been reported to range from 23 to 242 per 1 million P first-time vaccinees. Severe cases canbe treated with variola immune globulin, cidofovir, or both. After vaccinia vaccination, patients also may develop a generalized EM-like rash. This is a benign condition and does not require therapy. Eczema vaccinatum occurs in persons with a history of eczema or atopic dermatitis regardless of disease activity or severity. It has also been reported in persons without a history of dermatologic conditions. Eczema vaccinatum is characterized by high fever and generalized lymphadenopathy with an extensive vesicular and pustular eruption. The syndrome begins concurrently or shortly after the onset of local vaccinial lesions in the vaccinee. It may also occur in contacts 5 to 19 days after exposure.Th ere is a significant risk for secondary bacterial or fungal infections. This adverse reaction is associated with a poor prognosis and high mortality. Therapy consists of multiple doses of variola immune globulin, hemodynamic support, and treatment of secondary infections. Cidofovir might be useful for therapy, but there are no published clinical data on its efficacy. Historically, the rate of eczema vaccinatum per 1 million vaccinees was reported as 10.4 to 41.5. Monkeypox is enzootic in squirrels and monkeys in the rain forests of western and central Africa. The disease appears to be endemic in these regions of Africa, but multiple outbreaks have been described. FIG. 57.10 Monkeypox. Patient with pox during a monkeypox outbreak Clinical signs of monkeypox include respiratory distress, lymph- in the Democratic Republic of the Congo. (From Jahrling PB. Smallpox and adenopathy, and a centrifugally distributed vesiculopustular rash (Fig. related orthopoxviral infections. In: Guerrant RL, Walker DH, Weller PF, 57.10). The case-fatality rate has been reported to be approximately eds. Tropical Infectious Diseases: Principles, Pathogens and Practice. 3rd 10% in persons not vaccinated against smallpox. ed. Philadelphia: Saunders Elsevier; 2011:369–377.)

TABLE 57.5 Types of Skin Infections in Immunocompromised Hosts by Pathophysiologic Events TYPE OF INFECTION PATHOGEN SITE OF INFECTION HEALTHY HOST COMPROMISED HOST Primary skin infections (common Group A Streptococcus Epidermis, hair follicles Impetigo, ecthyma, Soft tissue infection, necrotizing pathogens) folliculitis Cellulitis, abscess Staphylococcus aureus Dermis Abscesses, intertrigo Soft tissue infection Unusually widespread cutaneous Dermatophytes, Candida Epidermis, intertriginous Dermatophytosis; epidermal Dermatophytosis; epidermal infection spp. sites, hair follicles (limited), folliculitis (extensive), folliculitis Candida spp. Oropharynx, esophagus, Candidiasis; intertrigo, Candidiasis; intertrigo, folliculitis, genitalia genital mucosal HSV Localized herpes, resolves Chronic herpetic ulcers spontaneously VZV Herpes zoster (mild) Herpes zoster (extensive) EBV Hairy leukoplakia MCV MCV (localized, nonfacial) Widespread MCV, resistant to therapy HPV Common and mucosal Widespread warts; squamous cell warts carcinoma in situ Opportunistic primary cutaneous NTM Dermis, hypodermis Swimming pool granuloma Soft tissue infection ± necrosis infection Nocardia Septicemia Molds Prototheca Systemic infection metastatic to Bacteria, fungal pneumonitis Dermis, hypodermis Soft tissue infection ± Soft tissue infection ± necrotic cutaneous and subcutaneous sites with fungemia necrotic nodules nodules EBV, Epstein-Barr virus; HPV, human papillomavirus; HSV, herpes simplex virus; MCV, molluscum contagiosum virus; NTM, nontuberculous mycobacteria; VZV, varicella-zoster virus. Data from Johnson RA. The immune compromised host in the twenty-first century: management of mucocutaneous infections. Semin Cutaneous Med Surg. 2000;19:19–61. 817 microbes both histologically and immunologically should be used. appearance that may include nodules, ulcers, indurated plaques, macu- Second, appropriate cultures and stains should be obtained to optimize lopapular eruptions, vesicles, and petechiae. the chance for identifying the pathogen. A 6- or 8-mm punch biopsy In immunocompromised patients cutaneous lesions resulting from Cha is usually adequate. Half of the tissue is sent for histopathologic evaluation hematogenous spread of infection are caused by three classes of organ- by routine methods and by special stains for fungi, mycobacteria, and isms: (1) P. aeruginosa and other bacteria; (2) the endemic systemic p bacteria. The other half is sent to the microbiology laboratory for culture mycoses caused by Histoplasma capsulatum, Coccidioides spp., and, ter 5 of aerobic and anaerobic bacteria, mycobacteria, and fungi (at 25° and rarely, Blastomyces dermatitidis; and (3) the opportunistic organisms 7

37°C) and for Gram stain, acid-fast, modified acid-fast, and direct fungal Aspergillus, C. neoformans, Candida, Rhizopus, and Nocardia. P. aeruginosa T stains of touch preparations or ground tissue. Recommendations for may cause either cellulitis or ecthyma gangrenosum, which may develop he Acutely Ill Patient With Fever and Ras processing specimens have been published.292 in the absence of bacteremia. Patients with malignancy may develop Solid-organ transplant recipients are at high risk for disease due to sepsis associated with a variety of uncommon bacteria that are also opportunistic bacterial, viral, and fungal pathogens. The risk for infection associated with skin lesions (e.g., A. hydrophila, C. canimorsus, and the most likely infecting pathogen depend on the type of transplant; septicum, mycobacteria, and Salmonella enterica serovar Typhimurium). type and dose of immunosuppressive medications; time since transplanta- Most commonly, H. capsulatum causes cellulitis, but it may also cause tion; presence of coexisting diseases, including viral infections; and papules, nodules, pustules, and hemorrhagic lesions. Metastatic spread epidemiologic exposures. to the skin from noncutaneous sites of infection most commonly occurs Cutaneous infections in immunocompromised persons may be with Aspergillus spp., C. neoformans, Candida spp., Rhizopus spp., and categorized into four groups based on pathophysiology: (1) infection Nocardia. With the exception of Candida, the initial portal of entry is originating in skin that is typical of those occurring in immuno- the respiratory tract. However, the respiratory tract infection may be competent persons, albeit with the potential for more serious illness; asymptomatic, with the initial signs of illness seen in the skin. In (2) extensive cutaneous involvement with pathogens that normally neutropenic patients cutaneous lesions due to Aspergillus spp. are often produce trivial or well-localized disease in immunocompetent patients; found in association with the sino-orbital form of disease. Neutropenic h (3) infection originating from a cutaneous source that is caused by patients may also develop disseminated infection with other fungi, such opportunistic pathogens that rarely cause disease in immunocompe- as Fusarium spp. and Trichosporon beigelii. tent patients but may cause either localized or widespread disease in HIV infection commonly results in dermatologic disorders in both immunocompromised patients; and (4) cutaneous or subcutaneous adults and children.298–302 Clinically, the skin lesions associated with infection that represents metastatic spread from a noncutaneous site. HIV infection may be classified yb morphologic appearance, stage of Only life-threatening infections with cutaneous manifestations are dis- HIV infection, pathophysiology (infectious, neoplastic, vascular, miscel- cussed further here. In general, most cases of result from laneous), and, for infectious diseases, etiologic agent. Skin eruptions secondary dissemination after initial infection of the lungs or other are observed in greater than 50% of patients with primary HIV infection, organ systems. Primary cutaneous infection resulting from direct inocu- generally developing on day 1 to 5 of the acute illness. The rash char- lation is less common. In transplant patients infections with viruses acteristically consists of 10 to hundreds of 5- to 10-mm, oval or round, and fungi are probably more common than skin infections caused pink to deep-red macules or slightly raised papules. Other skin manifesta- by bacteria. tions have included diffuse urticaria, vesicular and pustular exanthema, Immunocompromised patients are at increased risk for the develop- desquamation of palms and soles, and alopecia. Like other immuno- ment of cellulitis due to S. pyogenes and S. aureus. Neutropenic patients compromised patients, individuals with AIDS develop infections with are also susceptible to more unusual pathogens, such as members of opportunistic pathogens that rarely, if ever, cause infection in immu- the family Enterobacteriaceae and Pseudomonas spp. Patients with nocompetent people. These include unusually severe or persistent herpes leukemia or impaired cell-mediated immunity may develop erysipelas-like viral infections (HSV, VZV, CMV), staphylococcal infections including lesions due to Candida spp. or Cryptococcus neoformans. Both local CA-MRSA, nontuberculous mycobacterial infections, disseminated and diffuse skin infections with herpesviruses, especially HSV and VZV, candidiasis, infections with endemic fungi, ectoparasites, and soil- are very common. Cutaneous CMV infection has a highly variable dwelling fungi.

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art I United States: a practical guide for physicians and other Martínez J, et al. Congenital candidiasis: a rare and 2006;7:31–43. P Chapter 57 The Acutely Ill Patient With Fever and Rash

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