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The acutely ill patient with fever and rash often presents a diagnostic challenge for physicians. The distinctive appearance of an eruption in concert with a clinical syndrome may facilitate a prompt diagnosis and the institution of life-saving therapy or critical infectioncontrol interventions. Representative images of many of the rashes discussed in this chapter are included in Chap. 10.


Approach to the Patient:

FEVER AND RASH

A thorough history of patients with fever and rash includes the following relevant information: immune status, medications taken within the previous month, specific travel history, immunization status, exposure to domestic pets and other animals, history of animal (including arthropod) bites, existence of cardiac abnormalities, presence of prosthetic material, recent exposure to ill individuals, and exposure to sexually transmitted diseases. The history should also include the site of onset of the rash and its direction and rate of spread. A thorough physical examination entails close attention to the rash, with an assessment and precise definition of its salient features. First, it is critical to determine the type of lesions that make up the eruption. Macules are flat lesions defined by an area of changed color (i.e., a blanchable erythema). Papules are raised, solid lesions <5 mm in diameter; plaques are lesions >5 mm in diameter with a flat, plateau-like surface; and nodules are lesions >5 mm in diameter with a more rounded configuration.


Wheals (urticaria, hives) are papules or plaques that are pale pink and may appear annular (ringlike) as they enlarge; classic (nonvasculitic) wheals are transient, lasting only 24–48 h in any defined area. Vesicles (<5 mm) and bullae (>5 mm) are circumscribed, elevated lesions containing fluid. Pustules are raised lesions containing purulent exudate; vesicular processes such as varicella or herpes simplex may evolve to pustules. Nonpalpable purpura is a flat lesion that is due to bleeding into the skin; if <3 mm in diameter, the purpuric lesions are termed petechiae; if >3 mm, they are termed ecchymoses. Palpable purpura is a raised lesion that is due to inflammation of the vessel wall (vasculitis) with subsequent hemorrhage.An ulcer is a defect in the skin extending at least into the upper layer of the dermis, and an eschar (tâche noire) is a necrotic lesion covered with a black crust. Other pertinent features of rashes include their configuration (i.e., annular or target), the arrangement of their lesions, and their distribution (i.e., central or peripheral). For further discussion, see Chap. 14.


CLASSIFICATION OF RASH

This chapter reviews rashes that reflect systemic disease, but it does not include localized skin eruptions (i.e., cellulitis, impetigo) that may also be associated with fever (Chap. 21). Rashes are classified herein on the basis of the morphology and distribution of lesions. For practical purposes, this classification system is based on the most typical disease presentations. However, morphology may vary as rashes evolve, and the presentation of diseases with rashes is subject to many variations. For instance, the classic petechial rash of Rocky Mountain spotted fever (RMSF; Chap. 75) may initially consist of blanchable erythematous macules distributed peripherally; at times, the rash associated with RMSF may not be predominantly acral, or a rash may not develop at all. Diseases with fever and rash may be classified by type of eruption: centrally distributed maculopapular, peripheral, confluent desquamative erythematous, vesiculobullous, urticarial, nodular, purpuric, ulcerated, or eschar (Table 8-1). For a more detailed discussion of each disease associated with a rash, the reader is referred to the chapter dealing with that specific disease. (Reference chapters are cited in the text and listed in Table 8-1.)


CENTRALLY DISTRIBUTED MACULOPAPULAR ERUPTIONS

Centrally distributed rashes, in which lesions are primarily truncal, are the most common type of eruption. The rash of rubeola (measles) starts at the hairline 2–3 days into the illness and moves down the body, sparing the palms and soles (Chap. 95). It begins as discrete erythematous lesions, which become confluent as the rash spreads. Koplik’s spots (1- to 2-mm white or bluish lesions with an erythematous halo on the buccal mucosa) are pathognomonic for measles and are generally seen during the first 2 days of symptoms. They should not be confused with Fordyce’s spots (ectopic sebaceous glands), which have no erythematous halos and are found in the mouth of healthy individuals. Koplik’s spots may briefly overlap with the measles exanthem. Rubella (German measles) also spreads from the hairline downward; unlike that of measles, however, the rash of rubella tends to clear from originally affected areas as it migrates, and it may be pruritic (Chap. 96). Forchheimer’s spots (palatal petechiae) may develop but are nonspecific since they also develop in mononucleosis (Chap. 82) and scarlet fever (Chap. 36). Postauricular and suboccipital adenopathy and arthritis are common among adults with German measles. Exposure of pregnant women to ill individuals should be avoided, as rubella causes severe congenital abnormalities.


Numerous strains of enteroviruses (Chap. 94), primarily echoviruses and coxsackieviruses, cause nonspecific syndromes of fever and eruptions that may mimic rubella or measles. Patients with infectious mononucleosis caused by Epstein-Barr virus (Chap. 82) or with primary infection caused by HIV (Chap. 90) may exhibit pharyngitis, lymphadenopathy, and a nonspecific maculopapular exanthem. The rash of erythema infectiosum (fifth disease), which is caused by human parvovirus B19, primarily affects children 3–12 years old; it develops after fever has resolved as a bright, blanchable erythema on the cheeks (“slapped cheeks”) with perioral pallor (Chap. 85). A more diffuse rash (often pruritic) appears the next day on the trunk and extremities and then rapidly develops into a lacy reticular eruption that may wax and wane (especially with temperature change) over 3 weeks. Adults with fifth disease often have arthritis, and fetal hydrops can develop in association with this condition in pregnant women. Exanthem subitum (roseola) is caused by human herpesvirus 6 and is most common among children <3 years of age (Chap. 83). As in erythema infectiosum, the rash usually appears after fever has subsided. It consists of 2- to 3-mm rose-pink macules and papules that rarely coalesce, occur initially on the trunk and sometimes on the extremities (sparing the face), and fade within 2 days. Although drug reactions have many manifestations, including urticaria, exanthematous drug-induced eruptions are most common and are often difficult to distinguish from viral exanthems. Eruptions elicited by drugs are usually more intensely erythematous and pruritic than viral exanthems, but this distinction is not reliable.


A history of new medications and an absence of prostration may help to distinguish a drug-related rash from an eruption of another etiology. Rashes may persist for up to 2 weeks after administration of the offending agent is discontinued. Certain populations are more prone than others to drug rashes. Of HIV-infected patients, 50–60% develop a rash in response to sulfa drugs; 90% of patients with mononucleosis due to Epstein-Barr virus develop a rash when given ampicillin. Rickettsial illnesses (Chap. 75) should be considered in the evaluation of individuals with centrally distributed maculopapular eruptions. The usual setting for epidemic typhus is a site of war or natural disaster in which people are exposed to body lice. A diagnosis of recrudescent typhus should be considered in European immigrants to the United States. However, an indigenous form of typhus, presumably transmitted by flying squirrels, has been reported in the southeastern United States. Endemic typhus or leptospirosis (the latter caused by a spirochete; Chap. 72) may be seen in urban environments where rodents proliferate.


Outside the United States, other rickettsial diseases cause a spotted-fever syndrome and should be considered in residents of or travelers to endemic areas. Similarly, typhoid fever, a nonrickettsial disease caused by Salmonella typhi (Chap. 54), is usually acquired during travel outside the United States. Dengue fever, caused by a mosquito-transmitted flavivirus, occurs in tropical and subtropical regions of the world (Chap. 99). Some centrally distributed maculopapular eruptions have distinctive features. Erythema chronicum migrans (ECM), the rash of Lyme disease (Chap. 74), typically manifests as singular or multiple annular plaques. Untreated ECM lesions usually fade within a month but may persist for more than a year. Erythema marginatum, the rash of acute rheumatic fever (Chap. 37), has a distinctive pattern of enlarging and shifting transient annular lesions. Collagen vascular diseases may cause fever and rash. Patients with systemic lupus erythematosus typically develop a sharply defined, erythematous eruption in a butterfly distribution on the cheeks (malar rash) as well as many other skin manifestations. Still’s disease manifests as an evanescent salmon-colored rash on the trunk and proximal extremities that coincides with fever spikes.


PERIPHERAL ERUPTIONS

These rashes are alike in that they are most prominent peripherally or begin in peripheral (acral) areas before spreading centripetally. Early diagnosis and therapy are critical in RMSF (Chap. 75) because of its grave prognosis if untreated. Lesions evolve from macular to petechial, start on the wrists and ankles, spread centripetally, and appear on the palms and soles only later in the disease. The rash of secondary syphilis (Chap. 70), which may be generalized but is prominent on the palms and soles, should be considered in the differential diagnosis of pityriasis rosea, especially in sexually active patients. Atypical measles (Chap. 95) is seen in individuals contracting measles who received the killed measles vaccine between 1963 and 1967 in the United States and who were not subsequently protected with the live vaccine. Hand-footand- mouth disease (Chap. 94), most commonly caused by coxsackievirus A16, is distinguished by tender vesicles distributed peripherally and in the mouth; outbreaks commonly occur within families. The classic target lesions of erythema multiforme (EM) appear symmetrically on the elbows, knees, palms, soles, and face. In severe cases, these lesions spread diffusely and involve mucosal surfaces. Stevens-Johnson’s syndrome is considered a maximal form of erythema multiforme and is life-threatening. Lesions may develop on the hands and feet in endocarditis (Chap. 19).


CONFLUENT DESQUAMATIVE ERYTHEMAS

These eruptions consist of diffuse erythema frequently followed by desquamation. The eruptions caused by group A Streptococcus or Staphylococcus aureus are toxin mediated. Scarlet fever (Chap. 36) usually follows pharyngitis; patients have a facial flush, a “strawberry” tongue, and accentuated petechiae in body folds (Pastia’s lines). Kawasaki’s disease presents in the pediatric population as fissuring of the lips, a strawberry tongue, conjunctivitis, adenopathy, and sometimes cardiac abnormalities. Streptococcal toxic shock syndrome (Chap. 36) manifests with hypo-tension, multiorgan failure, and often a severe group A streptococcal infection (e.g., necrotizing fasciitis). Staphylococcal toxic shock syndrome (Chap. 35) also presents with hypotension and multiorgan failure, but usually only S. aureus colonization—not a severe S. aureus infection—is documented. Staphylococcal scalded-skin syndrome (Chap. 35) is seen primarily in children and in immunocompromised adults. Generalized erythema is often evident during the prodrome of fever and malaise; profound tenderness of the skin is distinctive. In the exfoliative stage, the skin can be induced to form bullae with light lateral pressure (Nikolsky’s sign). In a mild form, a scarlatiniform eruption mimics scarlet fever, but the patient does not exhibit a strawberry tongue or circumoral pallor. In contrast to the staphylococcal scalded-skin syndrome, in which the cleavage plane is superficial in the epidermis, toxic epidermal necrolysis, a maximal variant of Stevens-Johnson’s syndrome, involves sloughing of the entire epidermis, resulting in severe disease. Exfoliative erythroderma syndrome is a serious reaction associated with systemic toxicity that is often due to eczema, psoriasis, mycosis fungoides, or a severe drug reaction.


VESICULOBULLOUS ERUPTIONS

Varicella (Chap. 81) is highly contagious, often occurring in winter or spring. At any point in time, within a given region of the body, varicella lesions are in different stages of development. In immunocompromised hosts, varicella vesicles may lack the characteristic erythematous base or may appear hemorrhagic. Lesions of Pseudomonas “hot-tub” folliculitis (Chap. 53) are also pruritic and may appear similar to those of varicella. However, hot-tub folliculitis generally occurs in outbreaks after bathing in hot tubs or swimming pools, and lesions occur in regions occluded by bathing suits. Lesions of variola (smallpox; Chap. 6) also appear similar to those of varicella but are all at the same stage of development in a given region of the body.Variola lesions are most prominent on the face and extremities, whereas varicella lesions are most prominent on the trunk. Herpes simplex virus infection (Chap. 80) is characterized by hallmark grouped vesicles on an erythematous base. Primary herpes infection is accompanied by fever and toxicity, whereas recurrent disease is milder. Rickettsialpox (Chap. 75) is often documented in urban settings and is characterized by vesicles. It can be distinguished from varicella by an eschar at the site of the mouse-mite bite and the papule/plaque base of each vesicle. Disseminated Vibrio vulnificus infection (Chap. 57) or ecthyma gangrenosum due to Pseudomonas aeruginosa (Chap. 53) should be considered in immunosuppressed individuals with sepsis and hemorrhagic bullae.


URTICARIAL ERUPTIONS

Individuals with classic urticaria (“hives”) usually have a hypersensitivity reaction without associated fever. In the presence of fever, urticarial eruptions are usually due to urticarial vasculitis. Unlike individual lesions of classic urticaria, which last up to 48 h, these lesions may last up to 5 days. Etiologies include serum sickness (often induced by drugs such as penicillins, sulfas, salicylates, or barbiturates), connective-tissue disease (e.g., systemic lupus erythematosus or Sjögren’s syndrome), and infection (e.g., with hepatitis B virus, enteroviruses, or parasites). Malignancy may be associated with fever and chronic urticaria.


NODULAR ERUPTIONS

In immunocompromised hosts, nodular lesions often represent disseminated infection. Patients with disseminated candidiasis (often due to Candida tropicalis) may have a triad of fever,myalgias, and eruptive nodules (Chap. 107). Disseminated cryptococcosis lesions (Chap. 106) may resemble molluscum contagiosum (Chap. 84). Necrosis of nodules should raise the suspicion of aspergillosis (Chap. 108) or mucormycosis (Chap. 109). Erythema nodosum presents with exquisitely tender nodules on the lower extremities. Sweet’s syndrome should be considered in individuals with multiple nodules and plaques, often so edematous that they give the appearance of vesicles or bullae. Sweet’s syndrome may affect either healthy individuals or persons with lymphoproliferative disease.


PURPURIC ERUPTIONS

Acute meningococcemia (Chap. 44) classically presents in children as a petechial eruption, but initial lesions may appear as blanchable macules or urticaria. RMSF should be considered in the differential diagnosis of acute meningococcemia. Echovirus 9 infection (Chap. 94) may mimic acute meningococcemia; patients should be treated as if they have bacterial sepsis since prompt differentiation of these conditions may be impossible. Large ecchymotic areas of purpura fulminans (Chaps. 44 and 15) reflect severe underlying disseminated intravascular coagulation, which may be due to infectious or noninfectious causes. The lesions of chronic meningococcemia (Chap. 44) may have a variety of morphologies, including petechial. Purpuric nodules may develop on the legs and resemble erythema nodosum but lack its exquisite tenderness. Lesions of disseminated gonococcemia (Chap. 45) are distinctive, sparse, countable hemorrhagic pustules, usually located near joints. The lesions of chronic meningococcemia and those of gonococcemia may be indistinguishable in terms of appearance and distribution. Viral hemorrhagic fever (Chaps. 99 and 100) should be considered in patients with an appropriate travel history and a petechial rash. Thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome (Chaps. 51 and 55) are closely related and are noninfectious causes of fever and petechiae. Cutaneous small-vessel vasculitis (leukocytoclastic vasculitis) typically manifests as palpable purpura and has a wide variety of causes.


ERUPTIONS WITH ULCERS OR ESCHARS

The presence of an ulcer or eschar in the setting of a more widespread eruption can provide an important diagnostic clue. For example, the presence of an eschar may suggest the diagnosis of scrub typhus or rickettsialpox (Chap. 75) in the appropriate setting. In other illnesses (e.g., anthrax; Chap. 6), an ulcer or eschar may be the only skin manifestation.  ​