【學術】Evaluating the Febrile Patient with a Rash

一、分辨皮膚病灶：

LESION TYPE	DESCRIPTION
Macule	Circumscribed area of change in normal skin color, with no skin elevation or depression; may be any size
Papule	Solid, raised lesion up to 0.5 cm in greatest diameter
Nodule	Similar to papule but located deeper in the dermis or subcutaneous tissue; differentiated from papule by palpability and depth, rather than size
Plaque	Elevation of skin occupying a relatively large area in relation to height; often formed by confluence of papules
Pustule	Circumscribed elevation of skin containing purulent fluid of variable character (i.e., fluid may be white, yellow, greenish or hemorrhagic)
Vesicle	Circumscribed, elevated, fluid-containing lesion less than 0.5 cm in greatest diameter; may be intraepidermal or subepidermal in origin
Bulla	Same as vesicle, except lesion is more than 0.5 cm in greatest diameter

二、發燒 + 皮膚病灶可能有的疾病：

DISEASE	ETIOLOGY	DESCRIPTION OF RASH	EPIDEMIOLOGY	DIAGNOSTIC CLUES	BASIS FOR DIAGNOSIS
Rubeola	Measles virus	Macular-papular rash that may become confluent; begins on face, neck and shoulders and spreads centrifugally and inferiorly; fades in 4 to 6 days	Most common in children 5 to 9 years of age, nonimmune persons	Prodrome consisting of symptoms of upper respiratory tract infection, coryza, bark-like cough, malaise, photophobia and fever; Koplik's spots (prodromal stage); development of exanthem on fourth febrile day; late winter through early spring	Serology
Rubella	Rubella virus	Pink macules and papules that develop on forehead and spread inferiorly and to extremities within one day; fading of macules and papules in reverse order by third day	Young adults, nonimmune persons	Prodrome uncommon, especially in children; petechiae on soft palate (Forschheimer's spots); in adults: anorexia, malaise, conjunctivitis, headache and symptoms of mild upper respiratory infection	Serology
Erythema infectiosum (fifth disease)	Human parvovirus B19	Begins as classic bright-red facial rash (“slapped cheek“) and progresses to lacy reticular rash; may wax and wane for 6 to 8 weeks	Children 3 to 12 years of age	Can present as rheumatic syndrome in adults; prodrome of fever, anorexia, rash typically beginning after resolution of fever [corrected]	Serology
Roseola	Human herpes-virus 6	Diffuse maculopapular eruption, usually sparing face	Children 6 months to 3 years of age	Fever lasting 3 to 4 days, followed within 2 to 3 days by the rash, which resolves spontaneously in several days; almost always a self-limited benign disease; temporal relationship of fever followed by rash is helpful in making the diagnosis	Clinical findings, serology
Lyme disease	Borrelia burgdorferi	Macule or papule at site of tick bite, progressing to pathognomonic erythema migrans	All ages at risk for tick exposure in endemic areas	History of tick exposure; secondary erythematous, macular lesions; Borrelia lymphocytoma; highest incidence: May through September	Clinical findings, serology, polymerase chain reaction test
Erythema multiforme	Idiopathic in 50 percent of cases	Dull-red macules developing into papules with central vesicles or bullae; common on dorsa of hands, palms, soles, arms, knees, penis and vulva; often bilateral and symmetric	Adults 20 to 30 years of age; men affected more often than women	Major and minor forms; major form always with mucous membrane involvement and usually the result of drug reaction; minor form often associated with herpes simplex outbreak; rarely life-threatening	Clinical findings
Secondary syphilis	Treponema pallidum	Various presentations; brownish-red or pink macules and papules; generalized eruption or localized eruption on head, neck, palms or soles; condyloma lata common	Adolescents and adults 15 to 49 years of age; females affected more often than males	Develops 2 to 10 weeks after primary chancre; presents with or without fever; may have generalized lymphadenopathy and splenomegaly; may have recurrent eruptions with symptom-free periods	Dark-field examination, serology
Meningococcemia (acute)	Neisseria meningitidis	Variety of lesions but, characteristically,petechial lesions distributed on the trunk and extremities (although the lesions can be located anywhere); petechiae on mucous membranes	Highest incidence in children 6 months to 1 year of age	Acutely ill patient; high fever, tachypnea, tachycardia, mild hypotension; leukocytosis; meningitis develops in more than 50 percent of patients	Often, clinical findings; blood cultures
Meningococcemia (chronic)	N. meningitidis	Intermittent maculopapular lesions, often on a painful joint or pressure point; may have nodules on calves	Same as for acute form	Fever, myalgias, arthralgias, headache, anorexia; may recur for weeks or months, with average duration of 8 weeks; may progress to acute meningococcemia, meningitis or endocarditis	Blood cultures
Rocky Mountain spotted fever	Rickettsia rickettsii	Rash evolving from pink macules to red papules and finally to petechiae; rash beginning on wrists and ankles and spreading centripetally; involvement of palms and soles late in disease	Young adults with tick exposure; men affected more often than women	Onset typically abrupt; fever, severe headache and myalgias are prominent; rash appearing around fourth day of illness; may have relative bradycardia and leukopenia	Clinical findings, serology
Scarlet fever	Beta-hemolyticStreptococcus pyogenes	Punctate erythema beginning on trunk and spreading to extremities, becoming confluent; flushed face with perioral pallor; rash fading in 4 to 5 days and followed by desquamation	Children	Acute infection of tonsils or skin; linear petechiae in antecubital and axillary folds (Pastia's sign); rash appearing 2 to 3 days after infection; initially, “white strawberry tongue” but by fourth or fifth day, “red strawberry tongue”	Rapid strep test, wound or throat culture, antistreptolysin O titers
Toxic shock syndrome	Staphylococcus aureus	Diffuse “sunburn“ rash that desquamates over 1 to 2 weeks	All ages, but most common in menstruating females	High fever, hypotension and involvement of three or more organ systems; about 50 percent of cases occurring in menstruating women around onset of menses; postoperative patients at increased risk; condition out of proportion to wound appearance	Clinical criteria, vaginal and wound cultures
Kawasaki's disease	Idiopathic	Erythematous rash on hands and feet; morbilliform, scarlatiniform rash on trunk and perineum; hyperemic lips	Children less than 8 years of age, with peak incidence at 1 year; boys affected more often than girls	Winter and spring; high fevers, cervical lymphadenopathy, arthritis, arthralgias, cardiac involvement, mucous membrane involvement; can be complicated by coronary artery abnormalities in 20 to 25 percent of cases	Specific clinical criteria
Chickenpox	Varicella-zoster virus	Initially, papules, which evolve into vesicles (“dewdrops on a rose petal”) and eventually into pustules and crusts; rash beginning on face and spreading inferiorly to trunk and extremities	90 percent of cases in children less than 10 years of age; 5 percent of cases in persons older than 15 years	Prodrome consisting of headache, general aches, backache and malaise is typically absent in children; exposure history; may have all forms of lesions at the same time; vesicles evolving to shallow erosions common on mucous membranes of palate; may also have vesicles on nasal, conjunctival, gastrointestinal tract and genital mucosa	Clinical findings, confirmed by Tzanck test
Herpes zoster (shingles)	Varicella-zoster virus	Begins as erythematous maculopapular eruption, rapidly evolves to vesicles	All ages, but incidence increases with age and immunosuppression	Prodrome of unusual skin sensations; dermatomal pattern, with lesions rarely crossing midline; pain often severe; more common in thoracic and facial dermatomes	Clinical findings, confirmed by Tzanck test
Rickettsialpox	Rickettsia akari	Generalized maculopapular- vesicular exanthem; possible involvement of mucous membranes; no involvement of palms or soles	All ages; urban settings	Transmitted from mice to humans via mites; formation of papules 7 to 10 days after initial bite; typically, formation of a black eschar over healing lesion; febrile phase occurring 3 to 7 days after initial lesion and lasting up to a week; self-limited, usually mild course	Serology
Erythema nodosum	Various causes	Bright-red nodules (3 to 20 cm in diameter) scattered bilaterally but not symmetric; most frequently on lower legs but also found on knees and arms; rarely found on face and neck; lesions often tender and indurated	Adolescents and young adults 15 to 30 years of age; females affected more often than males	Thorough history and physical examination to identify known causes; throat culture for group A beta-hemolytic streptococci; chest radiograph to rule out sarcoidosis; arthralgias present in 50 percent of cases; fever and malaise common	Clinical findings

三、皮膚病灶逐一論述

• Maculopapular Rashes (Central V.S. Peripheral)

• Maculopapular eruptions are most frequently seen in viral illnesses and immune-mediated syndromes. These eruptions can have many causes, including drug reactions and bacterial infections. 
• Central distribution
• Viral Exanthems：
• Viral etiologies of rashes include rubeola, rubella, erythema infectiosum and roseola
• Lyme Disease and Erythema Migrans：
• Lyme disease is the most commonly reported vector-borne illness in the United States.
• Erythema migrans, the pathognomonic rash, develops in about 80 percent of patients with Lyme disease

• Drug-Related Eruptions
• Peripheral distribution
• Erythema Multiforme：
• The most common peripheral eruptive maculopapular rash, erythema multiforme occurs more frequently in men than in women and most often affects persons between 20 and 30 years of age. The rash, which can be recurrent, shows a predilection for palms, soles, knees and elbows.

• Rarely, erythema multiforme major can be life-threatening and can progress to necrotizing tracheobronchitis, meningitis, blindness, sepsis and renal tubular necrosis
• Etiology of erythema multiforme
• Idiopathic (more than 50 percent of cases)
• Radiation therapy
• Medications
• Penicillin
• Sulfonamides
• Phenytoin (Dilantin)
• Barbiturates
• Phenylbutazone
• Infectious causes
• Herpes simplex virus
• Epstein-Barr virus
• Adenovirus
• Coxsackievirus B5
• Vaccinia virus
• Mycoplasma species
• Chlamydia species
• Salmonella typhi
• Yersinia species
• Mycobacterium tuberculosis
• Histoplasma capsulatum
• Coccidioides immitis
• Secondary Syphilis：
• The rash of secondary syphilis can be diffuse, with localized eruptions often occurring on the head, neck, palms and soles. 
• Asymptomatic flat-topped macules and papules (mucous patches) are commonly found on the oral and genital mucosa. 
• Classic condyloma lata may also be found in the perineum
• Potentially life-threatening infections：
• Meningococcemia, Rocky Mountain spotted fever and dengue fever may initially present with erythematous maculopapular lesions before advancing to a petechial exanthem
•  Petechial Eruptions

• Petechial rashes warrant immediate evaluation to rule out severe, life-threatening illness. For proper assessment of an acutely ill patient with a petechial rash, the physician must be familiar with the common infectious and noninfectious etiologies.
• Meningococcal infections：
• Typical prodrome of cough, headache, sore throat, nausea and vomiting may be of short duration. Patients with acute meningococcemia appear ill and usually present with a characteristic petechial rash, a high, spiking fever, tachypnea, tachycardia and mild hypotension

• Chronic meningococcemia is a rare condition. Patients may present with intermittent rash, fever, arthritis and arthralgias occurring over a period of weeks to several months. 
• Maculopapular lesions usually located around a painful joint or pressure point, nodules on the lower extremities and petechiae of variable size
• Rocky Mountain spotted fever：
• Prodrome may include malaise, chills, a feverish feeling, anorexia and irritability. When rash is present, it develops on approximately the fourth day of illness. 
• Rash pattern:
• Initially - begins as pink macules, 2 to 6 mm in diameter, located on the wrists, forearms, ankles, palms and soles. 
• 6 to 18 hours - spreads centrally to involve the arms, thighs, trunk and face. 
• 1~3 days - the lesions evolve into deep-red papules.
• 2~4 days - after onset of the rash, the lesions become petechiae
• Other causes：
• Viral illnesses
• Coxsackievirus A9, 
• Echovirus 9, 
• Epstein-Barr virus and cytomegalovirus infections, 
• Atypical measles and viral hemorrhagic fevers caused by arboviruses and arenaviruses.
• Bacteria and others
• Disseminated gonococcal infections, 
• Bacteremia, 
• Staphylococcemia and thrombotic thrombocytopenic purpura.
• Diffuse Erythema with Desquamation
• Scarlet fever：
• Scarlet fever provides the classic example of an erythematous rash with subsequent desquamation. Most common between one and 10 years of age, scarlet fever usually follows an acute infection of the tonsils or skin by group A beta-hemolytic streptococci that produce an erythrogenic exotoxin.
• Rash pattern:
• 2~3 days after onset of illness - Fine punctate erythema on the superior trunk and face. The erythema quickly spreads to the extremities. When present, petechiae in the antecubital and axillary skin folds (Pastia's lines) can be helpful in making the diagnosis.
• 4~5 days -  Exanthem varies in intensity. However, it usually fades and followed by diffuse desquamation.
• Tongue - white, with red, swollen papillae (white strawberry tongue) → (4~5 days) → bright red (red strawberry tongue). 
• Oral mucosa - may have punctate erythema or petechiae.
• Toxic shock syndrome and scalded skin syndrome：
• Staphylococcus aureus is the organism responsible for classic toxic shock syndrome and scalded skin syndrome. Toxic shock syndrome can present with hypotension, erythema, fever and multisystem dysfunction
• Rash pattern
• The rash is usually diffuse and can present as bullous impetigo, scarlatiniform lesions or diffuse erythema. 

• The mucous membranes are spared in most patients. During the physical examination,we should attempt to elicit Nikolsky's sign (shearing of the skin with gentle lateral pressure).
• Kawasaki's disease：
• Acute febrile illness that affects infants and young children (mean age: 2.6 years). The disease is uncommon after the age of 12 years.
• In patients with Kawasaki's disease, fever begins abruptly, and the temperature is typically higher than 40°C (104°F). The fever lasts five to 30 days (mean duration: 8.5 days) and does not respond to antibiotics and antipyretic
• Rash pattern：
• 3 days - appeared within three days of the onset of fever. Frequently, the rash is scarlatiniform on the trunk and erythematous on the palms and soles, with subsequent distal desquamation. 
• Mucous membrane - Involvement is common and includes hyperemic bulbar conjunctiva, injected oropharynx, dry, cracked lips and a strawberry tongue.
• Other causes：
• Ehrlichiosis - a rickettsial-like infection, can occasionally be associated with a clinical picture similar to toxic shock syndrome, including diffuse erythema. 
• Streptococcus viridans bacteremia -  another rare cause of generalized erythema.
• Enteroviral infections, toxic epidermal necrolysis, graft-versus-host reaction, erythroderma and generalized pustular psoriasis (von Zumbusch's psoriasis) may present with diffuse erythema.
• Vesiculobullous-Pustular Eruptions
• Varicella-zoster virus：
• Varicella-zoster virus is the most infectious of the human herpesviruses. It is responsible for varicella (chickenpox) and herpes zoster (shingles)
• Varicella(chicken pox)
• The clinical presentation consists of rash, fever and general malaise. The rash typically begins on the face, scalp or trunk and then spreads to the extremities.
• Rash pattern
• Erythematous macules and progress to papules with an edematous base

• The papules quickly evolve into vesicles, with each vesicle initially having the appearance of “a dewdrop on a rose petal.”

• The vesicles evolve into pustules, which become umbilicated and subsequently crust over in the ensuing eight to 12 hours. 
• An enanthema may be noted, and vesicles may evolve to shallow erosions, primarily on the palate
• Herpes Zoster
• The characteristic vesicular rash of herpes zoster usually affects a single dermatome and rarely crosses the midline. 

• The most common locations are the chest (approximately 50 percent of cases) and the face (approximately 20 percent of cases).
•  A prodrome of unusual skin sensations may evolve into pain, burning and paresthesias, which precede the rash by two to three days.
• Rash pattern
• Initial - rash begins as an erythematous maculopapular eruption that rapidly evolves to a vesicular rash
• 7~10 days - Drying of the lesions with crust formation 
• 14~21 days - the lesions usually resolve 
• Other causes：
• Staphylococcal bacteremia - May present with a widespread pustular eruption. 
• Gonococcemia -  May also produce a pustular rash, although other lesion types, such as macules, petechiae and papules, are usually present.
• Immunocompromised patients - Disseminated herpes simplex virus infection must be considered. 
• Patients with underlying liver disease, renal dysfunction or diabetes - susceptible to infection with Vibrio vulnificus,
• Nodular Eruptions
• Erythema nodosum：
• Erythema nodosum is an acute inflammatory and immunologic process involving the panniculus adiposus (the fatty tissue layer underlying the skin).This condition is more common in women than in men.
• Etiology
• Idiopathic (40 percent of cases)
• Infectious causes
• Beta-hemolytic streptococci
• Yersinia species
• Hepatitis C virus
• Mycobacterium species
• Chlamydia trachomatis
• Coccidioides immitis
• Noninfectious causes
• Medications
• Sulfonamides
• Oral contraceptives
• Systemic lupus erythematosus
• Sarcoidosis
• Ulcerative colitis
• Behçet's syndrome
• Pregnancy
• Presenting features often include fever, malaise and arthralgias. The characteristic nodules are painful and tender. The lesions most often develop on the lower legs, knees and arms 

• The course of erythema nodosum depends on the specific cause, but spontaneous resolution can be expected within six weeks
• Other causes：
• Immunocompromised patients 
• Disseminated fungal infections may produce nodular lesions. 
• Disseminated candidiasis may present with diffuse nonerythematous nodules  
• Other fungal infections to consider include 
• Cryptococcosis, blastomycosis, histoplasmosis, coccidioidomycosis and sporotrichosis.
• Bacteria 
• Such as Nocardia, Pseudomonas and Mycobacterium species may produce nodular lesions.

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