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Harrison's Principles of Internal Medicine, 21e

Chapter 19: Fever and Rash

Elaine T. Kaye; Kenneth M. Kaye

INTRODUCTION
The acutely ill patient with fever and rash often presents a diagnostic challenge for physicians, yet the distinctive appearance of an eruption in concert
with a clinical syndrome can facilitate a prompt diagnosis and the institution of life­saving therapy or critical infection­control interventions.
Representative images of many of the rashes discussed in this chapter are included in Chap. A1.

APPROACH TO THE PATIENT WITH 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, recent
dietary exposures, existence of cardiac abnormalities, presence of prosthetic material, recent exposure to ill individuals, and sexual exposures. The
history should also include the site of onset of the rash and its direction and rate of spread.

Physical Examination

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 what type of lesions 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, plateau­like 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 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 Chaps. 56, 5 8, 122, and 129.

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. 129). The chapter is not intended to be all­inclusive, but it covers the most important and most common diseases
associated with fever and rash. Rashes are classified herein on the basis of lesion morphology and distribution. 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 (Chap. 58). For instance, the classic petechial rash of Rocky Mountain spotted fever (Chap. 187)
may initially consist of blanchable erythematous macules distributed peripherally; at times, however, the rash associated with this disease may not be
predominantly acral, or no rash may develop at all.

Diseases with fever and rash may be classified by type of eruption: centrally distributed maculopapular, peripheral, confluent desquamative
erythematous, vesiculobullous, urticaria­like, nodular, purpuric, ulcerated, or with eschars. Diseases are listed by these categories in Table 19­1, and
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in the A Your IP is 202.28.147.16
However, for a more detailed discussion of each disease associated with a rash, the reader is referred to the chapter
Chapter 19: Fever and Rash, Elaine T. Kaye; Kenneth
dealing with that specific disease. (Reference chaptersM.are
Kaye
cited in the text and listed in Table 19­1. ) Page 1 / 25
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TABLE 19­1
Diseases Associated with Fever and Rash
diseases with rashes is subject to many variations (Chap. 58). For instance, the classic petechial rash of Rocky Mountain spotted fever (Chap. 187)
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may initially consist of blanchable erythematous macules distributed peripherally; at times, however, the rash associated with this disease may not be
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predominantly acral, or no rash may develop at all.

Diseases with fever and rash may be classified by type of eruption: centrally distributed maculopapular, peripheral, confluent desquamative
erythematous, vesiculobullous, urticaria­like, nodular, purpuric, ulcerated, or with eschars. Diseases are listed by these categories in Table 19­1, and
many are highlighted in the text. However, 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 19­1. )

TABLE 19­1
Diseases Associated with Fever and Rash

GROUP
CLINICAL
DISEASE ETIOLOGY DESCRIPTION AFFECTED/EPIDEMIOLOGIC CHAPTER
SYNDROME
FACTORS

Centrally Distributed Maculopapular Eruptions

Acute — — — — 155
meningococcemiaa

Drug reaction with — — — — 60

eosinophilia and
systemic
symptoms (DRESS);
also termed drug­
induced
hypersensitivity
syndrome (DIHS)b;
Chikungunyac;

COVID­19c

Rubeola (measles, Paramyxovirus Discrete lesions that become Nonimmune individuals Cough, conjunctivitis, 205
first disease) (Fig. confluent as rash spreads coryza, severe
19­1, Fig. A1­2, from hairline downward, prostration
Fig. A1­3) usually sparing palms and
soles; lasts ≥3 days; Koplik’s
spots

Rubella (German Togavirus Spreads from hairline Nonimmune individuals Adenopathy, arthritis 206
measles, third downward, clearing as it
disease) (Fig. A1­ spreads; Forchheimer spots
4)

Erythema Human parvovirus B19 Bright­red “slapped­cheeks” Most common among children Mild fever; arthritis in 197
infectiosum (fifth appearance followed by lacy 3–12 years old; occurs in adults; rash following
disease) (Fig. A1­ reticular rash that waxes and winter and spring resolution of fever
1) wanes over 3 weeks; rarely,
papular­purpuric “gloves­
and­socks” syndrome on
hands and feet

Exanthem subitum Human herpesvirus 6 Diffuse maculopapular Usually affects children <3 Rash following 195
(roseola, sixth or, less commonly, the eruption over trunk and years old resolution of fever;
disease) (Fig. A1­ closely related human neck; resolves within 2 days similar to Boston
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5) herpesvirus 7 exanthem (echovirus
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may occur
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hands and feet Mahidol University
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Exanthem subitum Human herpesvirus 6 Diffuse maculopapular Usually affects children <3 Rash following 195
(roseola, sixth or, less commonly, the eruption over trunk and years old resolution of fever;
disease) (Fig. A1­ closely related human neck; resolves within 2 days similar to Boston
5) herpesvirus 7 exanthem (echovirus
16); febrile seizures
may occur

Primary HIV HIV Nonspecific diffuse macules Individuals recently infected Pharyngitis, 202
infection (Fig. A1­ and papules most commonly with HIV adenopathy,
6) on upper thorax, face, collar arthralgias
region; less commonly,
urticarial or vesicular lesions;
oral or genital ulcers

Infectious Epstein­Barr virus Diffuse maculopapular Adolescents, young adults Hepatosplenomegaly, 194
mononucleosis eruption (5% of cases; 30– pharyngitis, cervical
90% if ampicillin is given); lymphadenopathy,
urticaria, petechiae in some atypical
cases; periorbital edema lymphocytosis,
(50%); palatal petechiae heterophile antibody
(25%)

Other viral Echoviruses 2, 4, 9, 11, Wide range of skin findings Affect children more Nonspecific viral 204
exanthems 16, 19, 25; that may mimic rubella or commonly than adults syndromes
coxsackieviruses A9, B1, measles
B5; etc.

Exanthematous Drugs (antibiotics, Intensely pruritic, bright­red Occurs 2–3 days after Variable findings: fever 60
drug­induced anticonvulsants, macules and papules, exposure in previously and eosinophilia
eruption (Fig. A1­ diuretics, etc.) symmetric on trunk and sensitized individuals;
7) extremities; may become otherwise, after 2–3 weeks
confluent (but can occur anytime, even
shortly after drug is
discontinued)

Epidemic typhus Rickettsia prowazekii Maculopapular eruption Exposure to body lice; Headache, myalgias; 187
appearing in axillae, occurrence of recrudescent mortality rates 10–
spreading to trunk and later typhus as relapse after 30–50 40% if untreated;
to extremities; usually spares years milder clinical
face, palms, soles; evolves presentation in
from blanchable macules to recrudescent form
confluent eruption with
petechiae; rash evanescent in
recrudescent typhus (Brill­
Zinsser disease)

Endemic (murine) Rickettsia typhi Maculopapular eruption, Exposure to rat or cat fleas Headache, myalgias 187
typhus usually sparing palms, soles

Scrub typhus Orientia tsutsugamushi Diffuse macular rash starting Endemic in South Pacific, Headache, myalgias, 187
on trunk; eschar at site of Australia, Asia; transmitted by regional adenopathy;
mite bite mites mortality rates up to
30% if untreated
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Rickettsial spotted Rickettsia conorii Eschar common at bite site; Exposure to ticks; R. conorii in Headache, myalgias, 187
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fevers (Fig. 19­8) (boutonneuse fever), maculopapular (rarely, Mediterranean region, India, regional adenopathy
Rickettsia australis vesicular and petechial) Africa; R. australis in Australia;
 typhus usually sparing palms, soles
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Scrub typhus Orientia tsutsugamushi Diffuse macular rash starting Endemic in South Pacific, Headache, myalgias, 1 8 Provided
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on trunk; eschar at site of Australia, Asia; transmitted by regional adenopathy;

mite bite mites mortality rates up to
30% if untreated

Rickettsial spotted Rickettsia conorii Eschar common at bite site; Exposure to ticks; R. conorii in Headache, myalgias, 187
fevers (Fig. 19­8) (boutonneuse fever), maculopapular (rarely, Mediterranean region, India, regional adenopathy
Rickettsia australis vesicular and petechial) Africa; R. australis in Australia;
(North Queensland tick eruption on proximal R. sibirica in Siberia, Mongolia;
typhus), Rickettsia extremities, spreading to R. africae in Africa, Caribbean
sibirica (Siberian tick trunk and face
typhus), Rickettsia
africae (African tick­bite
fever), and others

Human Ehrlichia chaffeensis Maculopapular eruption Tick­borne; most common in Headache, myalgias, 187
monocytotropic (40% of cases), involves trunk U.S. Southeast, southern leukopenia
ehrlichiosisd and extremities; may be Midwest, and mid­Atlantic
petechial regions

Leptospirosis Leptospira interrogans Maculopapular eruption; Exposure to water Myalgias; aseptic 184
and other Leptospira conjunctivitis; scleral contaminated with animal meningitis; fulminant
species hemorrhage in some cases urine form:
icterohemorrhagic
fever (Weil’s disease)

Lyme disease (Fig. Borrelia burgdorferi Papule expanding to Bite of Ixodes tick vector Headache, myalgias, 186
A1­8) (sole cause in U.S.), erythematous annular lesion chills, photophobia
Borrelia afzelii, Borrelia with central clearing occurring acutely; CNS
garinii (erythema migrans; average disease, myocardial
diameter, 15 cm), sometimes disease, arthritis
with concentric rings, weeks to months later
sometimes with indurated or in some cases
vesicular center; multiple
secondary erythema migrans
lesions in some cases

Southern tick­ Unknown (possibly Similar to erythema migrans Bite of tick vector Compared with Lyme 186
associated rash Borrelia lonestari or of Lyme disease with several Amblyomma americanum disease: fewer
illness (STARI, other Borrelia differences, including: (Lone Star tick); often found in constitutional
Master’s disease) spirochetes) multiple secondary lesions regions where Lyme disease is symptoms, tick bite
less likely; lesions tending to uncommon, including more likely to be
be smaller (average southern United States recalled; other Lyme
diameter, ~8 cm); central disease sequelae
clearing more likely lacking

Typhoid fever (Fig. Salmonella typhi Transient, blanchable Ingestion of contaminated Variable abdominal 165
A1­9) erythematous macules and food or water (rare in U.S.) pain and diarrhea;
papules, 2–4 mm, usually on headache, myalgias,
trunk (rose spots) hepatosplenomegaly

Dengue fevere (Fig. Dengue virus (4 Rash in 50% of cases; initially Occurs in tropics and Headache; 209

A1­53) serotypes; flaviviruses) diffuse flushing; midway subtropics; transmitted by musculoskeletal pain
through illness, onset of mosquito (“breakbone fever”);
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maculopapular rash, which leukopenia;
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centrifugally to extremities (“saddleback”) fever
and face; pruritus,
 papules, 2–4 mm, usually on headache, myalgias,
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Dengue fevere (Fig. Dengue virus (4 Rash in 50% of cases; initially Occurs in tropics and Headache; 209

A1­53) serotypes; flaviviruses) diffuse flushing; midway subtropics; transmitted by musculoskeletal pain
through illness, onset of mosquito (“breakbone fever”);
maculopapular rash, which leukopenia;
begins on trunk and spreads occasionally biphasic
centrifugally to extremities (“saddleback”) fever
and face; pruritus,
hyperesthesia in some cases;
after defervescence,
petechiae on extremities may
occur

Rat­bite fever Spirillum minus Eschar at bite site; then Rat bite; primarily found in Regional adenopathy; 141
(sodoku) blotchy violaceous or red­ Asia; rare in U.S. recurrent fevers if
brown rash involving trunk untreated
and extremities

Relapsing fever Borrelia species Central rash at end of febrile Exposure to ticks or body lice Recurrent fever, 185
episode; petechiae in some headache, myalgias,
cases hepatosplenomegaly

Erythema Group A Streptococcus Erythematous annular Patients with rheumatic fever Pharyngitis preceding 388
marginatum papules and plaques polyarthritis, carditis,
(rheumatic fever) occurring as polycyclic subcutaneous
lesions in waves over trunk, nodules, chorea
proximal extremities;
evolving and resolving within
hours

Systemic lupus Autoimmune disease Macular and papular Most common in young to Arthritis; cardiac, 359
erythematosus erythema, often in sun­ middle­aged women; flares pulmonary, renal,
(SLE) (Fig. A1­10, exposed areas; discoid lupus precipitated by sun exposure hematologic, and
Fig. A1­11, Fig. lesions (local atrophy, scale, vasculitic disease
A1­12) pigmentary changes);
periungual telangiectasis;
malar rash; vasculitis
sometimes causing urticaria,
palpable purpura; oral
erosions in some cases

Still’s disease (Fig. Autoimmune disease Transient 2­ to 5­mm Children and young adults High spiking fever, —
A1­13) erythematous papules polyarthritis,
appearing at height of fever splenomegaly;
on trunk, proximal erythrocyte
extremities; lesions sedimentation rate
evanescent >100 mm/h

African Trypanosoma brucei Blotchy or annular Tsetse fly bite in eastern (T. Hemolymphatic 227
trypanosomiasis rhodesiense/gambiense erythematous macular and brucei rhodesiense) or disease followed by
(Fig. A1­47) papular rash (trypanid), western (T. brucei gambiense) meningoencephalitis;
primarily on trunk; pruritus; Africa Winterbottom’s sign
chancre at site of tsetse fly (posterior cervical
bite may precede rash by lymphadenopathy) (T.
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Arcanobacterial Arcanobacterium Diffuse, erythematous, Children and young adults Exudative pharyngitis, 150
pharyngitis (Corynebacterium) maculopapular eruption lymphadenopathy
 African Trypanosoma brucei Blotchy or annular Tsetse fly bite in eastern (T. Hemolymphatic 227
trypanosomiasis rhodesiense/gambiense erythematous macular and brucei rhodesiense) or disease followed by Mahidol University
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primarily on trunk; pruritus; Africa Winterbottom’s sign

chancre at site of tsetse fly (posterior cervical
bite may precede rash by lymphadenopathy) (T.
several weeks brucei gambiense)

Arcanobacterial Arcanobacterium Diffuse, erythematous, Children and young adults Exudative pharyngitis, 150
pharyngitis (Corynebacterium) maculopapular eruption lymphadenopathy
haemolyticum involving trunk and proximal
extremities; may desquamate

West Nile virus West Nile virus Maculopapular eruption Mosquito bite; rarely, blood Headache, weakness, 209
infection involving the trunk, transfusion or transplanted malaise, myalgia,
extremities, and head or organ neuroinvasive disease
neck; rash in 20–50% of cases (encephalitis,
meningitis, flaccid
paralysis)

Zika virus infection Zika virus Pruritic macular and papular Mosquito bite; sexual Arthralgia (especially 209
(Fig. A1­51) erythema; rash may begin on transmission or blood of small joints),
trunk and descend to lower transfusion less common myalgia,
body; conjunctival injection; lymphadenopathy,
palatal petechiae may occur headache, low­grade
fever; illness in
pregnancy may cause
severe birth defects,
including
microcephaly;
neurologic
complications,
including Guillain­
Barré, may occur

Peripheral Eruptions

Chronic — — — — 1 5 5, 1 5 6,
meningococcemia, 197
disseminated
gonococcal
infection,a human
parvovirus B19
infection,f MIRMg

Rocky Mountain Rickettsia rickettsii Rash beginning on wrists and Tick vector; widespread but Headache, myalgias, 187
spotted fever (Fig. ankles and spreading more common in abdominal pain;
19­2, Fig. A1­16) centripetally; appears on southeastern and southwest­ mortality rates up to
palms and soles later in central U.S. 40% if untreated
disease; lesion evolution
from blanchable macules to
petechiae

Secondary syphilis Treponema pallidum Coincident primary chancre Sexually transmitted Fever, constitutional 182
(Figs. A1­18, Fig. in 10% of cases; copper­ symptoms
A1­19, Fig. A1­20, colored, scaly papular
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Fig.
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19: eruption,
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soles; rash never vesicular in
adults; condyloma latum,
 from blanchable macules to
petechiae
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Secondary syphilis Treponema pallidum Coincident primary chancre Sexually transmitted Fever, constitutional 182
(Figs. A1­18, Fig. in 10% of cases; copper­ symptoms
A1­19, Fig. A1­20, colored, scaly papular
Fig. A1­21) eruption, diffuse but
prominent on palms and
soles; rash never vesicular in
adults; condyloma latum,
mucous patches, and
alopecia in some cases

Chikungunya fever Chikungunya virus Maculopapular eruption; Aedes aegypti and A. Severe polyarticular, 209
(Fig. A1­54) typically occurs on trunk, but albopictus mosquito bites; migratory arthralgias,
also occurs on extremities tropical and subtropical especially involving
and face regions small joints (e.g.,
hands, wrists, ankles)

Hand­foot­and­ Coxsackievirus A16 and Tender vesicles, erosions in Summer and fall; primarily Transient fever; 204
mouth disease enterovirus 71 most mouth; 0.25­cm papules on children <10 years old; enterovirus 71 can be
(Fig. A1­22) common causes; hands and feet with rim of multiple family members; associated with brain
coxsackievirus A6 erythema evolving into coxsackievirus A6 infection stem encephalitis,
associated with atypical tender vesicles; shedding of also occurs in young adults flaccid paralysis
syndrome nails (onychomadesis) can resembling polio, or
occur 1–2 months after acute aseptic meningitis
illness; coxsackievirus A6
lesions may also be
maculopapular, petechial,
purpuric, or erosive; atypical
form often extends to
perioral area, extremities,
trunk, buttocks, genitals, and
areas affected by eczema
(eczema coxsackium)

Erythema Infection, drugs, Target lesions (central Herpes simplex virus or 50% of patients <20 —h
multiforme (EM) idiopathic causes erythema surrounded by Mycoplasma pneumoniae years old; fever more
(Fig. A1­24) area of clearing and another infection; drug intake (i.e., common in most
rim of erythema) up to 2 cm; sulfa, phenytoin, penicillin) severe form, EM
symmetric on knees, elbows, major, which can be
palms, soles; spreads confused with
centripetally; papular, Stevens­Johnson
sometimes vesicular; when syndrome (but EM
extensive and involving major lacks
mucous membranes, termed prominent skin
EM major sloughing)

Rat­bite fever Streptobacillus Maculopapular eruption over Rat bite, ingestion of Myalgias; arthritis 141
(Haverhill fever) moniliformis palms, soles, and extremities; contaminated food (50%); fever
tends to be more severe at recurrence in some
joints; eruption sometimes cases
becoming generalized; may
be purpuric; may
desquamate

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Bacterial
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viridans streptococci), murmur
A1­23) nodes (tender pink nodules intravenous drug use
on finger or toe pads);
 tends to be more severe at recurrence in some
joints; eruption sometimes cases
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becoming generalized; may
be purpuric; may
desquamate

Bacterial Streptococcus, Subacute course (e.g., Abnormal heart valve (e.g., New or changing heart 128
endocarditis (Fig. Staphylococcus, etc. viridans streptococci): Osler’s viridans streptococci), murmur
A1­23) nodes (tender pink nodules intravenous drug use
on finger or toe pads);
petechiae on skin and
mucosa; splinter
hemorrhages. Acute course
(e.g., Staphylococcus aureus):
Janeway lesions (painless
erythematous or
hemorrhagic macules,
usually on palms and soles)

COVID­19 (Fig. A1­ SARS­CoV­2 Mild or asymptomatic COVID­ Infection with SARS­CoV­2; Ranging from
57) 19: Pernio (macules, papules, MIS­C in older asymptomatic to
or plaques that are tender, children/adolescents mild/ moderate with
erythematous/violaceous; loss of taste/smell,
acral, feet more common pharyngitis, cough,
than hands); fever, to severe with
Moderate/severe COVID­19: dyspnea, ARDS;
vesicles, urticaria, complications include
maculopapular erythema; thrombosis, especially
often pruritic; occur on trunk, with retiform purpura;
extremities; Severe COVID­19: lesions may be
Retiform purpura (net­like, delayed compared to
purple patches/plaques other COVID­19
often with necrosis); lesions symptoms; MIS­C
often asymptomatic; occur occurs ~2­6 weeks
on extremities, buttocks; following acute (often
Multisystem inflammatory asymptomatic)
syndrome in children (MIS­C): infection
findings similar to Kawasaki
disease

Confluent Desquamative Erythemas

Scarlet fever Group A Streptococcus Diffuse blanchable erythema Most common among children Fever, pharyngitis, 148
(second disease) (pyrogenic exotoxins A, beginning on face and 2–10 years old; usually follows headache
(Fig. A1­25) B, C) spreading to trunk and group A streptococcal
extremities; circumoral pharyngitis
pallor; “sandpaper” texture
to skin; accentuation of linear
erythema in skin folds
(Pastia’s lines); enanthem of
white evolving into red
“strawberry” tongue;
desquamation in second
week

Kawasaki2024­8­12
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A Your IP is 202.28.147.16 Children <8 years old Cervical adenopathy, 5 8, 3 6 3
Chapter 19:A1­29)
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lips, strawberry artery vasculitis
tongue; conjunctivitis; edema
of hands, feet; desquamation
 white evolving into red
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“strawberry” tongue;
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desquamation in second
week

Kawasaki disease Idiopathic Rash similar to scarlet fever Children <8 years old Cervical adenopathy, 5 8, 3 6 3
(Fig. A1­29) (scarlatiniform) or EM; pharyngitis, coronary
fissuring of lips, strawberry artery vasculitis
tongue; conjunctivitis; edema
of hands, feet; desquamation
later in disease

Streptococcal toxic Group A Streptococcus When present, rash often May occur in setting of severe Multiorgan failure, 148
shock syndrome (associated with scarlatiniform group A streptococcal hypotension;
pyrogenic exotoxin A infections (e.g., necrotizing mortality rate 30%
and/or B or certain M fasciitis, bacteremia,
types) pneumonia)

Staphylococcal S. aureus (toxic shock Diffuse erythema involving Colonization with toxin­ Fever >39°C (>102°F), 147
toxic shock syndrome toxin 1, palms; pronounced producing S. aureus hypotension,
syndrome enterotoxins B and erythema of mucosal multiorgan
others) surfaces; conjunctivitis; dysfunction
desquamation 7–10 days into
illness

Staphylococcal S. aureus, phage group Diffuse tender erythema, Colonization with toxin­ Irritability; nasal or 147
scalded­skin II often with bullae and producing S. aureus; occurs in conjunctival
syndrome (Fig. 19­ desquamation; Nikolsky’s children <10 years old (termed secretions
3, Fig. A1­28) sign Ritter’s disease in neonates) or
adults with renal dysfunction

Exfoliative Underlying psoriasis, Diffuse erythema (often Usually occurs in adults over Fever, chills (i.e., 5 8, 6 0
erythroderma eczema, drug eruption, scaling) interspersed with age 50; more common among difficulty with
syndrome (Fig. mycosis fungoides lesions of underlying men thermoregulation);
A1­27) condition lymphadenopathy

DRESS (drug­ Aromatic Maculopapular eruption Individuals genetically unable Lymphadenopathy, 60

induced anticonvulsants; other (mimicking exanthematous to detoxify arene oxides multiorgan failure
hypersensitivity drugs, including drug rash), sometimes (anticonvulsant metabolites), (especially hepatic),
syndrome [DIHS]) sulfonamides, progressing to exfoliative patients with slow N­ eosinophilia, atypical
(Fig. A1­48) minocycline erythroderma; profound acetylating capacity lymphocytes; mimics
edema, especially facial; (sulfonamides) sepsis
pustules may occur

Stevens­Johnson Drugs (80% of cases; Erythematous and purpuric Uncommon among children; Dehydration, sepsis 60
syndrome (SJS), often allopurinol, macules, sometimes more common among sometimes resulting
toxic epidermal anticonvulsants, targetoid, or diffuse patients with HIV infection, from lack of normal
necrolysis (TEN) antibiotics), infection, erythema progressing to systemic lupus skin integrity;
(Fig. A1­26) idiopathic factors bullae, with sloughing and erythematosus, certain HLA mortality rates up to
necrosis of entire epidermis; types, or slow acetylators 30%
Nikolsky’s sign; involves
mucosal surfaces; TEN (>30%
epidermal necrosis) is
maximal form; SJS involves
<10% of epidermis; SJS/TEN
overlap involves 10–30% of
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Vesiculobullous or Pustular Eruptions
 Nikolsky’s sign; involves
mucosal surfaces; TEN (>30% Mahidol University
epidermal necrosis) is Access Provided by:

maximal form; SJS involves

<10% of epidermis; SJS/TEN
overlap involves 10–30% of
epidermis

Vesiculobullous or Pustular Eruptions

Hand­foot­and­ — — — — —h
mouth syndromec;

staphylococcal
scalded­skin
syndromeb; TENb;
DRESSb; COVID­19c

Varicella Varicella­zoster virus Macules (2–3 mm) evolving Usually affects children; 10% Malaise; generally 193
(chickenpox) (Fig. (VZV) into papules, then vesicles of adults susceptible; most mild disease in
19­4, Fig. A1­30) (sometimes umbilicated), on common in late winter and healthy children;
an erythematous base spring; incidence down by 90% more severe disease
(“dewdrops on a rose petal”); in U.S. as a result of varicella with complications in
pustules then forming and vaccination adults and
crusting; lesions appearing in immunocompromised
crops; may involve scalp, children
mouth; intensely pruritic

Pseudomonas Pseudomonas Pruritic erythematous Bathers in hot tubs or Earache, sore eyes 164
“hot­tub” aeruginosa follicular, papular, vesicular, swimming pools; occurs in and/or throat; fever
folliculitis (Fig. A1­ or pustular lesions that may outbreaks may be absent;
55) involve axillae, buttocks, generally self­limited
abdomen, and especially
areas occluded by bathing
suits; can manifest as tender
isolated nodules on palmar
or plantar surfaces (the latter
designated “Pseudomonas
hot­foot syndrome”)

Variola (smallpox) Variola major virus Red macules on tongue and Nonimmune individuals Prodrome of fever, S3
(Fig. A1­50) palate evolving to papules exposed to smallpox headache, backache,
and vesicles; skin macules myalgias; vomiting in
evolving to papules, then 50% of cases
vesicles, then pustules over 1
week, with subsequent lesion
crusting; lesions initially
appearing on face and
spreading centrifugally from
trunk to extremities; differs
from varicella in that (1) skin
lesions in any given area are
at same stage of
development and (2) there is
a prominent distribution of
lesions on face and
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extremities (including palms,
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Primary herpes HSV Erythema rapidly followed Primary infection most Regional 192
 from varicella in that (1) skin
lesions in any given area are Mahidol University
at same stage of Access Provided by:

development and (2) there is

a prominent distribution of
lesions on face and
extremities (including palms,
soles)

Primary herpes HSV Erythema rapidly followed Primary infection most Regional 192
simplex virus (HSV) by hallmark painful grouped common among children and lymphadenopathy
infection vesicles that may evolve into young adults for HSV­1 and
pustules that ulcerate, among sexually active young
especially on mucosal adults for HSV­2; no fever in
surfaces; lesions at site of recurrent infection
inoculation: commonly
gingivostomatitis for HSV­1
and genital lesions for HSV­2;
recurrent disease milder (e.g.,
herpes labialis does not
involve oral mucosa)

Disseminated VZV or HSV Generalized vesicles that can Patients with Visceral organ 1 3 8, 1 9 2,
herpesvirus evolve to pustules and immunosuppression, eczema; involvement (e.g., 193
infection (Fig. A1­ ulcerations; individual neonates liver, lungs) in some
31) lesions similar for VZV and cases; neonatal
HSV. Zoster cutaneous disease particularly
dissemination: >25 lesions severe
extending outside involved
dermatome. HSV: extensive,
progressive mucocutaneous
lesions that may occur in
absence of dissemination,
sometimes disseminate in
eczematous skin (eczema
herpeticum); HSV visceral
dissemination may occur
with only localized
mucocutaneous disease; in
disseminated neonatal
disease, skin lesions
diagnostically helpful when
present, but rash absent in a
substantial minority of cases

Rickettsialpox (Fig. Rickettsia akari Eschar found at site of mite Seen in urban settings; Headache, myalgias, 187
A1­33) bite; generalized rash transmitted by mouse mites regional adenopathy;
involving face, trunk, mild disease
extremities; may involve
palms and soles; <100
papules and plaques (2–10
mm); centers of papules
develop vesicles or pustules

Acute generalized Drugs (mostly Tiny, sterile, nonfollicular Appears 2–21 days after start Acute fever, pruritus, 60
exanthematous
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Chapter 19: Fever
pustulosis and Rash,
(Fig. Elaine T. Kaye;
antimicrobials); also Kenneth M. Kaye
edematous skin; begins on whether patient has been Page 11 / 25
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sensitized
becomes generalized
 papules and plaques (2–10
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mm); centers of papules
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develop vesicles or pustules

Acute generalized Drugs (mostly Tiny, sterile, nonfollicular Appears 2–21 days after start Acute fever, pruritus, 60
exanthematous anticonvulsants or pustules on erythematous, of drug therapy, depending on leukocytosis
pustulosis (Fig. antimicrobials); also edematous skin; begins on whether patient has been
A1­49) viral face and in body folds, then sensitized
becomes generalized

Disseminated Vibrio V. vulnificus Erythematous lesions Patients with cirrhosis, Hypotension; 168
vulnificus infection evolving into hemorrhagic diabetes, renal failure; mortality rate 50%
bullae and then into necrotic exposure by ingestion of
ulcers contaminated saltwater,
seafood

Ecthyma P. aeruginosa, other Indurated plaque evolving Usually affects neutropenic Clinical signs of sepsis 164
gangrenosum (Fig. gram­negative rods, into hemorrhagic bulla or patients; occurs in up to 28%
A1­34) fungi pustule that sloughs, of individuals with
resulting in eschar formation; Pseudomonas bacteremia
erythematous halo; most
common in axillary, groin,
perianal regions

Mycoplasma­ Mycoplasma Severe mucositis of at least More common in males; Evidence of M.

induced rash and pneumoniae two sites (e.g., oropharynx, usually children (mean age pneumoniae infection
mucositis (MIRM) ocular, genital) with nearly 11–12 years old) (typically pneumonia);
universal hemorrhagic good prognosis;
crusting of lips; sparse, distinct from SJS/TEN;
vesiculobullous, or atypical rarely Chlamydophila
targetoid rash over <10% of pneumoniae can
body; lesions typically on cause similar
extremities but can be syndrome
truncal; rash sometimes
absent (MIRM sine rash)

Urticaria­Like Eruptions

COVID­19c

Urticarial vasculitis Serum sickness, often Erythematous, edematous Patients with serum sickness Fever variable; 3 6 3h
(Fig. 19­5, Fig. due to infection “urticaria­like” plaques, (including acute hepatitis B), arthralgias/arthritis
A1­35) (including acute pruritic or burning; unlike connective tissue disease
hepatitis B, enteroviral, urticaria: typical lesion
parasitic), drugs; duration >24 h (up to 5 days)
connective tissue and lack of complete lesion
disease blanching with compression
due to hemorrhage

Nodular Eruptions

Disseminated Fungal infections (e.g., Subcutaneous nodules (up Immunocompromised hosts Features vary with —h
infection (Fig. 19­ candidiasis, to 3 cm); fluctuance, draining (e.g., bone marrow transplant organism
6, Fig. A1­36, Fig. histoplasmosis, common with mycobacteria; recipients, patients
A1­37, Fig. A1­38) cryptococcosis, necrotic nodules (extremities, undergoing chemotherapy,
sporotrichosis, periorbital or nasal regions) HIV­infected patients)
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coccidioidomycosis);
Chapter 19: Fever and Rash, common
Elaine T. Kaye; Kenneth with Aspergillus,
M. Kaye Page 12 / 25
mycobacteria
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Erythema Infections (e.g., Large, violaceous, More common among females Arthralgias (50%); —h
 Disseminated Fungal infections (e.g., Subcutaneous nodules (up Immunocompromised hosts Features vary with Mahidol
—h University
infection (Fig. 19­ candidiasis, to 3 cm); fluctuance, draining (e.g., bone marrow transplant organism Access Provided by:

6, Fig. A1­36, Fig. histoplasmosis, common with mycobacteria; recipients, patients

A1­37, Fig. A1­38) cryptococcosis, necrotic nodules (extremities, undergoing chemotherapy,
sporotrichosis, periorbital or nasal regions) HIV­infected patients)
coccidioidomycosis); common with Aspergillus,
mycobacteria Mucor

Erythema Infections (e.g., Large, violaceous, More common among females Arthralgias (50%); —h
nodosum (septal streptococcal, fungal, nonulcerative, subcutaneous 15–30 years old features vary with
panniculitis) (Fig. mycobacterial, nodules; exquisitely tender; associated condition
A1­39) yersinial); drugs (e.g., usually on lower legs but
sulfas, penicillins, oral also on upper extremities
contraceptives);
sarcoidosis; idiopathic
causes

Sweet syndrome Yersinia infection; upper Tender red or blue More common among women Headache, arthralgias, 58
(acute febrile respiratory infection; edematous nodules giving and among persons 30–60 leukocytosis
neutrophilic inflammatory bowel impression of vesiculation; years old; 20% of cases
dermatosis) (Fig. disease; pregnancy; usually on face, neck, upper associated with malignancy
A1­40) malignancy (usually extremities; when on lower (men and women equally
hematologic); drugs (G­ extremities, may mimic affected in this group)
CSF) erythema nodosum

Bacillary Bartonella henselae, B. Many forms, including Immunosuppressed Peliosis of liver and 172
angiomatosis quintana erythematous, smooth individuals, especially those spleen in some cases;
vascular nodules; friable, with advanced HIV infection lesions sometimes
exophytic lesions; involving multiple
erythematous plaques (may organs; bacteremia
be dry, scaly); subcutaneous
nodules (may be
erythematous)

Purpuric Eruptions

Rocky Mountain — — — — —h
spotted fever, rat­
bite fever,
endocarditisc;
epidemic typhusf ;

dengue fevere,f;
human parvovirus
B19 infectionf ;
COVID­19c

Acute Neisseria meningitidis Initially pink maculopapular Most common among Hypotension, 155
meningococcemia lesions evolving into children, individuals with meningitis
petechiae; petechiae rapidly asplenia or terminal (sometimes preceded
becoming numerous, complement component by upper respiratory
sometimes enlarging and deficiency (C5–C8) infection)
becoming vesicular; trunk,
extremities most commonly
involved; may appear on
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face, hands, feet; may include
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below) reflecting DIC
 petechiae; petechiae rapidly asplenia or terminal (sometimes preceded
becoming numerous, complement component by upper respiratory Mahidol University
sometimes enlarging and deficiency (C5–C8) infection) Access Provided by:

becoming vesicular; trunk,

extremities most commonly
involved; may appear on
face, hands, feet; may include
purpura fulminans (see
below) reflecting DIC

Purpura fulminans Severe DIC Large ecchymoses with Individuals with sepsis (e.g., Hypotension 1 5 5, 3 0 4
(Fig. 19­7, Fig. sharply irregular shapes involving N. meningitidis),
A1­41) evolving into hemorrhagic malignancy, or massive
bullae and then into black trauma; asplenic patients at
necrotic lesions high risk for sepsis

Chronic N. meningitidis Variety of recurrent Individuals with complement Fevers, sometimes 155
meningococcemia eruptions, including pink deficiencies intermittent; arthritis,
(Fig. A1­42) maculopapular; nodular myalgias, headache
(usually on lower
extremities); petechial
(sometimes developing
vesicular centers); purpuric
areas with pale blue­gray
centers

Disseminated Neisseria gonorrhoeae Papules (1–5 mm) evolving Sexually active individuals Low­grade fever, 156
gonococcal over 1–2 days into (more often females), some tenosynovitis, arthritis
infection (Fig. A1­ hemorrhagic pustules with with complement deficiency
43) gray necrotic centers;
hemorrhagic bullae occurring
rarely; lesions (usually <40)
distributed peripherally near
joints (more commonly on
upper extremities)

Enteroviral Usually echovirus 9 or Disseminated petechial Often occurs in outbreaks Pharyngitis, headache; 204
petechial rash coxsackievirus A9 lesions (may also be aseptic meningitis
maculopapular, vesicular, or with echovirus 9
urticarial)

Viral hemorrhagic Arenaviruses, Petechial rash Residence in or travel to Triad of fever, shock, 2 0 9, 2 1 0
fever bunyaviruses, endemic areas, other virus hemorrhage from
filoviruses (including exposure mucosa or
Ebola), flaviviruses gastrointestinal tract
(including dengue)

Thrombotic Idiopathic, bloody Petechiae Individuals with E. coli Fever (not always 5 8, 1 0 0,
thrombocytopenic diarrhea caused by O157:H7 gastroenteritis present), 1 1 5, 1 6 1,
purpura/hemolytic­ Shiga toxin–generating (especially children), cancer microangiopathic 166
uremic syndrome bacteria (e.g., chemotherapy, HIV infection, hemolytic anemia,
Escherichia coli autoimmune diseases, thrombocytopenia,
O157:H7), deficiency in pregnant/postpartum women, renal dysfunction,
ADAMTS13 (cleaves von those with ADAMTS13 neurologic
Willebrand factor), deficiency dysfunction;
drugs (e.g., quinine, coagulation studies
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chemotherapy, normal
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immunosuppression)
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Cutaneous small­ Infections (including Palpable purpuric lesions Occurs in a wide spectrum of Fever (not always 58
 uremic syndrome bacteria (e.g., chemotherapy, HIV infection, hemolytic anemia,
Escherichia coli autoimmune diseases, thrombocytopenia, Mahidol University
O157:H7), deficiency in pregnant/postpartum women, renal dysfunction, Access Provided by:

ADAMTS13 (cleaves von those with ADAMTS13 neurologic

Willebrand factor), deficiency dysfunction;
drugs (e.g., quinine, coagulation studies
chemotherapy, normal
immunosuppression)

Cutaneous small­ Infections (including Palpable purpuric lesions Occurs in a wide spectrum of Fever (not always 58
vessel vasculitis group A streptococcal appearing in crops on legs or diseases, including connective present), malaise,
(leukocytoclastic infection, hepatitis B or other dependent areas; may tissue disease, arthralgias, myalgias;
vasculitis) (Fig. A1­ C), drugs, idiopathic become vesicular or cryoglobulinemia, malignancy, systemic vasculitis in
44) factors ulcerative Henoch­Schönlein purpura some cases; renal,
(HSP); more common among joint, and
children gastrointestinal
involvement common
in HSP

Eruptions with Ulcers and/or Eschars

Scrub typhus, — — — — —h
rickettsial spotted
fevers, rat­bite
fever, African
trypanosomiasisf ;

rickettsialpox,
ecthyma
gangrenosumg

Tularemia (Fig. Francisella tularensis Ulceroglandular form: Exposure to ticks, biting flies, Fever, headache, 170
A1­45, Fig. A1­46) erythematous, tender papule infected animals lymphadenopathy
evolves into necrotic, tender
ulcer with raised borders; in
35% of cases, eruptions
(maculopapular,
vesiculopapular, acneiform,
or urticarial; erythema
nodosum; or EM) may occur

Anthrax (Fig. A1­ Bacillus anthracis Pruritic papule enlarging and Exposure to infected animals Lymphadenopathy, S3
52) evolving into a 1­ by 3­cm or animal products, other headache
painless ulcer surrounded by exposure to anthrax spores
vesicles and then developing
a central eschar with edema;
residual scar

aSee “Purpuric Eruptions.”

b See “Confluent Desquamative Erythemas.”

cSee “Peripheral Eruptions.”

dRash is rare in human granulocytotropic ehrlichiosis or anaplasmosis (caused by Anaplasma phagocytophilum; most common in the upper midwestern and

northeastern United States).

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Chapter 19: hemorrhagic
eSee “Viral Fever and Rash, Elaine“Purpuric
fever” under T. Kaye;Eruptions”
Kennethfor
M.dengue
Kaye hemorrhagic fever/dengue shock syndrome. Page 15 / 25
©2024 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
f See “Centrally Distributed Maculopapular Eruptions.”
 b See “Confluent Desquamative Erythemas.”
Mahidol University
cSee “Peripheral Eruptions.” Access Provided by:

dRash is rare in human granulocytotropic ehrlichiosis or anaplasmosis (caused by Anaplasma phagocytophilum; most common in the upper midwestern and

northeastern United States).

eSee “Viral hemorrhagic fever” under “Purpuric Eruptions” for dengue hemorrhagic fever/dengue shock syndrome.

f See “Centrally Distributed Maculopapular Eruptions.”

gSee “Vesiculobullous or Pustular Eruptions.”

h See etiology­specific chapters.

Abbreviations: CNS, central nervous system; DIC, disseminated intravascular coagulation; G­CSF, granulocyte colony­stimulating factor; HLA, human leukocyte
antigen.

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, typically sparing the palms and soles (Fig. 19­1; see also Fig. A1­3) (Chap. 205). It
begins as discrete erythematous lesions, which become confluent as the rash spreads. Koplik’s spots (1­ to 2­mm white or bluish lesions with an
erythematous halo on the buccal mucosa) (Fig. A1­2) 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.

FIGURE 19­1

Centrally distributed, maculopapular eruption on the trunk in a patient with measles. (From EJ Mayeaux Jr et al: Measles, in Usatine RP et
al [eds]: Color Atlas and Synopsis of Family Medicine, 3rd ed. New York, McGraw­Hill, 2019, p. 797, Figure 132­2. Reproduced with permission from
Richard P. Usatine, MD.)

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Chapter 19: Fever
Rubella (German and Rash,
measles) Elaine
(Fig. A1­4)T.also
Kaye; Kenneth
spreads fromM.the
Kaye Page 16 / 25
hairline downward; unlike that of measles, however, the rash of rubella tends to clear
©2024 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
from originally affected areas as it migrates, and it may be pruritic (Chap. 206). Forchheimer spots (palatal petechiae) may develop but are
nonspecific because they also develop in infectious mononucleosis (Chap. 194), scarlet fever (Chap. 148), and Zika virus infection (Chap. 209)
FIGURE 19­1

Mahidol University
Centrally distributed, maculopapular eruption on the trunk in a patient with measles. (From EJ Mayeaux Jr et al: Measles, in Usatine RP et
Access Provided by:
al [eds]: Color Atlas and Synopsis of Family Medicine, 3rd ed. New York, McGraw­Hill, 2019, p. 797, Figure 132­2. Reproduced with permission from
Richard P. Usatine, MD.)

Rubella (German measles) (Fig. A1­4) 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. 206). Forchheimer spots (palatal petechiae) may develop but are
nonspecific because they also develop in infectious mononucleosis (Chap. 194), scarlet fever (Chap. 148), and Zika virus infection (Chap. 209)
(Fig. A1­51D). Postauricular and suboccipital adenopathy and arthritis are common among adults with rubella. Exposure of pregnant women to ill
individuals should be avoided, as rubella causes severe congenital abnormalities. Numerous strains of enteroviruses (Chap. 204), primarily
echoviruses and coxsackieviruses, cause nonspecific syndromes of fever and eruptions that may mimic rubella or measles. Patients with infectious
mononucleosis caused by Epstein­Barr virus (Chap. 194) or with primary HIV infection (Fig. A1­6; see also Chapter 202) 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”) (Fig. A1­1A) with perioral pallor (Chap. 197). A more diffuse
rash (often pruritic) appears the next day on the trunk and extremities and then rapidly develops into a lacy reticular eruption (Fig. A1­1B) 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, or less commonly by the closely related human herpesvirus 7, and is most common
among children <3 years of age (Chap. 195). As in erythema infectiosum, the rash usually appears after fever has subsided. It consists of 2­ to 3­mm
rose­pink macules and papules that coalesce only rarely, occur initially on the trunk (Fig. A1­5) and sometimes on the extremities (sparing the face),
and fade within 2 days.

Although drug reactions have many manifestations, including urticaria, exanthematous drug­induced eruptions (Chap. 60) (Fig. A1­7) 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 HIV­infected patients, 50–60% develop a rash in response to sulfa drugs; 30–90% of
patients with mononucleosis due to Epstein­Barr virus develop a rash when given ampicillin.
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Rickettsial
Chapter 19:illnesses (Chap.
Fever and 187)
Rash, should
Elaine be considered
T. Kaye; Kenneth in M.the
Kayeevaluation of individuals with centrally distributed maculopapular eruptions. The17
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are exposed to body lice. Endemic typhus or leptospirosis (the latter
caused by a spirochete) (Chap. 184) may be seen in urban environments where rodents proliferate. Outside the United States, other rickettsial
diseases cause a spotted­fever syndrome and should be considered in residents of or travelers to endemic areas. Similarly, typhoid fever, a
Although drug reactions have many manifestations, including urticaria, exanthematous drug­induced eruptions (Chap. 60) (Fig. A1­7) are most
Mahidol
common and are often difficult to distinguish from viral exanthems. Eruptions elicited by drugs are usually more intensely erythematous and University
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
Access Provided by:

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 HIV­infected patients, 50–60% develop a rash in response to sulfa drugs; 30–90% of
patients with mononucleosis due to Epstein­Barr virus develop a rash when given ampicillin.

Rickettsial illnesses (Chap. 187) 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. Endemic typhus or leptospirosis (the latter
caused by a spirochete) (Chap. 184) may be seen in urban environments where rodents proliferate. Outside the United States, other rickettsial
diseases cause a spotted­fever syndrome and should be considered in residents of or travelers to endemic areas. Similarly, typhoid fever, a
nonrickettsial disease caused by Salmonella typhi (Chap. 165) (Fig. A1­9), is usually acquired during travel outside the United States. Dengue fever
(Fig. A1­53), caused by a mosquito­transmitted flavivirus, occurs in tropical and subtropical regions of the world (Chap. 209).

Some centrally distributed maculopapular eruptions have distinctive features. Erythema migrans (Fig. A1­8), the rash of Lyme disease (Chap. 186),
typically manifests as single or multiple annular lesions. Untreated erythema migrans lesions usually fade within a month but may persist for more
than a year. Southern tick­associated rash illness (STARI) (Chap. 186) has an erythema migrans–like rash, but is less severe than Lyme disease and
often occurs in regions where Lyme is not endemic. Erythema marginatum, the rash of acute rheumatic fever (Chap. 359), has a distinctive pattern of
enlarging and shifting transient annular lesions.

Collagen vascular diseases may cause fever and rash. Patients with systemic lupus erythematosus (Chap. 356) typically develop a sharply defined,
erythematous eruption in a butterfly distribution on the cheeks (malar rash) (Fig. A1­10) as well as many other skin manifestations (Figs. A1­11, A 1 ­
1 2). Still’s disease presents as an evanescent, salmon­colored rash on the trunk and proximal extremities that coincides with fever spikes (Fig. A1­
1 3 ).

Hemophagocytic lymphohistiocytosis may be familial or triggered by infection, autoimmunity, or neoplasia. Cutaneous manifestations are protean and
can present as an erythematous maculopapular eruption, pyoderma gangrenosum, purpura, panniculitis, or Stevens Johnson syndrome.

Zika virus is a mosquito­transmitted flavivirus that is associated with severe birth defects (Chap. 209). Zika is widespread among tropical and
subtropical regions of the world. The eruption of Zika virus infection (Fig. A1­51A, A1­51B) is typically pruritic and often accompanied by
conjunctival injection (Fig. A1­51C).

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 Rocky Mountain spotted fever (Chap. 187) because of its grave prognosis if untreated. Lesions (Fig. 19­2; see also Fig.
A1­16) 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. 182), which may be generalized (Fig. A1­18) but is prominent on the palms and soles (Fig. A1­19),
should be considered in the differential diagnosis of pityriasis rosea, especially in sexually active patients. Chikungunya fever (Chap. 209), which is
transmitted by mosquito bite in tropical and subtropical regions, is associated with a maculopapular eruption (Fig. A1­54) and severe polyarticular
small­joint arthralgias. Hand­foot­and­mouth disease (Chap. 204), most commonly caused by coxsackievirus A16 or enterovirus 71, is distinguished
by tender vesicles distributed on the hands and feet and in the mouth (Fig. A1­22); coxsackievirus A6 causes an atypical syndrome with more
extensive lesions. The classic target lesions of erythema multiforme (Fig. A1­24) appear symmetrically on the elbows, knees, palms, soles, and face. In
severe cases, these lesions spread diffusely and involve mucosal surfaces. Lesions may develop on the hands and feet in endocarditis (Fig. A1­23)
(Chap. 128). Pernio, tender violaceous lesions that are acral (Fig. A1­57), occur most commonly on the feet, in asymptomatic or mild COVID­19.
Vesicles, urticaria, or maculopapular eruptions, often pruritic, may occur on the trunk and extremities in moderate or severe disease, while retiform
purpura occurs on the extremities and buttocks in severe COVID­19.

FIGURE 19­2

Peripheral eruption on the wrist and palm exhibiting erythematous macules in the process of evolving into petechial lesions in a
patient with Rocky Mountain spotted fever. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New
York, McGraw­Hill, 2017, p. 562, Figure 25­50; with permission.)

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FIGURE 19­2

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Peripheral eruption on the wrist and palm exhibiting erythematous macules in the process of evolving into petechial lesions in a
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patient with Rocky Mountain spotted fever. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New
York, McGraw­Hill, 2017, p. 562, Figure 25­50; with permission.)

CONFLUENT DESQUAMATIVE ERYTHEMAS

These eruptions consist of diffuse erythema frequently followed by desquamation. The eruptions caused by group A Streptococcus or Staphylococcus
aureus are toxin­mediated. Scarlet fever (Chap. 148) (Fig. A1­25) usually follows pharyngitis; patients have a facial flush, a “strawberry” tongue, and
accentuated petechiae in body folds (Pastia’s lines). Kawasaki disease (Fig. A1­29) (Chaps. 58 and 363) presents in the pediatric population as
fissuring of the lips, a strawberry tongue, conjunctivitis, adenopathy, and sometimes cardiac abnormalities. Streptococcal toxic shock syndrome
(Chap. 148) manifests with hypotension, multiorgan failure, and, often, a severe group A streptococcal infection (e.g., necrotizing fasciitis).
Staphylococcal toxic shock syndrome (Chap. 147) also presents with hypotension and multiorgan failure, but usually only S. aureus colonization—
not a severe S. aureus infection—is documented. Staphylococcal scalded­skin syndrome (Fig. A1­28) (Chap. 147) 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) (Fig. 19­3). 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 scalded­skin syndrome, in which the cleavage plane is superficial in the epidermis, toxic epidermal necrolysis (Chap. 60), a maximal
variant of Stevens­Johnson syndrome, involves sloughing of the entire epidermis (Fig. A1­26), resulting in severe disease. Exfoliative erythroderma
syndrome (Chaps. 58 and 6 0 ) is a serious reaction associated with systemic toxicity that is often due to eczema, psoriasis (Fig. A1­27), a drug
reaction, or mycosis fungoides. Drug rash with eosinophilia and systemic symptoms (DRESS), often due to antiepileptic and antibiotic agents (Chap.
6 0 ), initially appears similar to an exanthematous drug reaction (Fig. A1­48) but may progress to exfoliative erythroderma; it is accompanied by
multiorgan failure and has an associated mortality rate of ~10%.

FIGURE 19­3

Confluent desquamative erythema in a patient with Staphylococcal scalded­skin syndrome. Nikolsky sign evident as shearing of
epidermis due to gentle, lateral pressure. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York,
McGraw­Hill, 2017, p. 554, Figure 25­42; with permission.)

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FIGURE 19­3

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Confluent desquamative erythema in a patient with Staphylococcal scalded­skin syndrome. Nikolsky sign evident as shearing of
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epidermis due to gentle, lateral pressure. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York,
McGraw­Hill, 2017, p. 554, Figure 25­42; with permission.)

VESICULOBULLOUS OR PUSTULAR ERUPTIONS

Varicella (Chap. 193) is highly contagious, often occurring in winter or spring, and is characterized by pruritic lesions that, within a given region of the
body, are in different stages of development at any point in time (Fig. 19­4; see also Fig. A1­30). In immunocompromised hosts, varicella vesicles
may lack the characteristic erythematous base or may appear hemorrhagic. Lesions of Pseudomonas “hot­tub” folliculitis (Chap. 164) are also
pruritic and may appear similar to those of varicella (Fig. A1­55). However, hot­tub 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. S3) also appear similar to those of
varicella but are all at the same stage of development in a given region of the body (Figs. A1­50B, A1­50C). Variola lesions are most prominent on the
face (Fig. A1­50A) and extremities, while varicella lesions are most prominent on the trunk. Herpes simplex virus infection (Chap. 192) is
characterized by hallmark grouped vesicles on an erythematous base. Primary herpes infection is accompanied by fever and toxicity, while recurrent
disease is milder. Rickettsialpox (Chap. 187) is often documented in urban settings and is characterized by vesicles followed by pustules (Figs. A1­
33B, A1­33C). It can be distinguished from varicella by an eschar at the site of the mouse­mite bite (Fig. A1­33A) and the papule/plaque base of each
vesicle. Acute generalized exanthematous pustulosis (Fig. A1­49) should be considered in individuals who are acutely febrile and are taking new
medications, especially anticonvulsant or antimicrobial agents (Chap. 60). Disseminated Vibrio vulnificus infection (Chap. 168) or ecthyma
gangrenosum due to Pseudomonas aeruginosa (Fig. A1­34) (Chap. 164) should be considered in immunosuppressed individuals with sepsis and
hemorrhagic bullae. In children, Mycoplasma pneumoniae–induced rash and mucositis (MIRM) (Fig. A1­56) is characterized by a sparse, often
vesiculobullous eruption with prominent oral, ocular, or urogenital mucositis.

FIGURE 19­4

Vesicular and pustular lesions on the chest in a patient with varicella. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of
Clinical Dermatology, 8th ed. New York, McGraw­Hill, 2017, p. 695, Figure 27­48; with permission.)

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FIGURE 19­4
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Vesicular and pustular lesions on the chest in a patient with varicella. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of
Clinical Dermatology, 8th ed. New York, McGraw­Hill, 2017, p. 695, Figure 27­48; with permission.)

URTICARIA­LIKE ERUPTIONS

Individuals with classic urticaria (“hives”) (Fig. 19­5; see also Fig. A1­35) usually have a hypersensitivity reaction without associated fever. In the
presence of fever, urticaria­like eruptions are most often due to urticarial vasculitis (Chap. 363). Unlike individual lesions of classic urticaria, which
last up to 24 h, these lesions may last 3–5 days. Etiologies include serum sickness (often induced by drugs such as penicillins, sulfas, salicylates, or
barbiturates), connective­tissue disease (e.g., systemic lupus erythematosus or Sjögren’s syndrome), and infection (e.g., with hepatitis B virus,
enteroviruses, or parasites). Malignancy, especially lymphoma, may be associated with fever and chronic urticaria (Chap. 58).

FIGURE 19­5

Urticarial eruption. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw­Hill, 2017, p.
299, Figure 14­2; with permission.)

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FIGURE 19­5
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Urticarial eruption. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw­Hill, 2017, p.
299, Figure 14­2; with permission.)

NODULAR ERUPTIONS

In immunocompromised hosts, nodular lesions often represent disseminated infection. Patients with disseminated candidiasis (Fig. A1­37) (often
due to Candida tropicalis) may have a triad of fever, myalgias, and eruptive nodules (Chap. 216). Disseminated cryptococcosis lesions (Fig. 19­6; see
also Fig. A1­36) (Chap. 215) may resemble molluscum contagiosum (Chap. 196). Necrosis of nodules should raise the suspicion of aspergillosis
(Fig. A1­38) (Chap. 217) or mucormycosis (Chap. 218). Erythema nodosum presents with exquisitely tender nodules on the lower extremities (Fig.
A1­39). Sweet syndrome (Chap. 58) should be considered in individuals with multiple nodules and plaques, often so edematous (Fig. A1­40) that
they give the appearance of vesicles or bullae. Sweet syndrome may occur in individuals with infection, inflammatory bowel disease, or malignancy and
can also be induced by drugs.

FIGURE 19­6

Nodular eruption on the face due to disseminated Cryptococcus in a patient with HIV infection. (From K Wolff et al [eds]: Fitzpatrick’s
Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw­Hill, 2017, p. 641, Figure 26­57. Used with permission from Loïc Vallant,
MD.)

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FIGURE 19­6

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Nodular eruption on the face due to disseminated Cryptococcus in a patient with HIV infection. (From K Wolff et al [eds]: Fitzpatrick’s
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Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw­Hill, 2017, p. 641, Figure 26­57. Used with permission from Loïc Vallant,
MD.)

PURPURIC ERUPTIONS

Acute meningococcemia (Chap. 155) classically presents in children as a petechial eruption, but initial lesions may appear as blanchable macules or
urticaria. Rocky Mountain spotted fever should be considered in the differential diagnosis of acute meningococcemia. Echovirus 9 infection (Chap.
204) may mimic acute meningococcemia; patients should be treated as if they have bacterial sepsis because prompt differentiation of these conditions
may be impossible. Large ecchymotic areas of purpura fulminans (Fig. 19­7; see also Fig. A1­41) (Chaps. 155 and 304) reflect severe underlying
disseminated intravascular coagulation, which may be due to infectious or noninfectious causes. The lesions of chronic meningococcemia (Fig. A1­
4 2 ) (Chap. 155) 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. 156) are distinctive, sparse, countable hemorrhagic pustules (Fig.
A1­43), 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. 209 and 210) should be considered in patients with an appropriate travel history and a
petechial rash. Thrombotic thrombocytopenic purpura (Chaps. 58, 100, and 115) and hemolytic­uremic syndrome (Chaps. 115, 161, and 166)
are closely related and are noninfectious causes of fever and petechiae. Cutaneous small­vessel vasculitis (leukocytoclastic vasculitis) typically
manifests as palpable purpura (Fig. A1­44) and has a wide variety of causes (Chap. 58).

FIGURE 19­7

Purpura fulminans in a patient with acute meningococcemia. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of Clinical
Dermatology, 8th ed. New York, McGraw­Hill, 2017, p. 568, Figure 25­59; with permission.)

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FIGURE 19­7
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Purpura fulminans in a patient with acute meningococcemia. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of Clinical
Dermatology, 8th ed. New York, McGraw­Hill, 2017, p. 568, Figure 25­59; with permission.)

ERUPTIONS WITH ULCERS OR ESCHARS

The presence of an ulcer or eschar (Fig. 19­8) in the setting of a more widespread eruption can provide an important diagnostic clue. For example, an
eschar may suggest the diagnosis of scrub typhus or rickettsialpox (Fig. A1­33A) (Chap. 187) in the appropriate setting. In other illnesses (e.g.,
anthrax) (Fig. A1­52) (Chap. S3), an ulcer or eschar may be the only skin manifestation.

FIGURE 19­8

Eschar with surrounding erythema at the site of a tick bite in a patient with African tick­bite fever. (From K Wolff et al [eds]: Fitzpatrick’s
Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw­Hill, 2017, p. 561, Figure 25­49; with permission.)

FURTHER READING

Cherry JD: Cutaneous manifestations of systemic infections, in Feigin and Cherry’s Textbook of Pediatric Infectious Diseases, 8th ed. JD Cherry et al
(eds). Philadelphia,
Downloaded Elsevier,
2024­8­12 3:9 A2019, ppIP
Your 539–559.
is 202.28.147.16
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©2024
JulianoMcGraw
JJ et al:Hill.
TheAll Rights
acutely ill Reserved.
patient with Terms of Use
fever and rash,• in
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Mandell, • Notice
Douglas, and•Bennett’s
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Principles and Practice of Infectious Diseases, vol 1, 9th
ed. JI Bennett et al (eds). Philadelphia, Elsevier, 2020, pp 801–818.
 Mahidol University
FURTHER READING Access Provided by:

Cherry JD: Cutaneous manifestations of systemic infections, in Feigin and Cherry’s Textbook of Pediatric Infectious Diseases, 8th ed. JD Cherry et al
(eds). Philadelphia, Elsevier, 2019, pp 539–559.

Juliano JJ et al: The acutely ill patient with fever and rash, in Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, vol 1, 9th
ed. JI Bennett et al (eds). Philadelphia, Elsevier, 2020, pp 801–818.

Kang S et al (eds): Fitzpatrick’s Dermatology, 9th ed. New York, McGraw­Hill, 2019.

Wolff K et al: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw­Hill, 2017.

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