# 10 - 21 Fever and Rash

### 21 Fever and Rash

can aggravate the condition of patients with preexisting impairment 
of cardiac, pulmonary, or CNS function. Children with a history of 
febrile or nonfebrile seizure should be aggressively treated to reduce 
fever. However, it is unclear what triggers the febrile seizure, and 
there is no correlation between absolute temperature elevation and 
onset of a febrile seizure in susceptible children.
In hyperpyrexia, the use of cooling blankets facilitates the reduc­
tion of temperature; however, cooling blankets should not be used 
without oral antipyretics. In hyperpyretic patients with CNS disease 
or trauma (CNS bleeding), reducing core temperature mitigates the 
detrimental effects of high temperature on the brain.
For a discussion of treatment for hyperthermia, see Chap. 478.
■
■FURTHER READING
Dinarello CA et al: Treating inflammation by blocking interleukin-1 
in a broad spectrum of diseases. Nature Rev 11:633, 2012.
Gattorno M et al: Classification criteria for autoinflammatory recurrent 
fevers. Ann Rheum Dis 78:1025, 2019.
Kullenberg T et al: Long-term safety profile of anakinra in patients 
with severe cryopyrin-associated periodic syndromes. Rheumatology 
55:1499, 2016.
Sakkat A et al: Temperature control in critically ill patients with fever: 
A meta-analysis of randomized controlled trials. J Crit Care 61:89, 
2021.
Elaine T. Kaye, Kenneth M. Kaye

Fever and Rash
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 life-saving therapy or critical infection-control 
interventions. Representative images of many of the rashes discussed 
in this chapter are included in Chap. A1.
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, recent dietary exposures, exis­
tence 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 identification 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, 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 (ring­
like) 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. Pus­
tules are raised lesions containing purulent exudate; vesicles such as 
due to varicella or herpes simplex may evolve to pustules. Nonpal­
pable 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.
Fever and Rash
CHAPTER 21
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. 59, 61, 127, and 134.
■
■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. 134). The chapter is not intended 
to be all-inclusive, 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 pur­
poses, 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. 61). For instance, the classic petechial rash of Rocky Mountain 
spotted fever (Chap. 192) may initially consist of blanchable ery­
thematous 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 desquama­
tive erythematous, vesiculobullous, urticaria-like, nodular, purpuric, 
ulcerated, or with eschars. Diseases are listed by these categories in 
Table 21-1, 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 21-1.)
■
■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, typically sparing the palms and soles (Fig. 21-1; see also Fig. A1-3) 
(Chap. 211). It begins as discrete erythematous lesions, which become 
confluent as the rash spreads. Koplik’s spots (1- to 2-mm white or blu­
ish lesions with an erythematous halo on the buccal mucosa) (Fig. A1-2) 
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) (Fig. A1-4) 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. 212). Forchheimer spots (palatal petechiae) may develop but 
are nonspecific because they also develop in infectious mononucleosis 
(Chap. 199), scarlet fever (Chap. 153), and Zika virus infection 
(Chap. 215) (Fig. A1-51A-D). Postauricular and suboccipital adenop­
athy 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. 210), primarily echoviruses and coxsackieviruses, cause non­
specific syndromes of fever and eruptions that may mimic rubella or 
measles. Patients with infectious mononucleosis caused by Epstein-Barr 
virus (Chap. 199) or with primary HIV infection (Fig. A1-6; see also

TABLE 21-1  Diseases Associated with Fever and Rash
DISEASE
ETIOLOGY
DESCRIPTION
Centrally Distributed Maculopapular Eruptions
Acute meningococcemiaa
—
—
—
—

Drug reaction with 
eosinophilia and systemic 
symptoms (DRESS); also 
termed drug-induced 
hypersensitivity syndrome 
(DIHS)b; Chikungunyac; 
COVID-19c
—
—
—
—

PART 2
Cardinal Manifestations and Presentation of Diseases
Rubeola (measles, first 
disease) (Fig. 21-1, 

Fig. A1-2, Fig. A1-3)
Paramyxovirus
Discrete lesions that become confluent 
as rash spreads from hairline downward, 
usually sparing palms and soles; lasts 

≥3 days; Koplik’s spots
Rubella (German measles, 
third disease) (Fig. A1-4)
Togavirus
Spreads from hairline downward, clearing 
as it spreads; Forchheimer spots (palatal 
petechiae)
Erythema infectiosum 
(fifth disease) (Fig. A1-1)
Human parvovirus B19
Bright-red “slapped-cheeks” appearance 
followed by lacy reticular rash that waxes 
and wanes over 3 weeks; rarely, papularpurpuric “gloves-and-socks” syndrome on 
hands and feet
Exanthem subitum 
(roseola, sixth disease) 
(Fig. A1-5)
Human herpesvirus 6 
or, less commonly, the 
closely related human 
herpesvirus 7
Diffuse maculopapular eruption over trunk 
and neck; resolves within 2 days
Primary HIV infection 

(Fig. A1-6)
HIV
Nonspecific diffuse macules and papules 
most commonly on upper thorax, face, 
collar region; less commonly, urticarial or 
vesicular lesions; oral or genital ulcers
Infectious mononucleosis
Epstein-Barr virus
Diffuse maculopapular eruption historically 
in ~5% of cases increasing to ~90% of 
cases when antibiotics, particularly 
ampicillin, given, but recent observed 
rates of ~20% without antibiotics and 
little increase with antibiotics; urticaria, 
petechiae in some cases; periorbital 
edema (50%); palatal petechiae (25%)
Other viral exanthems
Echoviruses 2, 4, 9, 11, 16, 
19, 25; coxsackieviruses 
A9, B1, B5; etc.
Wide range of skin findings that may mimic 
rubella or measles
Exanthematous druginduced eruption 

(Fig. A1-7)
Drugs (antibiotics, 
anticonvulsants, 
diuretics, etc.)
Intensely pruritic, bright-red macules 
and papules, symmetric on trunk and 
extremities; may become confluent
Epidemic typhus
Rickettsia prowazekii
Maculopapular eruption appearing in 
axillae, spreading to trunk and later to 
extremities; usually spares face, palms, 
soles; evolves from blanchable macules 
to confluent eruption with petechiae; rash 
evanescent in recrudescent typhus 

(Brill-Zinsser disease)
Endemic (murine) typhus
Rickettsia typhi
Maculopapular eruption, usually sparing 
palms, soles
Scrub typhus
Orientia tsutsugamushi
Diffuse macular rash starting on trunk; 
eschar at site of mite bite

GROUP AFFECTED/
EPIDEMIOLOGIC 
FACTORS
CLINICAL SYNDROME
CHAPTER
Nonimmune 
individuals
Cough, conjunctivitis, 
coryza, severe prostration

Nonimmune 
individuals
Adenopathy, arthritis

Most common among 
children 3–12 years 
old; occurs in winter 
and spring
Mild fever; arthritis in 
adults; rash following 
resolution of fever

Usually affects 
children <3 years old
Rash following resolution 
of fever; similar to Boston 
exanthem (echovirus 16); 
febrile seizures may occur

Individuals recently 
infected with HIV
Pharyngitis, adenopathy, 
arthralgias

Adolescents, young 
adults
Hepatosplenomegaly, 
pharyngitis, cervical 
lymphadenopathy, atypical 
lymphocytosis, heterophile 
antibody

Affects children more 
commonly than adults
Nonspecific viral 
syndromes

Occurs 2–3 days 
after exposure in 
previously sensitized 
individuals; 
otherwise, after 
2–3 weeks (but can 
occur anytime, even 
shortly after drug is 
discontinued)
Variable findings: fever 
and eosinophilia

Exposure to body 
lice; occurrence of 
recrudescent typhus 
as relapse after 

30–50 years
Headache, myalgias; 
mortality rates 10–40% 
if untreated; milder 
clinical presentation in 
recrudescent form

Exposure to rat or cat 
fleas
Headache, myalgias

Endemic in South 
Pacific, Australia, 
Asia; transmitted by 
mites
Headache, myalgias, 
regional adenopathy; 
mortality rates up to 30% if 
untreated

(Continued)

(Continued)
TABLE 21-1  Diseases Associated with Fever and Rash
DISEASE
ETIOLOGY
DESCRIPTION
Rickettsial spotted fevers 
(Fig. 21-8)
Rickettsia conorii 
(boutonneuse fever), 
Rickettsia australis 
(North Queensland 
tick typhus), Rickettsia 
sibirica (Siberian tick 
typhus), Rickettsia 
africae (African tick-bite 
fever), and others
Eschar common at bite site; maculopapular 
(rarely, vesicular and petechial) eruption 
on proximal extremities, spreading to trunk 
and face
Human monocytotropic 
ehrlichiosisd
Ehrlichia chaffeensis
Maculopapular eruption (40% of cases), 
involves trunk and extremities; may be 
petechial
Leptospirosis
Leptospira interrogans 
and other Leptospira 
species
Maculopapular eruption; conjunctivitis; 
scleral hemorrhage in some cases
Lyme disease (Fig. A1-8)
Borrelia burgdorferi (sole 
cause in U.S.), Borrelia 
afzelii, Borrelia garinii
Papule expanding to erythematous 

annular lesion with central clearing 
(erythema migrans; average diameter, 

15 cm), sometimes with concentric rings, 
sometimes with indurated or vesicular 
center; multiple secondary erythema 
migrans lesions in some cases
Southern tick-associated 
rash illness (STARI, 
Master’s disease)
Unknown (possibly 
Borrelia lonestari 
or other Borrelia 
spirochetes)
Similar to erythema migrans of Lyme 
disease with several differences, 
including: multiple secondary lesions 
less likely; lesions tending to be smaller 
(average diameter, ~8 cm); central clearing 
more likely
Typhoid fever (Fig. A1-9)
Salmonella typhi
Transient, blanchable erythematous 
macules and papules, 2–4 mm, usually on 
trunk (rose spots)
Dengue fevere (Fig. A1-53)
Dengue virus 

(4 serotypes; flaviviruses)
Rash in 50% of cases; initially diffuse 
flushing; midway through illness, onset of 
maculopapular rash, which begins on trunk 
and spreads centrifugally to extremities 
and face; pruritus, hyperesthesia in some 
cases; after defervescence, petechiae on 
extremities may occur
Rat-bite fever (sodoku)
Spirillum minus
Eschar at bite site; then blotchy violaceous 
or red-brown rash involving trunk and 
extremities
Relapsing fever
Borrelia species
Central rash at end of febrile episode; 
petechiae in some cases
Erythema marginatum 
(rheumatic fever)
Group A Streptococcus
Erythematous annular papules and plaques 
occurring as polycyclic lesions in waves 
over trunk, proximal extremities; evolving 
and resolving within hours
Systemic lupus 
erythematosus (SLE) 

(Fig. A1-10, Fig. A1-11, 

Fig. A1-12)
Autoimmune disease
Macular and papular erythema, often in 
sun-exposed areas; discoid lupus lesions 
(local atrophy, scale, pigmentary changes); 
periungual telangiectasis; malar rash; 
vasculitis sometimes causing urticaria, 
palpable purpura; oral erosions in some 
cases
Still’s disease (Fig. A1-13)
Autoimmune disease
Transient 2- to 5-mm erythematous papules 
appearing at height of fever on trunk, 
proximal extremities; lesions evanescent

GROUP AFFECTED/
EPIDEMIOLOGIC 
FACTORS
CLINICAL SYNDROME
CHAPTER
Exposure to 
ticks; R. conorii 
in Mediterranean 
region, India, Africa; 
R. australis in 
Australia; R. sibirica 
in Siberia, Mongolia; 
R. africae in Africa, 
Caribbean
Headache, myalgias, 
regional adenopathy

Fever and Rash
CHAPTER 21
Tick-borne; most 
common in U.S. 
Southeast, southern 
Midwest, and midAtlantic regions
Headache, myalgias, 
leukopenia

Exposure to water 
contaminated with 
animal urine
Myalgias; aseptic 
meningitis; fulminant form: 
icterohemorrhagic fever 
(Weil’s disease)

Bite of Ixodes tick 
vector
Headache, myalgias, 
chills, photophobia 
occurring acutely; CNS 
disease, myocardial 
disease, arthritis weeks 
to months later in some 
cases

Bite of tick vector 
Amblyomma 
americanum (Lone 
Star tick); often found 
in regions where 
Lyme disease is 
uncommon, including 
southern United 
States
Compared with 
Lyme disease: fewer 
constitutional symptoms, 
tick bite more likely to 
be recalled; other Lyme 
disease sequelae lacking

Ingestion of 
contaminated food or 
water (rare in U.S.)
Variable abdominal 
pain and diarrhea; 
headache, myalgias, 
hepatosplenomegaly

Occurs in tropics 
and subtropics; 
transmitted by 
mosquito
Headache; 
musculoskeletal pain 
(“breakbone fever”); 
leukopenia; occasionally 
biphasic (“saddleback”) 
fever

Rat bite; primarily 
found in Asia; rare 
in U.S.
Regional adenopathy; 
recurrent fevers if 
untreated

Exposure to ticks or 
body lice
Recurrent fever, 
headache, myalgias, 
hepatosplenomegaly

Patients with 
rheumatic fever
Pharyngitis preceding 
polyarthritis, carditis, 
subcutaneous nodules, 
chorea

Most common in 
young to middleaged women; flares 
precipitated by sun 
exposure
Arthritis; cardiac, 
pulmonary, renal, 
hematologic, and 
vasculitic disease

Children and young 
adults
High spiking fever, 
polyarthritis, 
splenomegaly; erythrocyte 
sedimentation rate 

>100 mm/h
—
(Continued)

TABLE 21-1  Diseases Associated with Fever and Rash
(Continued)
DISEASE
ETIOLOGY
DESCRIPTION
African trypanosomiasis 
(Fig. A1-47)
Trypanosoma brucei 
rhodesiense/gambiense
Blotchy or annular erythematous macular 
and papular rash (trypanid), primarily on 
trunk; pruritus; chancre at site of tsetse fly 
bite may precede rash by several weeks
Arcanobacterial 
pharyngitis
Arcanobacterium 
(Corynebacterium) 
haemolyticum
Diffuse, erythematous, maculopapular 
eruption involving trunk and proximal 
extremities; may desquamate
PART 2
Cardinal Manifestations and Presentation of Diseases
West Nile virus infection
West Nile virus
Maculopapular eruption involving the 
trunk, extremities, and head or neck; rash 
in 20–50% of cases
Zika virus infection 

(Fig. A1-51)
Zika virus
Pruritic macular and papular erythema; 
rash may begin on trunk and descend to 
lower body; conjunctival injection; palatal 
petechiae may occur
Peripheral Eruptions
Chronic 
meningococcemia, 
disseminated gonococcal 
infection,a human 
parvovirus B19 infection,f 
RIMEg
—
—
—
—
160, 161, 202
Rocky Mountain spotted 
fever (Fig. 21-2, Fig. A1-16)
Rickettsia rickettsii
Rash beginning on wrists and ankles and 
spreading centripetally; appears on palms 
and soles later in disease; lesion evolution 
from blanchable macules to petechiae
Secondary syphilis 

(Fig. A1-18, Fig. A1-19, 

Fig. A1-20, Fig. A1-21)
Treponema pallidum
Coincident primary chancre in 10% of 
cases; copper-colored, scaly papular 
eruption, diffuse but prominent on palms 
and soles; rash never vesicular in adults; 
condyloma latum, mucous patches, and 
alopecia in some cases
Chikungunya fever 

(Fig. A1-54)
Chikungunya virus
Maculopapular eruption; typically occurs 
on trunk, but also occurs on extremities 
and face
Hand-foot-and-mouth 
disease (Fig. A1-22)
Coxsackievirus A16 
and enterovirus 71 
most common causes; 
coxsackievirus A6 
associated with atypical 
syndrome
Tender vesicles, erosions in mouth; 0.25- to 
1-cm papules on hands and feet with rim 
of erythema evolving into tender vesicles; 
shedding of nails (onychomadesis) can 
occur 1–2 months after acute 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 multiforme (EM) 
(Fig. A1-24)
Infection, drugs, 
idiopathic causes
Target lesions (central erythema 
surrounded by area of clearing and 
another rim of erythema) up to 2 cm; 
symmetric on knees, elbows, palms, soles; 
spreads centripetally; papular, sometimes 
vesicular; when extensive and involving 
mucous membranes, termed EM major

GROUP AFFECTED/
EPIDEMIOLOGIC 
FACTORS
CLINICAL SYNDROME
CHAPTER
Tsetse fly bite in 
eastern (T. brucei 
rhodesiense) or 
western (T. brucei 
gambiense) Africa
Hemolymphatic 
disease followed by 
meningoencephalitis; 
Winterbottom’s sign 
(posterior cervical 
lymphadenopathy) 

(T. brucei gambiense)

Children and young 
adults
Exudative pharyngitis, 
lymphadenopathy

Mosquito bite; rarely, 
blood transfusion or 
transplanted organ
Headache, weakness, 
malaise, myalgia, 
neuroinvasive disease 
(encephalitis, meningitis, 
flaccid paralysis)

Mosquito bite; sexual 
transmission or blood 
transfusion less 
common
Arthralgia (especially 
of small joints), myalgia, 
lymphadenopathy, 
headache, low-grade 
fever; illness in pregnancy 
may cause severe 
birth defects, including 
microcephaly; neurologic 
complications, including 
Guillain-Barré, may occur

Tick vector; 
widespread but 
more common in 
southeastern and 
southwest-central 
U.S.
Headache, myalgias, 
abdominal pain; mortality 
rates up to 40% if 
untreated

Sexually transmitted
Fever, constitutional 
symptoms

Aedes aegypti and A. 
albopictus mosquito 
bites; tropical and 
subtropical regions
Severe polyarticular, 
migratory arthralgias, 
especially involving small 
joints (e.g., hands, wrists, 
ankles)

Summer and fall; 
primarily children 

<10 years old; multiple 
family members; 
coxsackievirus A6 
infection also occurs 
in young adults
Transient fever; 
enterovirus 71 can be 
associated with brainstem 
encephalitis, flaccid 
paralysis resembling polio, 
or aseptic meningitis

Herpes simplex virus 
or Mycoplasma 
pneumoniae infection; 
drug intake (i.e., sulfa, 
phenytoin, penicillin)
50% of patients <20 years 
old; fever more common 
in most severe form, 
EM major, which can be 
confused with StevensJohnson syndrome (but 
EM major lacks prominent 
skin sloughing)
—h
(Continued)

(Continued)
TABLE 21-1  Diseases Associated with Fever and Rash
DISEASE
ETIOLOGY
DESCRIPTION
Rat-bite fever (Haverhill 
fever)
Streptobacillus 
moniliformis
Maculopapular eruption over palms, soles, 
and extremities; tends to be more severe 
at joints; eruption sometimes becoming 
generalized; may be purpuric; may 
desquamate
Bacterial endocarditis 
(Fig. A1-23)
Streptococcus, 
Staphylococcus, etc.
Subacute course (e.g., viridans 
streptococci): Osler’s nodes (tender pink 
nodules 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)
COVID-19 (Fig. A1-57)
SARS-CoV-2
Mild or asymptomatic COVID-19: Pernio 
(macules, papules, or plaques that are 
tender, erythematous/violaceous; acral, 
feet more common than hands). Moderate/
severe COVID-19: Vesicles, urticaria, 
maculopapular erythema; often pruritic; 
occur on trunk, extremities. Severe 

COVID-19: Retiform purpura (net-like, 
purple patches/plaques often with 
necrosis); lesions often asymptomatic; 
occur on extremities, buttocks. 
Multisystem inflammatory syndrome 
in children (MIS-C): Findings similar to 
Kawasaki disease
Confluent Desquamative Erythemas
Scarlet fever (second 
disease) (Fig. A1-25)
Group A Streptococcus 
(pyrogenic exotoxins 

A, B, C)
Diffuse blanchable erythema beginning 
on face and spreading to trunk 
and extremities; circumoral 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
Kawasaki disease 

(Fig. A1-29)
Idiopathic
Rash similar to scarlet fever 
(scarlatiniform) or EM; fissuring of lips, 
strawberry tongue; conjunctivitis; edema 
of hands, feet; desquamation later in 
disease
Streptococcal toxic shock 
syndrome
Group A Streptococcus 
(associated with 
pyrogenic exotoxin A 
and/or B or certain 

M types)
When present, rash often scarlatiniform
May occur in setting 
of severe group 
A streptococcal 
infections (e.g., 
necrotizing fasciitis, 
bacteremia, 
pneumonia)
Staphylococcal toxic 
shock syndrome
S. aureus (toxic shock 
syndrome toxin 1, 
enterotoxins B and 
others)
Diffuse erythema involving palms; 
pronounced erythema of mucosal 
surfaces; conjunctivitis; desquamation 
7–10 days into illness
Staphylococcal scaldedskin syndrome (Fig. A1-28)
S. aureus, phage group II
Diffuse tender erythema, often with bullae 
and desquamation; Nikolsky’s sign
Exfoliative erythroderma 
syndrome (Fig. A1-27)
Underlying psoriasis, 
eczema, drug eruption, 
mycosis fungoides
Diffuse erythema (often scaling) 
interspersed with lesions of underlying 
condition

GROUP AFFECTED/
EPIDEMIOLOGIC 
FACTORS
CLINICAL SYNDROME
CHAPTER
Rat bite, ingestion of 
contaminated food
Myalgias; arthritis (50%); 
fever recurrence in some 
cases

Abnormal heart 
valve (e.g., viridans 
streptococci), 
intravenous drug use
New or changing heart 
murmur

Fever and Rash
CHAPTER 21
Infection with SARSCoV-2; MIS-C in older 
children/adolescents
Ranging from 
asymptomatic to mild/
moderate with loss of 
taste/smell, pharyngitis, 
cough, fever, to severe 
with dyspnea, ARDS; 
complications include 
thrombosis, especially 
with retiform purpura; 
lesions may be delayed 
compared to other 
COVID-19 symptoms; 
MIS-C occurs ~2-6 weeks 
following acute (often 
asymptomatic) infection
 
Most common among 
children 2–10 years 
old; usually follows 
group A streptococcal 
pharyngitis
Fever, pharyngitis, 
headache

Children <8 years old
Cervical adenopathy, 
pharyngitis, coronary 
artery vasculitis
61, 375
Multiorgan failure, 
hypotension; mortality 
rate 30%

Colonization with 
toxin-producing 

S. aureus
Fever >39°C (>102°F), 
hypotension, multiorgan 
dysfunction

Colonization with 
toxin-producing 

S. aureus; occurs in 
children <10 years 
old (termed Ritter’s 
disease in neonates) 
or adults with renal 
dysfunction
Irritability; nasal or 
conjunctival secretions

Usually occurs in 
adults over age 50; 
more common among 
men
Fever, chills (i.e., difficulty 
with thermoregulation); 
lymphadenopathy
61, 63
(Continued)

TABLE 21-1  Diseases Associated with Fever and Rash
(Continued)
DISEASE
ETIOLOGY
DESCRIPTION
DRESS (drug reaction 
with eosinophilia and 
systemic symptoms; also 
known as drug-induced 
hypersensitivity syndrome 
[DIHS]) (Fig. A1-48)
Aromatic 
anticonvulsants; 
other drugs, including 
sulfonamides, 
minocycline
Maculopapular eruption (mimicking 
exanthematous drug rash), sometimes 
progressing to exfoliative erythroderma; 
profound edema, especially facial; 
pustules may occur
PART 2
Cardinal Manifestations and Presentation of Diseases
Stevens-Johnson 
syndrome (SJS), toxic 
epidermal necrolysis 
(TEN) (Fig. 21-3, 

Fig. A1-26)
Drugs (80% of cases; 
often allopurinol, 
anticonvulsants, 
antibiotics), infection, 
idiopathic factors
Erythematous and purpuric macules, 
sometimes targetoid, or diffuse erythema 
progressing to bullae, with sloughing and 
necrosis of entire epidermis; 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 epidermis
Vesiculobullous or Pustular Eruptions
Hand-foot-andmouth syndromec; 
staphylococcal scaldedskin syndromeb; TENb; 
DRESS/DIHSb; COVID-19c
—
—
—
—
—h
Varicella (chickenpox) 
(Fig. 21-4, Fig. A1-30)
Varicella-zoster virus 
(VZV)
Macules (2–3 mm) evolving into papules, 
then vesicles (sometimes umbilicated), 
on an erythematous base (“dewdrops on 
a rose petal”); pustules then forming and 
crusting; lesions appearing in crops; may 
involve scalp, mouth; intensely pruritic
Pseudomonas “hot-tub” 
folliculitis (Fig. A1-55)
Pseudomonas 
aeruginosa
Pruritic erythematous follicular, papular, 
vesicular, or pustular lesions that may 
involve axillae, buttocks, abdomen, and 
especially areas occluded by bathing 
suits; can manifest as tender isolated 
nodules on palmar or plantar surfaces (the 
latter designated “Pseudomonas hot-foot 
syndrome”)
Variola (smallpox) 

(Fig. A1-50)
Variola major virus
Red macules on tongue and palate 
evolving to papules and vesicles; skin 
macules evolving to papules, then 
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 
extremities (including palms, soles)
Mpox
(Fig. A1-59)
Monkeypox virus
Classically, lesions similar in morphology 
and distribution to those of variola 
(smallpox); 2022 outbreak: macules evolve 
to papules, vesicles, and pustules, with 
subsequent crusting over 1–2 weeks; 
often umbilicated; unlike traditional Mpox, 
lesions may be in different stages of 
development and typically number fewer 
than 20; lesions often painful; mucosal 
lesions (anorectal, oropharyngeal, 
ocular) may occur at sites of inoculation; 
disease may be severe and progressive in 
advanced HIV

GROUP AFFECTED/
EPIDEMIOLOGIC 
FACTORS
CLINICAL SYNDROME
CHAPTER
Individuals 
genetically unable to 
detoxify arene oxides 
(anticonvulsant 
metabolites), 
patients with slow 
N-acetylating 
capacity 
(sulfonamides)
Lymphadenopathy, 
multiorgan failure 
(especially hepatic), 
eosinophilia, atypical 
lymphocytes; HHV6 
viremia; mimics sepsis

Uncommon among 
children; more 
common among 
people living with 
HIV systemic lupus 
erythematosus, 
certain HLA types, or 
slow acetylators
Dehydration, sepsis 
sometimes resulting 
from lack of normal skin 
integrity; mortality rates 
up to 30%

Usually affects 
children; 10% of 
adults susceptible; 
most common in late 
winter and spring; 
incidence down 
by 90% in U.S. as a 
result of varicella 
vaccination
Malaise; generally 
mild disease in 
healthy children; more 
severe disease with 
complications in adults 
and immunocompromised 
children

Bathers in hot tubs 
or swimming pools; 
occurs in outbreaks
Earache, sore eyes and/
or throat; fever may 
be absent; generally 
self-limited

Nonimmune 
individuals exposed to 
smallpox
Prodrome of fever, 
headache, backache, 
myalgias; vomiting in 50% 
of cases
S4
Nonimmune 
individuals exposed 
to monkeypox; virus 
endemic to Central 
and West Africa; 
2022 outbreak: 
among nonendemic 
countries including 
Europe, U.S.; most 
cases in men who 
have sex with men
Classically, similar to 
smallpox, though with 
lymphadenopathy 
and typically milder; 
2022 outbreak: fever, 
lymphadenopathy, 
headache, proctitis, or 
pharyngitis

(Continued)

(Continued)
TABLE 21-1  Diseases Associated with Fever and Rash
DISEASE
ETIOLOGY
DESCRIPTION
Primary herpes simplex 
virus (HSV) infection
(Fig. A1-58)
HSV
Erythema rapidly followed by hallmark 
painful grouped vesicles that may evolve 
into pustules that ulcerate, especially 
on mucosal surfaces; lesions at site of 
inoculation: commonly gingivostomatitis 
for HSV-1 and genital lesions for HSV-2; 
recurrent disease milder (e.g., herpes 
labialis typically does not involve oral 
mucosa)
Disseminated herpesvirus 
infection (Fig. A1-31, 

Fig. A1-58D)
VZV or HSV
Generalized nongrouped vesicles that 
can evolve to pustules and ulcerations; 
individual lesions similar for VZV and 
HSV. Zoster cutaneous dissemination: 
>25 lesions extending outside involved 
dermatome. HSV: extensive, progressive 
mucocutaneous lesions may occur in 
absence of dissemination; HSV may 
disseminate in eczematous skin (eczema 
herpeticum); HSV visceral dissemination 
may occur with only localized 
mucocutaneous disease; in disseminated 
HSV neonatal disease, skin lesions 
diagnostically helpful when present, but 
rash absent in a substantial minority of 
cases
Rickettsialpox
(Fig. A1-33)
Rickettsia akari
Eschar found at site of mite bite; 
generalized rash involving face, trunk, 
extremities; may involve palms and soles; 
<100 papules and plaques (2–10 mm); 
centers of papules develop vesicles or 
pustules
Acute generalized 
exanthematous pustulosis 
(Fig. A1-49)
Drugs (mostly 
anticonvulsants or 
antimicrobials); also viral
Tiny, sterile, nonfollicular pustules on 
erythematous, edematous skin; begins 
on face and in body folds, then becomes 
generalized
Disseminated Vibrio 
vulnificus infection
V. vulnificus
Erythematous lesions evolving into 
hemorrhagic bullae and then into necrotic 
ulcers
Ecthyma gangrenosum 
(Fig. A1-34)
P. aeruginosa, other 
gram-negative rods, fungi
Indurated plaque evolving into 
hemorrhagic bulla or pustule that 
sloughs, resulting in eschar formation; 
erythematous halo; most common in 
axillary, groin, perianal regions
Reactive infectious 
mucocutaneous 
eruption (RIME) (this 
generalized term 
encompasses multiple 
infectious etiologies, and 
includes Mycoplasma 
pneumoniae–induced 
rash and mucositis 
[MIRM])
M. pneumoniae, 
Chlamydia pneumoniae, 
human metapneumovirus, 
parainfluenzavirus 2, 
rhinovirus, influenza B 
virus, SARS-CoV-2
Severe mucositis of at least two sites 
(e.g., oropharynx, ocular, genital) with 
nearly universal hemorrhagic crusting of 
lips; sparse, vesiculobullous, or atypical 
targetoid rash over <10% of body; lesions 
typically on extremities but can be truncal; 
rash sometimes absent
Urticaria-Like Eruptions
COVID-19c
 
 
 
 
 
Urticarial vasculitis 

(Fig. 21-5, Fig. A1-35)
Serum sickness, 
often due to infection 
(including acute hepatitis 
B, enteroviral, parasitic), 
drugs; connective tissue 
disease
Erythematous, edematous “urticarialike” plaques, pruritic or burning; unlike 
urticaria: typical lesion duration >24 h (up 
to 5 days) and lack of complete lesion 
blanching with compression due to 
hemorrhage

GROUP AFFECTED/
EPIDEMIOLOGIC 
FACTORS
CLINICAL SYNDROME
CHAPTER
Primary infection 
most common among 
children and young 
adults for HSV-1 
and among sexually 
active young adults 
for HSV-2; no fever in 
recurrent infection
Regional 
lymphadenopathy

Fever and Rash
CHAPTER 21
Patients with 
immunosuppression, 
eczema; neonates
Visceral organ 
involvement (e.g., liver, 
lungs) in some cases; 
neonatal disease 
particularly severe
143, 197, 198
Seen in urban 
settings; transmitted 
by mouse mites
Headache, myalgias, 
regional adenopathy; mild 
disease

Appears 2–21 days 
after start of drug 
therapy, depending on 
whether patient has 
been sensitized
Acute fever, pruritus, 
leukocytosis

Patients with 
cirrhosis, diabetes, 
renal failure; 
exposure by ingestion 
of contaminated 
saltwater, seafood
Hypotension; mortality 
rate 50%

Usually affects 
neutropenic patients; 
occurs in up to 
28% of individuals 
with Pseudomonas 
bacteremia
Clinical signs of sepsis

More common 
in males; usually 
children (mean age 
11–12 years old)
Cough, respiratory 
infection symptoms often 
precede rash by ~1 week, 
good prognosis; distinct 
from SJS/TEN
Patients with serum 
sickness (including 
acute hepatitis B), 
connective tissue 
disease
Fever variable; arthralgias/
arthritis
375h
(Continued)

TABLE 21-1  Diseases Associated with Fever and Rash
(Continued)
DISEASE
ETIOLOGY
DESCRIPTION
Nodular Eruptions
Disseminated infection 
(Fig. 21-6, Fig. A1-36, 

Fig. A1-37, Fig. A1-38)
Fungal infections 
(e.g., candidiasis, 
histoplasmosis, 
cryptococcosis, 
sporotrichosis, 
coccidioidomycosis); 
mycobacteria
Subcutaneous nodules (up to 3 cm); 
fluctuance, draining common with 
mycobacteria; necrotic nodules 
(extremities, periorbital or nasal regions) 
common with Aspergillus, Mucor
PART 2
Cardinal Manifestations and Presentation of Diseases
Erythema nodosum 
(septal panniculitis) 

(Fig. A1-39)
Infections (e.g., 
streptococcal, fungal, 
mycobacterial, 
yersinial); drugs (e.g., 
sulfas, penicillins, 
oral contraceptives); 
sarcoidosis; idiopathic 
causes
Large, violaceous, nonulcerative, 
subcutaneous nodules; exquisitely tender; 
usually on lower legs but also on upper 
extremities
Sweet syndrome (acute 
febrile neutrophilic 
dermatosis) (Fig. A1-40)
Yersinia infection; upper 
respiratory infection; 
inflammatory bowel 
disease; pregnancy; 
malignancy (usually 
hematologic); drugs 
(G-CSF)
Tender red or blue edematous nodules 
giving impression of vesiculation; usually 
on face, neck, upper extremities; when on 
lower extremities, may mimic erythema 
nodosum
Bacillary angiomatosis
Bartonella henselae, 

B. quintana
Many forms, including erythematous, 
smooth vascular nodules; friable, 
exophytic lesions; erythematous plaques 
(may be dry, scaly); subcutaneous nodules 
(may be erythematous)
Purpuric Eruptions
Rocky Mountain spotted 
fever, rat-bite fever, 
endocarditisc; epidemic 
typhusf; dengue fevere,f; 
human parvovirus B19 
infectionf; COVID-19c
—
—
—
—
—h
Acute meningococcemia
Neisseria meningitidis
Initially pink maculopapular lesions 
evolving into petechiae; petechiae rapidly 
becoming numerous, sometimes enlarging 
and becoming vesicular; trunk, extremities 
most commonly involved; may appear on 
face, hands, feet; may include purpura 
fulminans (see below) reflecting DIC
Purpura fulminans 

(Fig. A1-41)
Severe DIC
Large ecchymoses with sharply irregular 
shapes evolving into hemorrhagic bullae 
and then into black necrotic lesions
Chronic 
meningococcemia 

(Fig. A1-42)
N. meningitidis
Variety of recurrent eruptions, including 
pink maculopapular; nodular (usually on 
lower extremities); petechial (sometimes 
developing vesicular centers); purpuric 
areas with pale blue-gray centers
Disseminated gonococcal 
infection (Fig. A1-43)
Neisseria gonorrhoeae
Papules (1–5 mm) evolving over 1–2 days 
into hemorrhagic pustules with gray 
necrotic centers; hemorrhagic bullae 
occurring rarely; lesions (usually <40) 
distributed peripherally near joints (more 
commonly on upper extremities)
Enteroviral petechial rash
Usually echovirus 9 or 
coxsackievirus A9
Disseminated petechial lesions (may also 
be maculopapular, vesicular, or urticarial)
Viral hemorrhagic fever
Arenaviruses, 
bunyaviruses, filoviruses 
(including Ebola), 
flaviviruses (including 
dengue)
Petechial rash
Residence in or travel 
to endemic areas, 
other virus exposure

GROUP AFFECTED/
EPIDEMIOLOGIC 
FACTORS
CLINICAL SYNDROME
CHAPTER
Immunocompromised 
hosts (e.g., bone 
marrow transplant 
recipients, patients 
undergoing 
chemotherapy, HIVinfected patients)
Features vary with 
organism
—h
More common among 
females 15–30 years 
old
Arthralgias (50%); features 
vary with associated 
condition
—h
More common among 
women and among 
persons 30–60 years 
old; 20% of cases 
associated with 
malignancy (men 
and women equally 
affected in this group)
Headache, arthralgias, 
leukocytosis

Immunosuppressed 
individuals, especially 
those with advanced 
HIV infection
Peliosis of liver and 
spleen in some cases; 
lesions sometimes 
involving multiple organs; 
bacteremia

Most common among 
children, individuals 
with asplenia or 
terminal complement 
component deficiency 
(C5–C8)
Hypotension, meningitis 
(sometimes preceded 
by upper respiratory 
infection)

Individuals with 
sepsis (e.g., involving 
N. meningitidis), 
malignancy, or 
massive trauma; 
asplenic patients at 
high risk for sepsis
Hypotension
160, 315
Individuals with 
complement 
deficiencies
Fevers, sometimes 
intermittent; arthritis, 
myalgias, headache

Sexually active 
individuals (more 
often females), some 
with complement 
deficiency
Low-grade fever, 
tenosynovitis, arthritis

Often occurs in 
outbreaks
Pharyngitis, headache; 
aseptic meningitis with 
echovirus 9

Triad of fever, shock, 
hemorrhage from mucosa 
or gastrointestinal tract
215, 216
(Continued)

(Continued)
TABLE 21-1  Diseases Associated with Fever and Rash
DISEASE
ETIOLOGY
DESCRIPTION
Thrombotic 
thrombocytopenic 
purpura/hemolytic-uremic 
syndrome
Idiopathic, bloody 
diarrhea caused 
by Shiga toxin–
generating bacteria 
(e.g., Escherichia coli 
O157:H7), deficiency in 
ADAMTS13 (cleaves 
von Willebrand factor), 
drugs (e.g., quinine, 
chemotherapy, 
immunosuppression)
Petechiae
Individuals with 
Shiga toxin producing 
bacterial (commonly 
E. coli O157:H7) 
gastroenteritis 
(especially children), 
cancer chemotherapy, 
HIV infection, 
autoimmune diseases, 
pregnant/postpartum 
women, those with 
ADAMTS13 deficiency
Cutaneous smallvessel vasculitis 
(leukocytoclastic 
vasculitis) (Fig. 21-7, 

Fig. A1-44)
Infections (including 
group A streptococcal 
infection, hepatitis B 
or C), drugs, idiopathic 
factors
Palpable purpuric lesions appearing in 
crops on legs or other dependent areas; 
may become vesicular or ulcerative
Eruptions with Ulcers and/or Eschars
Scrub typhus, rickettsial 
spotted fevers, ratbite fever, African 
trypanosomiasisf; 
rickettsialpox, ecthyma 
gangrenosumg
—
—
—
—
—h
Tularemia (Fig. A1-45, 

Fig. A1-46)
Francisella tularensis
Ulceroglandular form: erythematous, 
tender papule 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. A1-52)
Bacillus anthracis
Pruritic papule enlarging and evolving into 
a 1- by 3-cm painless ulcer surrounded 
by vesicles and then developing a central 
eschar with edema; residual scar
aSee “Purpuric Eruptions.” bSee “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). eSee “Viral hemorrhagic fever” under “Purpuric 
Eruptions” for dengue hemorrhagic fever/dengue shock syndrome. fSee “Centrally Distributed Maculopapular Eruptions.” gSee “Vesiculobullous or Pustular Eruptions.” 
hSee etiology-specific chapters.
Abbreviations: ARDS, acute respiratory distress syndrome; CNS, central nervous system; DIC, disseminated intravascular coagulation; G-CSF, granulocyte colonystimulating factor; HLA, human leukocyte antigen.
Chapter 208) may exhibit pharyngitis, lymphadenopathy, and a non­
specific 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. A1-1A) with perioral pallor 
(Chap. 202). 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. A1-1B) 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 condi­
tion 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. 200). As in erythema 
infectiosum, the rash usually appears after fever has subsided. It con­
sists of 2- to 3-mm rose-pink macules and papules that coalesce only 
rarely, occur initially on the trunk (Fig. A1-5) and sometimes on the 
extremities (sparing the face), and fade within 2 days.
Although drug reactions have many manifestations, including urti­
caria, exanthematous drug-induced eruptions (Chap. 63) (Fig. A1-7) 
are most common and are often difficult to distinguish from viral 

GROUP AFFECTED/
EPIDEMIOLOGIC 
FACTORS
CLINICAL SYNDROME
CHAPTER
Fever (not 
always present), 
microangiopathic 
hemolytic anemia, 
thrombocytopenia, renal 
dysfunction, neurologic 
dysfunction; coagulation 
studies normal
61, 105, 120, 
166, 172
Fever and Rash
CHAPTER 21
Occurs in a wide 
spectrum of diseases, 
including connective 
tissue disease, 
cryoglobulinemia, 
malignancy, HenochSchönlein purpura 
(HSP); more common 
among children
Fever (not always 
present), malaise, 
arthralgias, myalgias; 
systemic vasculitis in 
some cases; renal, joint, 
and gastrointestinal 
involvement common in 
HSP

Exposure to ticks, 
biting flies, infected 
animals
Fever, headache, 
lymphadenopathy

Exposure to infected 
animals or animal 
products, other 
exposure to anthrax 
spores
Lymphadenopathy, 
headache
S4
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 prostra­
tion may help to distinguish a drug-related rash from an eruption of 
another etiology. Rashes may persist for up to 2 weeks after admin­
istration of the offending agent is discontinued. Certain populations 
are more prone than others to drug rashes. Of people living with HIV, 
50–60% develop a rash in response to sulfa drugs.
Rickettsial illnesses (Chap. 192) should be considered in the evalua­
tion 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. 189) may be seen in urban 
environments where rodents proliferate. Outside the United States, other 
rickettsial diseases cause a spotted-fever syndrome and should be consid­
ered in residents of or travelers to endemic areas. Similarly, typhoid fever, 
a nonrickettsial disease caused by Salmonella typhi (Chap. 171) 
(Fig. A1-9), is usually acquired during travel outside the United States. 
Dengue fever (Fig. A1-53), caused by a mosquito-transmitted flavivirus, 
occurs in tropical and subtropical regions of the world (Chap. 215).
Some centrally distributed maculopapular eruptions have distinc­
tive features. Erythema migrans (Fig. A1-8), the rash of Lyme disease

PART 2
Cardinal Manifestations and Presentation of Diseases
FIGURE 21-1  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, McGraw-Hill, 2019, 
p. 797, Figure 132-2. Reproduced with permission from Richard P. Usatine, MD.)
(Chap. 191), 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 tick-associated rash illness 
(STARI) (Chap. 191) 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. 371), has a distinctive pattern of enlarging and shifting tran­
sient annular lesions.
Collagen vascular diseases may cause fever and rash. Patients with 
systemic lupus erythematosus (Chap. 368) typically develop a sharply 
defined, erythematous eruption in a butterfly distribution on the 
cheeks (malar rash) (Fig. A1-10) as well as many other skin manifes­
tations (Figs. A1-11, A1-12). Still’s disease presents as an evanescent, 
salmon-colored rash on the trunk and proximal extremities that coin­
cides with fever spikes (Fig. A1-13).
Hemophagocytic lymphohistiocytosis may be familial or triggered 
by infection, autoimmunity, or neoplasia. Cutaneous manifestations 
are protean and can present as an erythematous maculopapular erup­
tion, pyoderma gangrenosum, purpura, panniculitis, or Stevens-Johnson 
syndrome.
Zika virus is a mosquito-transmitted flavivirus that is associated 
with severe birth defects (Chap. 215). Zika is widespread among tropi­
cal and subtropical regions of the world. The eruption of Zika virus 
infection (Fig. A1-51A, A1-51B) is typically pruritic and often accom­
panied by conjunctival injection (Fig. A1-51C).
■
■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. 192) because of its grave prognosis if untreated. Lesions 
(Fig. 21-2; see also Fig. A1-16) 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. 187), which may be generalized (Fig. A1-18) but is prominent 
on the palms and soles (Fig. A1-19), should be considered in the differ­
ential diagnosis of pityriasis rosea, especially in sexually active patients. 

FIGURE 21-2  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, McGraw-Hill, 2017, p. 562, Figure 
25-50; with permission.)
Chikungunya fever (Chap. 215), which is transmitted by mosquito bite 
in tropical and subtropical regions, is associated with a maculopapular 
eruption (Fig. A1-54) and severe polyarticular small-joint arthralgias. 
Hand-foot-and-mouth disease (Chap. 210), 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. A1-22); 
coxsackievirus A6 causes an atypical syndrome with more extensive 
lesions. The classic target lesions of erythema multiforme (Fig. A1-24A) 
appear symmetrically on the elbows, knees, palms, soles, and face. 
In severe cases, these lesions spread diffusely and involve mucosal 
surfaces (Fig. A1-24B, C). Lesions may develop on the hands and feet 
in endocarditis (Fig. A1-23) (Chap. 133). Pernio, tender violaceous 
lesions that are acral (Fig. A1-57), occur most commonly on the feet in 
asymptomatic or mild COVID-19. Vesicles, urticaria, or maculopapu­
lar eruptions, often pruritic, may occur on the trunk and extremities 
in moderate or severe disease, whereas retiform purpura occurs on the 
extremities and buttocks in severe COVID-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. 153) 
(Fig. A1-25) usually follows pharyngitis; patients have a facial flush, a 
“strawberry” tongue, and accentuated petechiae in body folds (Pastia’s 
lines). Kawasaki disease (Fig. A1-29) (Chaps. 61 and 375) presents in 
the pediatric population as fissuring of the lips, a strawberry tongue, 
conjunctivitis, adenopathy, and sometimes cardiac abnormalities. 
Streptococcal toxic shock syndrome (Chap. 153) manifests with hypo­
tension, multiorgan failure, and, often, a severe group A streptococ­
cal infection (e.g., necrotizing fasciitis). Staphylococcal toxic shock 
syndrome (Chap. 152) 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 
(Fig. A1-28) (Chap. 152) is seen primarily in children and in immu­
nocompromised 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 bul­
lae with light lateral pressure (Nikolsky’s sign) (Fig. A1-28B). In a mild 
form, a scarlatiniform eruption mimics scarlet fever, but the patient

FIGURE 21-3  Confluent desquamation in a patient with toxic epidermal necrolysis. 
(From KS-M Kane et al: Color Atlas & Synopsis of Pediatric Dermatology, 3rd ed. 
New York, McGraw Hill, 2017, Figure 15-6; with permission.)
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 (Chap. 63), 
a maximal variant of Stevens-Johnson syndrome, involves sloughing 
of the entire epidermis (Fig. 21-3, see also Fig. A1-26), resulting in 
severe disease. Exfoliative erythroderma syndrome (Chaps. 61 and 63) is a 
serious reaction associated with systemic toxicity that is often due to 
eczema, psoriasis (Fig. A1-27), a drug reaction, or mycosis fungoides. 
Drug reaction with eosinophilia and systemic symptoms (DRESS) (also 
termed drug-induced hypersensitivity syndrome [DIHS]), often due to 
antiepileptic or antibiotic agents (Chap. 63), initially appears similar 
to an exanthematous drug reaction (Fig. A1-48) but may progress to 
exfoliative erythroderma; it is accompanied by multiorgan failure and 
has an associated mortality rate of ~10%.
■
■VESICULOBULLOUS OR PUSTULAR ERUPTIONS
Varicella (Chap. 198) 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. 21-4; see also Fig. A1-30). In immunocompromised 
FIGURE 21-4  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, McGraw-Hill, 2017, p. 695, Figure 27-48; with 
permission.)

hosts, varicella vesicles may lack the characteristic erythematous base 
or may appear hemorrhagic. Lesions of Pseudomonas “hot-tub” folliculi­
tis (Chap. 170) are also pruritic and may appear similar to those of 
varicella (Fig. A1-55). 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. S4) also appear similar to those of varicella but are all at the same 
stage of development in a given region of the body (Figs. A1-50B and 
A1-50C). Variola lesions are most prominent on the face (Fig. 
A1-50A) and extremities, while varicella lesions are most promi­
nent on the trunk. Mpox, endemic to Africa, can present similarly 
to variola, although with lower mortality. A 2022 Mpox outbreak in 
nonendemic nations was characterized by presence of fewer lesions 
(Fig. A1-59) and milder disease. Herpes simplex virus infection (Chap. 
197) is characterized by hallmark grouped vesicles on an erythematous 
base. Primary herpes infection (Fig. A1-58A, B) is accompanied by 
fever and toxicity, while recurrent disease (Fig. A1-58C) is milder. 
Rickettsialpox (Chap. 192) is often documented in urban settings 
and is characterized by vesicles followed by pustules (Figs. A1-33B, 
A1-33C). It can be distinguished from varicella by an eschar at the site 
of the mouse-mite bite (Fig. A1-33A) and the papule/plaque base of 
each vesicle. Acute generalized exanthematous pustulosis (Fig. A1-49) 
should be considered in individuals who are acutely febrile and are 
taking new medications, especially anticonvulsant or antimicrobial 
agents (Chap. 63). Disseminated Vibrio vulnificus infection (Chap. 173) 
or ecthyma gangrenosum due to Pseudomonas aeruginosa (Fig. A1-34) 
(Chap. 170) should be considered in immunosuppressed individuals 
with sepsis and hemorrhagic bullae. In children, reactive infectious 
mucocutaneous eruption (RIME, encompasses MIRM) can occur with 
Mycoplasma pneumoniae or other respiratory pathogen infection 

(Fig. A1-56) and is characterized by a sparse, often vesiculobullous 
eruption with prominent oral, ocular, or urogenital mucositis.

Fever and Rash
CHAPTER 21
■
■URTICARIA-LIKE ERUPTIONS
Individuals with classic urticaria (“hives”) (Fig. 21-5; see also Fig. A1-35) 
usually have a hypersensitivity reaction without associated fever. In the 
presence of fever, urticaria-like eruptions are most often due to urticarial 
vasculitis (Chap. 375). 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 
FIGURE 21-5  Urticarial eruption. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas 
and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw-Hill, 2017, p. 299, 
Figure 14-2; with permission.)

barbiturates), connective-tissue disease (e.g., systemic lupus erythema­
tosus 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. 61).

■
■NODULAR ERUPTIONS
In immunocompromised hosts, nodular lesions often represent dis­
seminated infection. Patients with disseminated candidiasis (Fig. A1-37) 
(often due to Candida tropicalis) may have a triad of fever, myalgias, 
and eruptive nodules (Chap. 222). Disseminated cryptococcosis lesions 
(Fig. 21-6; see also Fig. A1-36) (Chap. 221) may resemble molluscum 
contagiosum (Chap. 201). Necrosis of nodules should raise the sus­
picion of aspergillosis (Fig. A1-38) (Chap. 223) or mucormycosis 
(Chap. 224). Erythema nodosum presents with exquisitely tender 
nodules on the lower extremities (Fig. A1-39). Sweet syndrome 
(Chap. 61) should be considered in individuals with multiple nod­
ules and plaques, often so edematous (Fig. A1-40) that they give the 
appearance of vesicles or bullae. Sweet syndrome may occur in indi­
viduals with infection, inflammatory bowel disease, or malignancy and 
can also be induced by drugs.
PART 2
Cardinal Manifestations and Presentation of Diseases
■
■PURPURIC ERUPTIONS
Acute meningococcemia (Chap. 160) classically presents in children as 
a petechial eruption, but initial lesions may appear as blanchable mac­
ules or urticaria. Rocky Mountain spotted fever should be considered 
in the differential diagnosis of acute meningococcemia. Echovirus 9 
infection (Chap. 210) may mimic acute meningococcemia; patients 
should be treated as if they have bacterial sepsis because prompt dif­
ferentiation of these conditions may be impossible. Large ecchymotic 
areas of purpura fulminans (Fig. A1-41) (Chaps. 160 and 315) reflect 
severe underlying disseminated intravascular coagulation, which may 
be due to infectious or noninfectious causes. The lesions of chronic 
meningococcemia (Fig. A1-42) (Chap. 160) may have a variety of 
morphologies, including petechial. Purpuric nodules may develop on 
the legs and resemble erythema nodosum but lack its exquisite tender­
ness. Lesions of disseminated gonococcemia (Chap. 161) are distinctive, 
sparse, countable hemorrhagic pustules (Fig. A1-43), usually located 
near joints. The lesions of chronic meningococcemia and those of 
gonococcemia may be indistinguishable in terms of appearance and 
FIGURE 21-6  Nodular eruption on the face due to disseminated Cryptococcus in 
a patient living with HIV. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and 
Synopsis of Clinical Dermatology, 8th ed. New York, McGraw-Hill, 2017, p. 641, Figure 
26-57. Used with permission from Loïc Vallant, MD.)

FIGURE 21-7  Purpuric lesions of cutaneous small vessel vasculitis in a patient 
with Henoch-Schonlein purpura. (Courtesy of Peter Lio, MD; with permission)
distribution. Viral hemorrhagic fever (Chaps. 215 and 216) should be 
considered in patients with an appropriate travel history and a pete­
chial rash. Thrombotic thrombocytopenic purpura (Chaps. 61, 105, 
and 120) and hemolytic-uremic syndrome (Chaps. 120, 166, and 172) 
are closely related and are noninfectious causes of fever and petechiae. 
Cutaneous small-vessel vasculitis (leukocytoclastic vasculitis) typically 
manifests as palpable purpura (Fig. 21-7, see also Fig. A1-44) and has 
a wide variety of causes (Chap. 61).
■
■ERUPTIONS WITH ULCERS OR ESCHARS
The presence of an ulcer or eschar (Fig. 21-8) in the setting of a more 
widespread eruption can provide an important diagnostic clue. For 
FIGURE 21-8  Eschar with surrounding erythema at the site of a tick bite in a patient 
with African tick-bite fever. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and 
Synopsis of Clinical Dermatology, 8th ed. New York, McGraw-Hill, 2017, p. 561, Figure 
25-49; with permission.)