134 PART 2 Cardinal Manifestations and Presentation of Diseases

TABLE 19-1 Diseases Associated with Fever and Rash

DISEASE ETIOLOGY DESCRIPTION

GROUP AFFECTED/

EPIDEMIOLOGIC

FACTORS CLINICAL SYNDROME CHAPTER

Centrally Distributed Maculopapular Eruptions

Acute meningococcemiaa — — — — 155

Drug reaction with

eosinophilia and systemic

symptoms (DRESS); also

termed drug-induced

hypersensitivity syndrome

(DIHS)b

; Chikungunyac

;

COVID-19c

— — — — 60

Rubeola (measles, first

disease) (Fig. 19-1,

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

Nonimmune individuals Cough, conjunctivitis,

coryza, severe

prostration

205

Rubella (German measles,

third disease)

(Fig. A1-4)

Togavirus Spreads from hairline downward, clearing as

it spreads; Forchheimer spots

Nonimmune individuals Adenopathy, arthritis 206

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

Most common among

children 3–12 years old;

occurs in winter and

spring

Mild fever; arthritis in

adults; rash following

resolution of fever

197

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

Usually affects children

<3 years old

Rash following

resolution of fever;

similar to Boston

exanthem (echovirus

16); febrile seizures may

occur

195

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

Individuals recently

infected with HIV

Pharyngitis, adenopathy,

arthralgias

202

Infectious mononucleosis Epstein-Barr virus Diffuse maculopapular eruption (5% of

cases; 30–90% if ampicillin is given);

urticaria, petechiae in some cases;

periorbital edema (50%); palatal petechiae

(25%)

Adolescents, young

adults

Hepatosplenomegaly,

pharyngitis, cervical

lymphadenopathy,

atypical lymphocytosis,

heterophile antibody

194

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

Affect children more

commonly than adults

Nonspecific viral

syndromes

204

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

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

60

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)

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

187

Endemic (murine) typhus Rickettsia typhi Maculopapular eruption, usually sparing

palms, soles

Exposure to rat or cat

fleas

Headache, myalgias 187

Scrub typhus Orientia tsutsugamushi Diffuse macular rash starting on trunk;

eschar at site of mite bite

Endemic in South

Pacific, Australia, Asia;

transmitted by mites

Headache, myalgias,

regional adenopathy;

mortality rates up to

30% if untreated

187

Rickettsial spotted fevers

(Fig. 19-8)

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

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

187

(Continued)

135 Fever and Rash CHAPTER 19

TABLE 19-1 Diseases Associated with Fever and Rash

DISEASE ETIOLOGY DESCRIPTION

GROUP AFFECTED/

EPIDEMIOLOGIC

FACTORS CLINICAL SYNDROME CHAPTER

Human monocytotropic

ehrlichiosisd

Ehrlichia chaffeensis Maculopapular eruption (40% of cases),

involves trunk and extremities; may be

petechial

Tick-borne; most

common in U.S.

Southeast, southern

Midwest, and midAtlantic regions

Headache, myalgias,

leukopenia

187

Leptospirosis Leptospira interrogans

and other Leptospira

species

Maculopapular eruption; conjunctivitis;

scleral hemorrhage in some cases

Exposure to water

contaminated with

animal urine

Myalgias; aseptic

meningitis; fulminant

form: icterohemorrhagic

fever (Weil’s disease)

184

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

Bite of Ixodes tick vector Headache, myalgias,

chills, photophobia

occurring acutely; CNS

disease, myocardial

disease, arthritis weeks

to months later in some

cases

186

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

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

186

Typhoid fever

(Fig. A1-9)

Salmonella typhi Transient, blanchable erythematous macules

and papules, 2–4 mm, usually on trunk (rose

spots)

Ingestion of

contaminated food or

water (rare in U.S.)

Variable abdominal

pain and diarrhea;

headache, myalgias,

hepatosplenomegaly

165

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

Occurs in tropics and

subtropics; transmitted

by mosquito

Headache;

musculoskeletal

pain (“breakbone

fever”); leukopenia;

occasionally biphasic

(“saddleback”) fever

209

Rat-bite fever (sodoku) Spirillum minus Eschar at bite site; then blotchy violaceous

or red-brown rash involving trunk and

extremities

Rat bite; primarily found

in Asia; rare in U.S.

Regional adenopathy;

recurrent fevers if

untreated

141

Relapsing fever Borrelia species Central rash at end of febrile episode;

petechiae in some cases

Exposure to ticks or

body lice

Recurrent fever,

headache, myalgias,

hepatosplenomegaly

185

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

Patients with rheumatic

fever

Pharyngitis preceding

polyarthritis, carditis,

subcutaneous nodules,

chorea

388

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

Most common in young

to middle-aged women;

flares precipitated by

sun exposure

Arthritis; cardiac,

pulmonary, renal,

hematologic, and

vasculitic disease

359

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

Children and young

adults

High spiking fever,

polyarthritis,

splenomegaly;

erythrocyte

sedimentation rate

>100 mm/h

—

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

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)

227

Arcanobacterial

pharyngitis

Arcanobacterium

(Corynebacterium)

haemolyticum

Diffuse, erythematous, maculopapular

eruption involving trunk and proximal

extremities; may desquamate

Children and young

adults

Exudative pharyngitis,

lymphadenopathy

150

(Continued)

(Continued)

136 PART 2 Cardinal Manifestations and Presentation of Diseases

TABLE 19-1 Diseases Associated with Fever and Rash

DISEASE ETIOLOGY DESCRIPTION

GROUP AFFECTED/

EPIDEMIOLOGIC

FACTORS CLINICAL SYNDROME CHAPTER

West Nile virus infection West Nile virus Maculopapular eruption involving the trunk,

extremities, and head or neck; rash in

20–50% of cases

Mosquito bite; rarely,

blood transfusion or

transplanted organ

Headache, weakness,

malaise, myalgia,

neuroinvasive

disease (encephalitis,

meningitis, flaccid

paralysis)

209

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

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

209

Peripheral Eruptions

Chronic

meningococcemia,

disseminated gonococcal

infection,a

 human

parvovirus B19 infection,f

MIRMg

— — — — 155, 156,

197

Rocky Mountain

spotted fever

(Fig. 19-2, 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

Tick vector; widespread

but more common

in southeastern and

southwest-central U.S.

Headache, myalgias,

abdominal pain;

mortality rates up to

40% if untreated

187

Secondary syphilis

(Figs. 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

Sexually transmitted Fever, constitutional

symptoms

182

Chikungunya fever

(Fig. A1-54)

Chikungunya virus Maculopapular eruption; typically occurs

on trunk, but also occurs on extremities and

face

Aedes aegypti and

A. albopictus mosquito

bites; tropical and

subtropical regions

Severe polyarticular,

migratory arthralgias,

especially involving

small joints (e.g., hands,

wrists, ankles)

209

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-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)

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 brain

stem encephalitis,

flaccid paralysis

resembling polio, or

aseptic meningitis

204

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

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 Stevens-Johnson

syndrome (but EM major

lacks prominent skin

sloughing)

—h

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

Rat bite, ingestion of

contaminated food

Myalgias; arthritis

(50%); fever recurrence

in some cases

141

(Continued)

(Continued)

137 Fever and Rash CHAPTER 19

TABLE 19-1 Diseases Associated with Fever and Rash

DISEASE ETIOLOGY DESCRIPTION

GROUP AFFECTED/

EPIDEMIOLOGIC

FACTORS CLINICAL SYNDROME CHAPTER

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)

Abnormal heart

valve (e.g., viridans

streptococci),

intravenous drug use

New or changing heart

murmur

128

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

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

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

Most common among

children 2–10 years

old; usually follows

group A streptococcal

pharyngitis

Fever, pharyngitis,

headache

148

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

Children <8 years old Cervical adenopathy,

pharyngitis, coronary

artery vasculitis

58, 363

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)

Multiorgan failure,

hypotension; mortality

rate 30%

148

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

Colonization with toxinproducing S. aureus

Fever >39°C (>102°F),

hypotension, multiorgan

dysfunction

147

Staphylococcal scaldedskin syndrome

(Fig. 19-3, Fig. A1-28)

S. aureus, phage group II Diffuse tender erythema, often with bullae

and desquamation; Nikolsky’s sign

Colonization with toxinproducing S. aureus;

occurs in children

<10 years old (termed

Ritter’s disease in

neonates) or adults with

renal dysfunction

Irritability; nasal or

conjunctival secretions

147

Exfoliative erythroderma

syndrome

(Fig. A1-27)

Underlying psoriasis,

eczema, drug eruption,

mycosis fungoides

Diffuse erythema (often scaling) interspersed

with lesions of underlying condition

Usually occurs in adults

over age 50; more

common among men

Fever, chills (i.e.,

difficulty with

thermoregulation);

lymphadenopathy

58, 60

DRESS (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

Individuals genetically

unable to detoxify arene

oxides (anticonvulsant

metabolites), patients

with slow N-acetylating

capacity (sulfonamides)

Lymphadenopathy,

multiorgan failure

(especially hepatic),

eosinophilia, atypical

lymphocytes; mimics

sepsis

60

Stevens-Johnson

syndrome (SJS), toxic

epidermal necrolysis

(TEN)

(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

Uncommon among

children; more common

among patients with HIV

infection, systemic lupus

erythematosus, certain

HLA types, or slow

acetylators

Dehydration, sepsis

sometimes resulting

from lack of normal skin

integrity; mortality rates

up to 30%

60

(Continued)

(Continued)

138 PART 2 Cardinal Manifestations and Presentation of Diseases

TABLE 19-1 Diseases Associated with Fever and Rash

DISEASE ETIOLOGY DESCRIPTION

GROUP AFFECTED/

EPIDEMIOLOGIC

FACTORS CLINICAL SYNDROME CHAPTER

Vesiculobullous or Pustular Eruptions

Hand-foot-andmouth syndromec

;

staphylococcal scaldedskin syndromeb

; TENb

;

DRESSb

; COVID-19c

— — — — —h

Varicella (chickenpox)

(Fig. 19-4, 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

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

193

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”)

Bathers in hot tubs or

swimming pools; occurs

in outbreaks

Earache, sore eyes and/

or throat; fever may

be absent; generally

self-limited

164

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)

Nonimmune individuals

exposed to smallpox

Prodrome of fever,

headache, backache,

myalgias; vomiting in

50% of cases

S3

Primary herpes simplex

virus (HSV) infection

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 does not involve

oral mucosa)

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

192

Disseminated herpesvirus

infection

(Fig. A1-31)

VZV or HSV Generalized 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 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

Patients with

immunosuppression,

eczema; neonates

Visceral organ

involvement (e.g., liver,

lungs) in some cases;

neonatal disease

particularly severe

138, 192,

193

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

Seen in urban settings;

transmitted by mouse

mites

Headache, myalgias,

regional adenopathy;

mild disease

187

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

Appears 2–21 days after

start of drug therapy,

depending on whether

patient has been

sensitized

Acute fever, pruritus,

leukocytosis

60

(Continued)

(Continued)

139 Fever and Rash CHAPTER 19

TABLE 19-1 Diseases Associated with Fever and Rash

DISEASE ETIOLOGY DESCRIPTION

GROUP AFFECTED/

EPIDEMIOLOGIC

FACTORS CLINICAL SYNDROME CHAPTER

Disseminated Vibrio

vulnificus infection

V. vulnificus Erythematous lesions evolving into

hemorrhagic bullae and then into necrotic

ulcers

Patients with cirrhosis,

diabetes, renal failure;

exposure by ingestion of

contaminated saltwater,

seafood

Hypotension; mortality

rate 50%

168

Ecthyma gangrenosum

(Fig. A1-34)

P. aeruginosa, other gramnegative 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

Usually affects

neutropenic patients;

occurs in up to

28% of individuals

with Pseudomonas

bacteremia

Clinical signs of sepsis 164

Mycoplasma-induced

rash and mucositis

(MIRM)

Mycoplasma pneumoniae 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 (MIRM sine rash)

More common in males;

usually children (mean

age 11–12 years old)

Evidence of M.

pneumoniae infection

(typically pneumonia);

good prognosis;

distinct from SJS/TEN;

rarely Chlamydophila

pneumoniae can cause

similar syndrome

Urticaria-Like Eruptions

COVID-19c

Urticarial vasculitis

(Fig. 19-5, Fig. A1-35)

Serum sickness, often due

to infection (including acute

hepatitis B, enteroviral,

parasitic), drugs;

connective tissue disease

Erythematous, edematous “urticaria-like”

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

Patients with serum

sickness (including

acute hepatitis B),

connective tissue

disease

Fever variable;

arthralgias/arthritis

363h

Nodular Eruptions

Disseminated infection

(Fig. 19-6, 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

Immunocompromised

hosts (e.g., bone marrow

transplant recipients,

patients undergoing

chemotherapy, HIVinfected patients)

Features vary with

organism

—h

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

More common among

females 15–30 years old

Arthralgias (50%);

features vary with

associated condition

—h

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

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

58

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)

Immunosuppressed

individuals, especially

those with advanced

HIV infection

Peliosis of liver and

spleen in some cases;

lesions sometimes

involving multiple

organs; bacteremia

172

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

Most common among

children, individuals

with asplenia or terminal

complement component

deficiency (C5–C8)

Hypotension, meningitis

(sometimes preceded

by upper respiratory

infection)

155

(Continued)

(Continued)

140 PART 2 Cardinal Manifestations and Presentation of Diseases

TABLE 19-1 Diseases Associated with Fever and Rash

DISEASE ETIOLOGY DESCRIPTION

GROUP AFFECTED/

EPIDEMIOLOGIC

FACTORS CLINICAL SYNDROME CHAPTER

Purpura fulminans

(Fig. 19-7, Fig. A1-41)

Severe DIC Large ecchymoses with sharply irregular

shapes evolving into hemorrhagic bullae and

then into black necrotic lesions

Individuals with

sepsis (e.g., involving

N. meningitidis),

malignancy, or massive

trauma; asplenic

patients at high risk for

sepsis

Hypotension 155, 304

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

Individuals with

complement

deficiencies

Fevers, sometimes

intermittent; arthritis,

myalgias, headache

155

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)

Sexually active

individuals (more often

females), some with

complement deficiency

Low-grade fever,

tenosynovitis, arthritis

156

Enteroviral petechial rash Usually echovirus 9 or

coxsackievirus A9

Disseminated petechial lesions (may also be

maculopapular, vesicular, or urticarial)

Often occurs in

outbreaks

Pharyngitis, headache;

aseptic meningitis with

echovirus 9

204

Viral hemorrhagic fever Arenaviruses,

bunyaviruses, filoviruses

(including Ebola),

flaviviruses (including

dengue)

Petechial rash Residence in or travel

to endemic areas, other

virus exposure

Triad of fever,

shock, hemorrhage

from mucosa or

gastrointestinal tract

209, 210

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 E. coli

O157:H7 gastroenteritis

(especially children),

cancer chemotherapy,

HIV infection,

autoimmune diseases,

pregnant/postpartum

women, those with

ADAMTS13 deficiency

Fever (not

always present),

microangiopathic

hemolytic anemia,

thrombocytopenia, renal

dysfunction, neurologic

dysfunction; coagulation

studies normal

58, 100,

115, 161,

166

Cutaneous smallvessel vasculitis

(leukocytoclastic

vasculitis)

(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

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

58

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

Exposure to ticks, biting

flies, infected animals

Fever, headache,

lymphadenopathy

170

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

Exposure to infected

animals or animal

products, other

exposure to anthrax

spores

Lymphadenopathy,

headache

S3

a

See “Purpuric Eruptions.” b

See “Confluent Desquamative Erythemas.” c

See “Peripheral Eruptions.” d

Rash is rare in human granulocytotropic ehrlichiosis or anaplasmosis

(caused by Anaplasma phagocytophilum; most common in the upper midwestern and northeastern United States). e

See “Viral hemorrhagic fever” under “Purpuric

Eruptions” for dengue hemorrhagic fever/dengue shock syndrome. f

See “Centrally Distributed Maculopapular Eruptions.” g

See “Vesiculobullous or Pustular Eruptions.” h

See

etiology-specific chapters.

Abbreviations: CNS, central nervous system; DIC, disseminated intravascular coagulation; G-CSF, granulocyte colony-stimulating factor; HLA, human leukocyte antigen.

(Continued)

141 Fever and Rash CHAPTER 19

at the hairline 2–3 days into the illness and moves down the body, typically sparing the palms and soles (Fig. 19-1; see also Fig. A1-3) (Chap.

205). It begins as discrete erythematous lesions, which become confluent as the rash spreads. Koplik’s spots (1- to 2-mm white or bluish

lesions with an erythematous halo on the buccal mucosa) (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. 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. A1-51D). 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 Epstein-Barr

virus (Chap. 194) or with primary HIV infection (Fig. A1-6; 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. A1-1A) 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. 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 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 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 urticaria, exanthematous drug-induced eruptions (Chap. 60) (Fig. A1-7)

are most common and are often difficult to distinguish from viral

exanthems. Eruptions elicited by drugs are usually more intensely erythematous and pruritic than viral exanthems, but this distinction is not

reliable. A history of new medications and an absence of prostration

may help to distinguish a drug-related rash from an eruption of another

etiology. Rashes may persist for up to 2 weeks after administration of

the offending agent is discontinued. Certain populations are more prone

than others to drug rashes. Of HIV-infected patients, 50–60% develop a

rash in response to sulfa drugs; 30–90% of patients with mononucleosis

due to Epstein-Barr 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 spotted-fever syndrome and should be considered in residents of or travelers to endemic areas. Similarly, typhoid

fever, a nonrickettsial disease caused by Salmonella typhi (Chap. 165)

(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. 209).

Some centrally distributed maculopapular eruptions have distinctive features. Erythema migrans (Fig. A1-8), 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 tick-associated 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. A1-10) as well as many other skin manifestations (Figs. A1-11, A1-12). Still’s disease presents as an evanescent,

salmon-colored rash on the trunk and proximal extremities that coincides 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

eruption, pyoderma gangrenosum, purpura, panniculitis, or Stevens

Johnson syndrome.

Zika virus is a mosquito-transmitted 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. A1-51A, A1-51B) is typically pruritic and often

accompanied 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. 187) because of its grave prognosis if untreated. Lesions

(Fig. 19-2; 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. 182), which may be generalized (Fig. A1-18) but is prominent

on the palms and soles (Fig. A1-19), 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

FIGURE 19-1 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.)